Conditions: Ulcerative Colitis
Keywords: Mild Moderate
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 107
Healthy volunteers: no

Brief summary:
To assess clinical response to MMX mesalamine/mesalazine between a low and high dose in children and adolescents aged 5-17 years with mild to moderate Ulcerative Colitis (UC) or who are in remission.

Detailed description:

Arms:
arm 1: Once daily, tablets - the amount depends on the participants weight; 900 milligram per day (mg/day) for participants weighing 18 kg to less than or equal to (\<=) 23 kilograms (kg); 1200 mg/day for participants weighing greater than (\>) 23 kg to \<= 35 kg; 1800 mg/day for participants weighing \> 35 kg to \<= 50 kg; 2400 mg/day for participants weighing \> 50 kg to \<= 90 kg. arm 2: Once daily, tablets - the amount depends on the participants weight;1800 mg/day for participants weighing 18 kg to \<= 23 kg; 2400 mg/day for participants weighing \> 23 kg to \<= 35 kg; 3600 mg/day for participants weighing \> 35 kg to \<= 50 kg; 4800 mg/day for participants weighing \> 50 kg to \<= 90 kg.

Interventions: intervention 1: MMX Mesalamine/Mesalazine (Low Dose) intervention 2: MMX Mesalamine/Mesalazine (High Dose)
Intervention descriptions: intervention 1: Once daily, tablets - the amount depends on the participants weight; 900 milligram per day (mg/day) for participants weighing 18 kg to less than or equal to (\<=) 23 kilograms (kg); 1200 mg/day for participants weighing greater than (\>) 23 kg to \<= 35 kg; 1800 mg/day for participants weighing \> 35 kg to \<= 50 kg; 2400 mg/day for participants weighing \> 50 kg to \<= 90 kg. intervention 2: Once daily, tablets - the amount depends on the participants weight;1800 mg/day for participants weighing 18 kg to \<= 23 kg; 2400 mg/day for participants weighing \> 23 kg to \<= 35 kg; 3600 mg/day for participants weighing \> 35 kg to \<= 50 kg; 4800 mg/day for participants weighing \> 50 kg to \<= 90 kg.

Protocol document:
Prot_000.pdf: 










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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different
products).  For instructions on reporting adverse events (AEs) related to product complaints, see 
Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA)


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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................3
EMERGENCY CONTACT INFORMATION................................................................................5
PRODUCT QUALITY COMPLAINTS..........................................................................................6
TABLE OF CONTENTS.................................................................................................................7
LIST OF TABLES.........................................................................................................................12
LIST OF FIGURES .......................................................................................................................12
LIST OF APPENDICES................................................................................................................12
ABBREVIATIONS .......................................................................................................................13
DEFINITIONS...............................................................................................................................14
STUDY SYNOPSIS ......................................................................................................................15
STUDY SCHEDULES..................................................................................................................22
1.
BACKGROUND INFORMATION.......................................................................................31
1.1
Indication and Current Treatment Options...............................................................31
1.2
Product Background and Clinical Information ........................................................31
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................32
2.1
Rationale for the Study.............................................................................................32
2.2
Study Objectives ......................................................................................................33
2.2.1
Primary Objectives.................................................................................................33
2.2.2
Secondary Objectives.............................................................................................33
2.2.3
Exploratory Objectives ..........................................................................................34
3.
STUDY DESIGN ...................................................................................................................34
3.1
Study Design and Flow Chart ..................................................................................34
3.2
Duration and Study Completion Definition .............................................................37
3.3
Sites and Regions .....................................................................................................37
4.
STUDY POPULATION.........................................................................................................37
4.1
Inclusion Criteria......................................................................................................37
4.2
Exclusion Criteria.....................................................................................................38
4.3
Re-randomization.....................................................................................................40
4.4
Reproductive Potential .............................................................................................40
4.4.1
Female Contraception............................................................................................40
4.5
Discontinuation of Subjects .....................................................................................41
4.5.1
Reasons for Discontinuation..................................................................................41
4.5.2
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit..................................42
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................42


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5.1
Prior Treatment ........................................................................................................42
5.2
Concomitant Treatment............................................................................................42
5.3
Prohibited Treatment................................................................................................43
6.
INVESTIGATIONAL PRODUCT ........................................................................................44
6.1
Identity of Investigational Product...........................................................................44
6.1.1
Blinding the Treatment Assignment......................................................................44
6.2
Administration of Investigational Product(s)...........................................................44
6.2.1
Interactive Response Technology for Investigational Product Management ........44
6.2.2
Allocation of Subjects to Treatment ......................................................................44
6.2.3
Dosing....................................................................................................................45
6.2.4
Unblinding the Treatment Assignment..................................................................46
6.3
Labeling, Packaging, Storage, and Handling ...........................................................46
6.3.1
Labeling .................................................................................................................46
6.3.2
Packaging...............................................................................................................47
6.3.3
Storage ...................................................................................................................47
6.4
Drug Accountability.................................................................................................48
6.5
Subject Compliance..................................................................................................49
7.
STUDY PROCEDURES........................................................................................................49
7.1
Study Schedule.........................................................................................................49
7.1.1
Screening Period....................................................................................................49
7.1.1.1
Screening Visit (Visit 1).........................................................................49
7.1.1.2
Recommended Telephone Call (Day ⎼7 to ⎼4)......................................52
7.1.1.3
Baseline Visit (Visit 2)...........................................................................52
7.1.1.4
Subject Visit Schedule Summary Post-baseline.....................................54
7.1.2
Double-blind Acute Phase .....................................................................................54
7.1.2.1
Recommended Telephone Call (Day ⎼7 to ⎼4)......................................54
7.1.2.2
Double-blind Acute Phase Weeks 2 and 4 (Visits 3 and 3.1, 
respectively) ...........................................................................................54
7.1.2.3
Double-blind Acute Phase Week 8/Withdrawal (Visit 3.2)...................55
7.1.3
Open-label Acute Phase.........................................................................................56
7.1.3.1
Recommended Telephone Call (Days ⎼7 to ⎼4) ....................................56
7.1.3.2
Open-label Acute Phase Weeks 2 and 4 (Visits 4 and 4.1, 
respectively) ...........................................................................................56
7.1.3.3
Open-label Acute Phase Week 8/Withdrawal (Visit 4.2).......................56
7.1.4
Double-blind Maintenance Phase ..........................................................................57
7.1.4.1
Recommended Telephone Call (Days ⎼7 to ⎼4) ....................................57
7.1.4.2
Double-blind Maintenance Phase Weeks 2-4 (Visit 5)..........................57
7.1.4.3
Double-blind Maintenance Phase Week 13 (Visit 5.1)..........................58


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7.1.4.4
Double-blind Maintenance Phase Week 26/Withdrawal (Visit 5.2)......58
7.1.5
Follow-up Period (Visit 6).....................................................................................59
7.1.6
Additional Care of Subjects After the Study .........................................................59
7.2
Study Evaluations and Procedures ...........................................................................59
7.2.1
Efficacy..................................................................................................................59
7.2.1.1
Partial UC-DAI Score ............................................................................60
7.2.1.2
Modified Full UC-DAI Score ................................................................62
7.2.2
Safety .....................................................................................................................63
7.2.2.1
Medical and Medication History............................................................64
7.2.2.2
Physical Examination.............................................................................64
7.2.2.3
Height and Weight .................................................................................64
7.2.2.4
Adverse Event Collection.......................................................................64
7.2.2.5
Vital Signs..............................................................................................64
7.2.2.6
Clinical Laboratory Evaluations.............................................................65
7.2.2.7
Pregnancy Test .......................................................................................66
7.2.2.8
Stool Assessment....................................................................................66
7.2.3
Pharmacokinetic Procedures..................................................................................67
7.2.3.1
Blood Sample Collection and Handling Procedures..............................67
7.2.3.2
Shipment of Plasma Pharmacokinetic Samples .....................................68
7.2.3.3
Plasma Drug Assay Methodology..........................................................68
............................................................................68
7.2.4.1
Health-related Quality-of-Life Assessments..........................................69
7.2.5
Volume of Blood to be Drawn from Each Subject................................................71
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................71
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................71
8.1.1
Severity Categorization..........................................................................................72
8.1.2
Relationship Categorization...................................................................................72
8.1.3
Outcome Categorization ........................................................................................73
8.1.4
Symptoms of the Disease Under Study .................................................................73
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................73
8.1.6
Pregnancy...............................................................................................................74
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................74
8.2
Serious Adverse Event Procedures ..........................................................................75
8.2.1
Reference Safety Information................................................................................75
8.2.2
Reporting Procedures.............................................................................................75
8.2.3
Serious Adverse Event Definition .........................................................................76
8.2.4
Serious Adverse Event Collection Timeframe ......................................................76


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8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................76
8.2.6
Fatal Outcome........................................................................................................77
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................77
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................77
9.1
Data Collection.........................................................................................................77
9.2
Clinical Data Management.......................................................................................77
9.3
Data Handling Considerations..................................................................................78
9.4
Statistical Analysis Process......................................................................................78
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......78
9.6
Sample Size Calculation and Power Considerations................................................79
9.7
Study Population ......................................................................................................79
9.8
Efficacy Analyses.....................................................................................................79
9.8.1
Primary Efficacy Endpoint ....................................................................................79
9.8.1.1
Double-blind Acute Phase......................................................................79
9.8.1.2
Double-blind Maintenance Phase...........................................................80
9.8.2
Sensitivity Analyses of the Primary Endpoint.......................................................80
9.8.3
Secondary Efficacy Endpoints...............................................................................80
9.8.3.1
Double-blind Acute Phase......................................................................81
9.8.3.2
Double-blind Maintenance Phase...........................................................81
9.8.4
Exploratory Efficacy Endpoints.............................................................................81
9.8.5
Exploratory Pharmacokinetic Endpoint.................................................................82
9.9
Safety Analyses........................................................................................................82
9.10
Other Analyses .........................................................................................................83
9.10.1 Health-related Quality-of-Life Analyses ...............................................................83
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................83
10.1
Sponsor’s Responsibilities .......................................................................................83
10.1.1 Good Clinical Practice Compliance.......................................................................83
10.1.2 Indemnity/Liability and Insurance.........................................................................83
10.1.3 Public Posting of Study Information......................................................................84
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................84
10.1.5 Study Suspension, Termination, and Completion..................................................84
10.2
Investigator’s Responsibilities .................................................................................84
10.2.1 Good Clinical Practice Compliance.......................................................................84
10.2.2 Protocol Adherence and Investigator Agreement..................................................85
10.2.3 Documentation and Retention of Records.............................................................85
10.2.3.1
Electronic Case Report Forms................................................................85


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10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................85
10.2.3.3
Audit/Inspection.....................................................................................86
10.2.3.4
Financial Disclosure...............................................................................86
10.3
Ethical Considerations..............................................................................................86
10.3.1 Informed Consent/Assent.......................................................................................86
10.3.2 Institutional Review Board or Ethics Committee..................................................87
10.4
Privacy and Confidentiality......................................................................................88
10.5
Study Results/Publication Policy .............................................................................88
11. REFERENCES .......................................................................................................................90
12. APPENDICES ........................................................................................................................91


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LIST OF TABLES
Table 1:
Double-blind Acute Phase.............................................................................22
Table 2:
Open-label Acute Phase ................................................................................26
Table 3:
Double-blind Maintenance Phase..................................................................28
Table 4:
Minimally Required Number of Subjects per Weight Group .......................35
Table 5:
Common Prior Excluded Treatments ............................................................43
Table 6:
Volume of Blood to be Drawn From Each Subject.......................................71
LIST OF FIGURES
Figure 1:
Study Design Flow Chart ..............................................................................36
LIST OF APPENDICES
Appendix 1
Protocol History.............................................................................................92
Appendix 2
The Modified Full Ulcerative Colitis Disease Activity Index 
(UC-DAI) ....................................................................................................100
Appendix 3
Subject Questionnaires ................................................................................101
Appendix 4
Pediatric Ulcerative Colitis Activity Index .................................................102
.......................................................................103


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ABBREVIATIONS
5-ASA
5-aminosalicylic acid
Ac-5-ASA
acetyl-5-aminosalicylic acid
AE
adverse event
CMH
Cochran-Mantel-Haenszel
CRO
contract research organization
DMC
Data Monitoring Committee
DUCS
Daily Ulcerative Colitis Scale
EC
Ethics Committee
eCRF
electronic case report form
e-diary
electronic diary
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
-HCG
beta-human chorionic gonadotropin
ICH
International Council for Harmonisation
IRB
Institutional Review Board
IRT
interactive response technology
LAR
legally authorized representative
MMX
Multi-Matrix System
PGA
Physician’s Global Assessment
PRO
patient-reported outcome
PUCAI
Pediatric Ulcerative Colitis Activity Index
ObsRO
observer-reported outcome
SAE
serious adverse event
SAP
statistical analysis plan
TEAE
treatment-emergent adverse event
UC
ulcerative colitis
UC-DAI
Ulcerative Colitis Disease Activity Index
US
United States


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DEFINITIONS
Clinical response: partial Ulcerative Colitis Disease Activity Index (UC-DAI) ≤1 (with rectal 
bleeding=0 and stool frequency ≤1 and Physician’s Global Assessment [PGA]=0)
Clinical and endoscopic response: UC-DAI ≤2 (with rectal bleeding=0 and stool frequency ≤1
and PGA=0) and with mucosal healing (endoscopy score ≤1) based on central reading


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STUDY SYNOPSIS
Protocol number:  SPD476-319
Drug: MMX Mesalamine/mesalazine
Title of the study:  A Phase 3, Multicenter, Randomized, Double-blind Study to Determine the Safety and 
Efficacy of MMX Mesalamine/Mesalazine in Pediatric Subjects with Mild to Moderate Ulcerative Colitis, in 
both Acute and Maintenance Phases
Number of subjects (total and for each treatment arm):
More than 100 subjects will be screened, and up to 80 subjects will be enrolled in the Double-blind Acute Phase 
of the study. More than 65 subjects will be screened (in addition to an expected 28 subjects who will enter the 
Double-blind Maintenance Phase from one of the Acute Phases) and at least 80 subjects will be enrolled in the 
Double-blind Maintenance Phase of the study.
Investigators: Multicenter study
Sites and Regions: 
It is anticipated that sites in the following regions will participate: North America, Europe, and the Middle East.  
Approximately 48 active study sites are planned.
Study period (planned):
2013-2018
Clinical phase:
3
Objectives:
Primary:  
The primary objective of the Double-blind Acute Phase of the study is to assess clinical response to 
Multi-Matrix System (MMX®) mesalamine/mesalazine between a low and high dose in children and 
adolescents aged 5-17 years with mild to moderate ulcerative colitis (UC).
The primary objective of the Double-blind Maintenance Phase of the study is to assess maintenance of clinical 
response to MMX mesalamine/mesalazine between a low and high dose in children and adolescents aged 
5-17 years who are in remission.
Secondary:
Double-blind Acute Phase  
The secondary objectives of the Double-blind Acute Phase are to:

Assess clinical and endoscopic response to treatment with MMX mesalamine/mesalazine between a low 
and high dose in children and adolescents aged 5-17 years with mild to moderate UC in the Double-blind 
Acute Phase

Assess changes in the Daily Ulcerative Colitis Scale (DUCS) for children and caregivers between a low 
and high dose of MMX mesalamine/mesalazine in children and adolescents aged 5-17 years with mild to 
moderate UC in the Double-blind Acute Phase

Assess improvement in Pediatric Ulcerative Colitis Activity Index (PUCAI) score between a low and high 
dose of MMX mesalamine/mesalazine in children and adolescents aged 5-17 years with mild to moderate 
UC in the Double-blind Acute Phase.
Double-blind Maintenance Phase
The secondary objectives of the Double-blind Maintenance Phase are to:

Assess clinical and endoscopic response to treatment with MMX mesalamine/mesalazine between a low 
and high dose in children and adolescents aged 5-17 years who are in remission in the Double-blind 
Maintenance Phase


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
Assess changes in the DUCS for children and caregivers between a low and high dose of MMX 
mesalamine/mesalazine in children and adolescents aged 5-17 years who are in remission in the Double-
blind Maintenance Phase

Assess remission using the PUCAI score between a low and high dose of MMX mesalamine/mesalazine in 
children and adolescents aged 5-17 years who are in remission in the Double-blind Maintenance Phase.
Safety
The safety objectives include the evaluation of the safety and tolerability of a low and high dose MMX 
mesalamine/mesalazine in children and adolescents aged 5-17 years with mild to moderate UC, in the 
Double-blind Acute Phase, the Open-label Acute Phase, and the Double-blind Maintenance Phase.
Rationale:
MMX mesalamine/mesalazine is approved for both the induction of remission in adult patients with mild to 
moderate UC and for maintenance of remission of UC.  No data are available on the use of MMX 
mesalamine/mesalazine in children and adolescents; this study aims to evaluate the effect of MMX 
mesalamine/mesalazine in children and adolescents with mild to moderate UC or who are in remission aged 
5-17 years.
Investigational product, dose, and mode of administration:

MMX mesalamine/mesalazine, administered orally, randomized in a 1:1 ratio stratified by body weight 
group to the following doses:

900mg/day or 1800mg/day for subjects weighing 18 to 23kg

1200mg/day or 2400mg/day for subjects weighing >23 to 35kg

1800mg/day or 3600mg/day for subjects weighing >35 to 50kg

2400mg/day or 4800mg/day for subjects weighing >50 to 90kg

MMX mesalamine/mesalazine tablet strengths 300, 600, and 1200mg with matching placebos to maintain 
the blind between low and high dose groups
Methodology:
This is a prospective study with a Screening Period of 3 to 21 days, an 8-week Double-blind Acute Phase, and a 
26-week Double-blind Maintenance Phase.  Each phase includes 2 arms, and subjects will be randomized to 1 
of 2 doses (low or high) of MMX mesalamine/mesalazine (900-4800mg/day, given once daily) at the beginning 
of each phase.  Randomization will be in a 1:1 ratio stratified by body weight group. There is an additional 8-
week, Open-label Acute Phase for subjects who do not achieve a clinical response or who have withdrawn from 
the Double-blind Acute Phase after a minimum of 2 weeks and, in the investigator’s opinion, have not benefited 
from treatment in the Double-blind Acute Phase.  Clinical response is defined as partial Ulcerative Colitis 
Disease Activity Index (UC-DAI) ≤1 (with rectal bleeding=0 and stool frequency ≤1 and Physician’s Global 
Assessment [PGA]=0) at the end of the Double-blind Acute Phase.  In this Open-label Acute Phase, subjects are 
treated with the high dose of MMX mesalamine/mesalazine for their weight group.
At the Baseline Visit (Visit 2): 

Subjects with partial UC-DAI ≥2 (with a combined rectal bleeding and stool frequency score ≥1 and
PGA=1 or 2) and with mucosal appearance (endoscopy score)=2 or 3 will be eligible to enter the 
Double-blind Acute Phase.

Subjects with partial UC-DAI ≤1 (with rectal bleeding=0 and stool frequency ≤1 and PGA=0) and with 
mucosal appearance (endoscopy score)=0 or 1 will be eligible to enter the Double-blind Maintenance 
Phase. 


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Subjects with partial UC-DAI score between 1 and 2 will not be eligible to enter the Double-blind Acute Phase 
or the Double-blind Maintenance Phase.
A minimum of 1 score each for stool frequency and rectal bleeding must be available in order to randomize 
subjects into either the Double-blind Acute Phase or the Double-blind Maintenance Phase. Subjects with no 
symptom score data available will be considered screen failures as these symptom score data are used to 
calculate the partial UC-DAI score needed for enrollment.
Subjects who do not meet all the eligibility criteria for either the Double-blind Acute Phase or the Double-blind 
Maintenance Phase will be considered screen failures. Subjects may be rescreened after consultation with the 
medical monitor.
Subjects with a clinical response after completion of treatment in either the Double-blind Acute Phase or the 
Open-label Acute Phase will be eligible to enter the Double-blind Maintenance Phase based on partial UC-DAI 
score (ie, without additional endoscopy).
Subjects without a clinical response after completion of acute treatment in the Open-label Acute Phase must be 
withdrawn.
All subjects will have a Screening Visit (Visit 1), and screened subjects who are eligible will proceed to the 
Baseline Visit (Visit 2).  Study visits occur at the following time points after the Baseline Visit (Visit 2), 
dependent on the subject’s partial UC-DAI score:
Double-blind Acute Phase: Week 2, Week 4, Week 8 (Double-blind Acute Phase Withdrawal)
Open-label Acute Phase: Week 2, Week 4, Week 8 (Open-label Acute Phase Withdrawal)
Double-blind Maintenance Phase:  Weeks 2-4 (investigational product dispensation only), Week 13, Week 26 
(Double-blind Maintenance Phase Withdrawal)
Inclusion and exclusion criteria:
Inclusion Criteria:
General:
1.
Ability to voluntarily provide written, signed, and dated (personally or via a legally authorized 
representative [LAR]) informed consent or assent as applicable to participate in the study.
2.
Subject’s parent/LAR demonstrates an understanding, ability, and willingness to fully comply with study 
procedures and restrictions.
3.
Male and female children and adolescents aged 5-17 years, inclusive, at the Baseline Visit (Visit 2).
4.
Body weight 18-90kg at the Screening Visit (Visit 1) and the Baseline Visit (Visit 2).
5.
Male, or non-pregnant, non-lactating female who agrees to comply with any applicable contraceptive 
requirements of the protocol or females of non-childbearing potential.
6.
Diagnosed with mild to moderate UC, established by sigmoidoscopy or colonoscopy with compatible 
histology.  Screened subjects may also have an unconfirmed diagnosis of mild to moderate UC; however,
the diagnosis of mild to moderate UC must have been established by sigmoidoscopy or colonoscopy with 
compatible histology prior to the Baseline Visit (Visit 2).
7.
Subject is able to swallow the investigational product whole.
Double-blind Acute Phase: 
8.
Partial UC-DAI score ≥2 (with a combined rectal bleeding and stool frequency score ≥1 and PGA=1 or 2) 
and with mucosal appearance (endoscopy score)=2 or 3 at the Baseline Visit (Visit 2), for which 
5-aminosalicylic acid (5-ASA) would be used as part of normal treatment.


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9.
If the subject is on 5-ASA treatment prior to study entry, then the dose must be stable.  Stable therapy is 
defined as no change in dose, or no initiation of 5-ASA, from the onset of the current acute flare through 
discontinuation of therapy (required at the Baseline Visit [Visit 2]).  Please see exclusion criterion 28 for an 
additional 5-ASA dose-related requirement.
Double-blind Maintenance Phase: 
10. Partial UC-DAI score ≤1 (with rectal bleeding=0 and stool frequency ≤1 and PGA=0) and with mucosal 
appearance (endoscopy score)=0 or 1 at the Baseline Visit (Visit 2).
Exclusion Criteria:
General:
1.
Severe UC (defined by PGA=3) at the Baseline Visit (Visit 2).
2.
Crohn’s disease, bleeding disorders, and/or active peptic ulcer disease.
3.
Asthma, only if known to be 5-ASA sensitive.
4.
Positive stool culture for enteric pathogens (including Salmonella, Shigella, Yersinia, Aeromonas, 
Plesiomonas, or Campylobacter).  Clostridium difficile toxin, ova, or parasites present.
5.
Previous colonic surgery.
6.
History of hepatic impairment that, in the opinion of the investigator, may be incompatible with 
mesalamine treatment.
7.
Moderate to severe renal impairment, in the opinion of the investigator.
8.
Immediate or significant risk of toxic megacolon, in the opinion of the investigator.
9.
History of pancreatitis.
10. History of Reye’s syndrome.
11. Systemic or rectal corticosteroid use within 4 weeks prior to the Screening Visit (Visit 1).  Topical, 
intranasal, or inhaled use is not exclusionary.
12. Immunomodulator (6-mercaptopurine, azathioprine) use within 6 weeks prior to the Screening Visit 
(Visit 1).
13. History of biologic (eg, anti-tumor necrosis factor agents, integrin receptor antagonists) within 1 year prior 
to the Screening Visit (Visit 1). 
14. Antibiotic use within 7 days prior to the Screening Visit (Visit 1).  
15. Any anti-inflammatory drugs, not including 5-ASA treatment but including non-steroidal anti-
inflammatory drugs such as aspirin, cyclooxygenase-2 inhibitors or ibuprofen, within 7 days prior to the 
Screening Visit (Visit 1) unless used at over-the-counter levels for <3 days.  However, prophylactic use of a 
stable dose of aspirin up to 325mg/day for cardiac disease is permitted.
16. Oral anticoagulant use (with the exception of subjects who have been on a stable dose of vitamin K 
antagonists such as warfarin for at least 90 days prior to the Screening Visit [Visit 1] and who are medically 
stable).
17. Treatment with anti-diarrheals and/or anti-spasmodics within 3 days prior to the Screening Visit (Visit 1). 
18. Vaccination/immunization within 21 days prior to the Screening Visit (Visit 1).
19. Predisposed to the development of myo- or pericarditis.
20. Previously been randomized into this study and withdrawn.  


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21. Current or recurrent disease that could affect the action, absorption, or disposition of the investigational 
product, or could affect clinical or laboratory assessments.
22. Current or relevant history of physical or psychiatric illness, any medical disorder that may require 
treatment, including surgery, or make the subject unlikely to fully complete the study, or any condition that 
presents undue risk from the investigational product or procedures.
23. Current use of any medication (including over-the-counter, herbal, or homeopathic preparations) that could 
affect (improve or worsen) the condition being studied, or could affect the action, absorption, or disposition 
of the investigational product(s), or clinical or laboratory assessment.  (Current use is defined as use within 
21 days of the Screening Visit [Visit 1], or pharmacokinetic equivalent of 5 half-lives, whichever is longer.)
24. Known or suspected intolerance or hypersensitivity to the investigational product(s) (aminosalicylates 
[5-ASA]), closely related compounds (including but not limited to salicylates), or any of the stated 
ingredients. 
25. Known history of alcohol or other substance abuse within the last year.
26. Within 30 days prior to the first dose of investigational product:
- Have used an investigational product
- Have been enrolled in a clinical study (including vaccine studies) that, in the investigator’s opinion, may 
impact this study.
Double-blind Acute Phase:
27. Mucosal appearance (defined by endoscopic score=0 or 1) based on central reading or local reading (if 
central reading is not available) at the Screening Visit (Visit 1) or Baseline Visit (Visit 2).
28. Current relapse on a 5-ASA dose higher than the low dose tested in the study (900mg for subjects weighing 
18 to 23kg, 1200mg for subjects weighing >23 to 35kg, 1800mg for subjects weighing >35 to 50kg, 
and 2400mg for subjects weighing >50 to 90kg).
29. Acute flare with onset >6 weeks prior to the Baseline Visit (Visit 2) if being treated with 5-ASA for the 
flare.  There is no limit to the onset of flare prior to the Baseline Visit (Visit 2) if the flare is untreated.
Double-blind Maintenance Phase:
30. Mucosal appearance (endoscopic score)=2 or 3 based on central reading or local reading (if central reading 
is not available) at the Screening Visit (Visit 1) or Baseline Visit (Visit 2).
Re-randomization:  Subjects with a clinical response, ie, partial UC-DAI ≤1 (defined as rectal bleeding=0 and
stool frequency ≤1 and PGA=0) after completion of treatment in either the Double-blind or the Open-label 
Acute Phases will be eligible for re-randomization into the Double-blind Maintenance Phase provided they still 
meet all Baseline (Visit 2) inclusion and exclusion criteria (where re-assessed).  
Note that an additional eligibility endoscopy is not required for entry into the Double-blind Maintenance Phase 
for subjects who achieve a clinical response after completion of treatment in either the Double-blind Acute 
Phase or the Open-label Acute Phase.
Subjects eligible for either the Double-blind Acute or the Double-blind Maintenance Phase can be re-
randomized if they initially failed randomization for the following reasons: incorrect use of IVRS, late or 
missing central laboratory or endoscopy results, or other reasons of this type as long as they meet inclusion and 
exclusion criteria. Re-randomization can only take place after consultation with the medical monitor.
Subjects may be re-randomized into the Double-blind Maintenance Phase if they turned 18 during participation 
in either Acute Phase of the study.


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Maximum duration of subject involvement in the study:

Planned duration of screening period: 3 to 21 days

Planned duration of treatment period: up to 42 weeks

Planned duration of follow-up: 7 days
Endpoints and statistical analysis:
Primary Efficacy Endpoints 
Double-blind Acute Phase:
The primary efficacy endpoint for the Double-blind Acute Phase is defined as the proportion of subjects with a 
clinical response (defined as partial UC-DAI ≤1 with rectal bleeding=0 and stool frequency ≤1 and PGA=0) at 
Week 8.  This endpoint will be compared between treatment arms using a continuity-corrected chi-squared test.
Double-blind Maintenance Phase:
The primary efficacy endpoint for the Double-blind Maintenance Phase is defined as the proportion of subjects 
who have maintained a clinical response (defined as partial UC-DAI ≤1 with rectal bleeding=0 and stool 
frequency ≤1 and PGA=0) at Week 26.  This endpoint will be compared between treatment arms using a 
Cochran-Mantel-Haenszel (CMH) test stratifying by Week 8 responder status.
Secondary Efficacy Endpoints 
Double-blind Acute Phase:

The proportion of subjects with a clinical and endoscopic response at Week 8, defined as UC-DAI ≤2 with 
rectal bleeding=0 and stool frequency ≤1 and PGA=0, and with mucosal healing (endoscopy score ≤1) 
based on central reading.  In addition, there must be at least a 1-point reduction in endoscopy score from 
baseline.  This endpoint will be compared between treatment arms using a continuity-corrected chi-squared 
test.

The proportion of subjects with a clinical and endoscopic response at Week 8, defined as UC-DAI ≤2 with 
rectal bleeding=0 and stool frequency ≤1 and PGA=0, and with mucosal healing (endoscopy score ≤1) 
based on local reading.  In addition, there must be at least a 1-point reduction in endoscopy score from 
baseline. This endpoint will be compared between treatment arms using a continuity-corrected chi-squared 
test.

The change in the DUCS score from baseline to Week 8 of the Double-blind Acute Phase.  This endpoint 
will be compared between treatment arms using an analysis of covariance, including the baseline DUCS 
score as a covariate in the model.

The percentage of subjects with an improvement (change of ≥20 points) in PUCAI score from baseline to 
Week 8 of the Double-blind Acute Phase.  This endpoint will be compared between treatment arms using a 
continuity-corrected chi-squared test.
Double-blind Maintenance Phase:

The proportion of subjects who have maintained a clinical and endoscopic response at Week 26, defined as 
UC-DAI ≤2 with rectal bleeding=0 and stool frequency ≤1 and PGA=0, and with mucosal healing 
(endoscopy score ≤1) based on central reading.  This endpoint will be compared between treatment arms 
using a CMH test stratifying by Week 8 responder status.

The proportion of subjects who have maintained a clinical and endoscopic response at Week 26, defined as 
UC-DAI ≤2 with rectal bleeding=0 and stool frequency ≤1 and PGA=0, and with mucosal healing 
(endoscopy score ≤1) based on local reading.  This endpoint will be compared between treatment arms 
using a CMH test stratifying by Week 8 responder status.

The change in the DUCS score from Double-blind Maintenance Phase Week 0 to Week 26.  This endpoint 
will be compared between treatment arms using an analysis of covariance, including the DUCS score at 
Double-blind Maintenance Phase Week 0 and Week 8 responder status as covariates in the model.


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
The percentage of subjects in remission (PUCAI <10) at Double-blind Maintenance Phase Week 26.  This 
endpoint will be compared between treatment arms using a CMH test stratifying by Week 8 responder 
status.
Sensitivity Analyses of the Primary Endpoint
The following sensitivity analyses will be performed for both the Double-blind Acute and the Double-blind 
Maintenance Phase primary endpoints:

A modified clinical response, defined as partial UC-DAI≤1 with rectal bleeding=0 and stool frequency ≤1 
will be analyzed in a similar way to the primary endpoint analysis in order to investigate the effect of 
removing the PGA component from the responder definition.

An observed-case analysis will be performed, where data from those who completed Week 26 and those 
who withdrew from the study early and  are presented and analyzed separately, using a similar analysis to 
the primary endpoint.  

A complete-case analysis, where subjects who withdraw early from the study will be excluded, will be 
performed in a similar way to the primary endpoint analysis.

A last observation carried forward analysis, using data from the final on-treatment assessment, will be 
performed in a similar way to the primary endpoint analysis.

Logistic modeling will be conducted to investigate the effect of doses in mg/kg on the clinical response in 
the Double-blind Acute and Double-blind Maintenance Phases.  
Safety Endpoints 
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities.  Treatment-
emergent AEs (TEAEs) will be defined in the statistical analysis plan.  The number of events, incidence, and 
percentage of TEAEs will be presented by treatment arm (ie, low or high dose), and overall, by system organ 
class, and by preferred term.  Treatment-emergent AEs will be further summarized by treatment arm for severity 
and relationship to investigational product.  Treatment-emergent AEs related to investigational product, TEAEs 
leading to withdrawal, serious AEs, and deaths will be summarized by treatment arm.
Clinical laboratory tests and vital signs, and their changes from baseline will be summarized by treatment arm 
and visit.  
Sample Size Justification 
The sample size of 80 subjects originally selected for each of the Double-blind Acute and Double-blind 
Maintenance Phases was chosen based on both practical considerations and on agreement with the United States 
Food and Drug Administration.








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Table 1:
Double-blind Acute Phase
Visit
1
(Screening)
Recommended 
Telephone 
calla
2
(Baseline)
3b
3.1
3.2c, d, e, f
6g
Week/Monthh
Day –21 to –3
Day –7 to ⎼4
Week 0
Week 2
Week 4
Week 8/Withdrawal
Follow-up
m Rectal bleeding, stool frequency, DUCS, and Overall Current Health e-diary entry is completed once a day before bedtime every day from the evening of the Screening Visit 
(Visit 1), preferably for at least the 3 days immediately prior to the Baseline Visit (Visit 2).  Rectal bleeding, stool frequency, DUCS and Overall Current Health e-diary entry is 
completed once a day before bedtime for the 5 days immediately prior to Visits 3, 3.1, and 3.2 of the Double-blind Acute Phase.
n Global Change in Health to be completed by caregivers of children aged 5-10 years and by children aged 11-17 years; IMPACT III to be completed by children aged 8-17 years 
only (see Section 7.2.4.1).
o The average stool frequency and rectal bleeding scores will be calculated and available to the investigator through a report from the e-diary provider.
p Components of the partial UC-DAI.
q Components of the modified full UC-DAI.
r For subjects entering the Double-Blind Acute Phase only: Subjects with an unconfirmed diagnosis of UC must have endoscopy performed during the Screening Visit (Visit 1).  
Subjects with a previously confirmed diagnosis must have endoscopy at the Screening Visit (Visit 1) or at the Baseline Visit (Visit 2) if endoscopy has not been performed within 
21 days prior to the Screening Visit (Visit 1).
s Only for subjects continuing into the Open- label Acute or Double- blind Maintenance Phase.




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Table 2:
Open-label Acute Phase
Visit
Recommended 
Telephone calla
4
4.1
4.2b, c, d, e
6f
Weekg
Day ⎼7 to ⎼4
Week 2
Week 4
Week 8/Withdrawal
Follow-up
Investigational product 
dispensed


m
Investigational product collected 
and compliance calculated



Adverse events





Concomitant medication




Re-randomization (subjects 
entering Double-blind 
Maintenance Phase only)

Abbreviations: DUCS=Daily Ulcerative Colitis Scale for children and caregivers; e-diary=electronic diary; IRT= interactive response technology; PGA=Physician’s Global 
Assessment; PUCAI=Pediatric Ulcerative Colitis Activity Index; UC-DAI=Ulcerative Colitis Disease Activity Index.
a Approximately 4 to 7 days prior to Visit 4 and prior to each subsequent visit (Visits 4.1 and 4.2), it is recommended that site staff telephone the subject or the subject’s caregiver 
to remind them to enter UC-DAI symptoms (rectal bleeding and stool frequency) into the e-diary every night, even if the subject has no symptoms.
b Subjects will continue into the Double-blind Maintenance Phase if partial UC-DAI ≤1 (with rectal bleeding=0 and stool frequency ≤1 and PGA=0) and are eligible to continue 
into the Double-blind Maintenance Phase.
c Subjects will be withdrawn from the study if they have not achieved a partial UC-DAI ≤1 (with rectal bleeding=0 and stool frequency ≤1 and PGA=0).
d This will be the final visit for subjects not continuing into the Double-blind Maintenance Phase.
e The Baseline Visit (Visit 2) does not need to be repeated for subjects entering the Double-blind Maintenance Phase at the end of the Open-label Acute Phase.  Visit 4.2 will be 
considered the Week 0 visit for the Double-blind Maintenance Phase.
f Follow-up assessment in this phase applies only to subjects who are discontinuing the study; may be performed via telephone call within 7 days of the last dose of investigational 
product.
g A visit window of 3 days is permitted for all study visits.
h The serum pregnancy test will be performed for all female subjects of childbearing potential at Week 8/Withdrawal (Visit 4.2). Urine pregnancy tests will be performed at all 
other visits.
i Rectal bleeding, stool frequency, DUCS, and Overall Current Health e-diary entry is completed once a day before bedtime every day for 5 days immediately prior to Visits 4, 4.1 
and 4.2 of the Open-label Acute Phase.
j The average stool frequency and rectal bleeding scores will be calculated and available to the investigator through a report from the e-diary provider.
k Components of the partial UC-DAI.
l Components of the modified full UC-DAI.
m Only for subjects continuing into the Double-blind Maintenance Phase.




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Table 3:
Double-blind Maintenance Phase
Visit
1
(Screening)a
Recommended 
Telephone 
callb
2
(Baseline)a
5
5.1
5.2
6c
Day/Monthd
Day –21 to –
3
Day ⎼7 to ⎼4
Week 0
Weeks 2-4
Week 13
Week 26/ 
Withdrawal
Follow-up
Review DUCS instructions, ability 
to read and understand e-diary 
with subject/caregiver

Subject/caregiver e-diary entry: 
rectal bleeding, stool frequency, 
DUCS, and Overall Current 
Healthh




Assessment of e-diary compliancea

Global Change in Healthi

IMPACT IIIi


PUCAI (where applicable)


Average stool frequency j, k, l



Average rectal bleeding j, k, l



PGA k, l


Endoscopy (flexible 
sigmoidoscopy or colonoscopy) 
for study eligibilityd, l, m


Endoscopy (flexible 
sigmoidoscopy or colonoscopy), 
where possiblel

IRT entry





Calculate partial UC-DAI


Investigational product dispensed



Investigational product collected 
and compliance calculated



Adverse events







Concomitant medication









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1.
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options 
Ulcerative colitis (UC) is a serious chronic inflammatory disease of the colon and rectum.  The 
major clinical feature is bloody diarrhea.  While an acute attack can occasionally be fatal, the 
characteristic course for most patients is one of remissions and exacerbations over a number of 
years.  Life expectancy after recovery from a first attack is unchanged; however, morbidity can 
be long-lasting and may be associated with various extra-intestinal and late complications.  
Extensive disease is observed in 60-80% of all cases when UC onset is in childhood, which is 
twice as often as in adults.  Extensive disease results in a worse disease course, since disease 
course is correlated to disease severity.  In children, 30-40% colectomy rates are seen at 10 years 
compared to 20% in adults with UC (Turner et al. 2012).  Children may also develop unique and 
troublesome complications, including growth failure and delayed puberty.  Although infrequent 
and geographically dispersed, UC has been reported as early as infancy.  Most children with UC, 
however, are diagnosed in late childhood and adolescence.  The peak incidence of inflammatory 
bowel disease occurs in patients between the ages of 15 and 25 years.  Approximately 20% of 
patients with UC present before the age of 20 years (Mendeloff and Calkins 1988).  There are 
approximately 50,000 children currently with UC in the US, primarily post-pubertal.  
Clinical pediatricians agree that mesalamine has a role in therapy of UC in children, and 
pediatric gastroenterology guidelines contain reference to mesalamine therapy in UC.  The side 
effect profile of mesalamine is broadly similar to placebo, and there are no indications from the 
literature that use of mesalamine in children is associated with a higher incidence of side effects.  
The only acetyl-5-aminosalicylic acid (5-ASA)/mesalamine product that is currently licensed in 
the US for use in children/adolescents (aged 5 years and older with UC) and that is available in 
non-tablet formulation is balsalazide (COLAZAL, Salix Pharmaceuticals, Inc) capsules.  
Balsalazide is a prodrug that is enzymatically cleaved in the colon to produce mesalamine.  
Capsule contents can be sprinkled on apple sauce if the capsules are too big to swallow.
The approval of 5-ASA products in other countries for use on children/adolescents varies.
1.2
Product Background and Clinical Information
Commercially available Multi-Matrix System (MMX) mesalamine/mesalazine is a novel, high-
strength formulation of 5-ASA (1.2g of mesalamine/mesalazine per tablet), which uses MMX 
technology designed to release 5-ASA throughout the colon.  For the purpose of this study, 2 
pediatric formulations (300mg and 600mg tablets) were developed, which are smaller than the 
commercially available product.
The patented MMX delivery system utilizes hydrophilic and lipophilic matrices enclosed within 
a gastro-resistant, pH-dependent coating to facilitate prolonged exposure of the colonic mucosa 
to 5-ASA.  The gastro-resistant coating that covers the multi-matrix core delays release of 
5-ASA until the tablet is exposed to approximately pH of 7.0 or higher, normally in the terminal 
ileum, at which time the coating disintegrates.


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Due to the presence of the hydrophilic matrix, the tablet core is designed to swell upon exposure 
to intestinal fluid (in a manner similar to that of a sponge exposed to water) to form a viscous gel 
mass.  This viscous gel mass is expected to slow the diffusion of the active drug from the tablet 
core into the colonic lumen.  As the tablet and its surrounding gel mass progress through the 
colon, pieces of the gel mass are expected to gradually break away from the core.  This allows 
release of some 5-ASA in proximity to the colonic mucosa.  In addition, literature suggests that 
the hydrophilic matrix may also adhere to the colonic mucosa, thus delivering 5-ASA to its site 
of action.
The lipophilic matrix, together with 5-ASA, is interspersed within the hydrophilic matrix 
creating a partially hydrophobic environment, which slows the penetration of aqueous fluids into 
the tablet core.  This is expected to slow the drug dissolution and provide a further extended 
release of the active medication, potentially prolonging therapeutic activity.
Always refer to the latest version of the MMX Mesalazine (Mesalamine) Investigator’s Brochure 
for the overall risk/benefit assessment and the most accurate and current information regarding 
the drug metabolism, pharmacokinetics, efficacy and safety of MMX mesalamine/mesalazine. 
2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
MMX mesalamine/mesalazine is approved for both the induction of remission in adult patients 
with mild to moderate UC and for maintenance of remission of UC.  Currently, limited data are 
available on the safety and efficacy of MMX mesalamine/mesalazine in children and adolescents 
with UC.  
This study, a Pediatric Research Equity Act post-approval commitment with United States (US) 
Food and Drug Administration (FDA), is designed to find the appropriate dosage of MMX 
mesalamine/mesalazine for once-daily dosing across a range of weight groups, in children and 
adolescents aged 5-17 years with mild to moderate UC or who are in remission. As improved 
compliance may be achieved with once-daily dosing, a better overall treatment benefit may be 
obtained compared to existing alternatives for pediatric patients.
The data from this study will:

Determine whether MMX mesalamine/mesalazine is safe and effective for use in children 
and adolescents (aged 5-17 years) with mild to moderate UC or who are in remission.

Aid in selection of appropriate doses in the pediatric population.
The study allows all subjects to receive active MMX mesalamine/mesalazine. The doses for the 
study were determined from pharmacokinetic modeling using data from the SPD476-112 study, 
a pharmacokinetic study in children and adolescents with mild to moderate UC. 
The inclusion of placebo and standard of care arms were considered in the design of this study.  
The use of placebo was considered impractical given the alternative treatments currently 
available to children and adolescents with UC. 


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As standard of care varies and there is no standard formulation or dose of 5-ASA licensed and 
approved across regions, a standard of care/comparator arm was not included.
2.2
Study Objectives
2.2.1
Primary Objectives
The primary objective of the Double-blind Acute Phase of the study is to assess clinical response 
to MMX mesalamine/mesalazine between a low and high dose in children and adolescents aged 
5-17 years with mild to moderate UC.
The primary objective of the Double-blind Maintenance Phase of the study is to assess 
maintenance of clinical response to MMX mesalamine/mesalazine between a low and high dose 
in children and adolescents aged 5-17 years who are in remission.
2.2.2
Secondary Objectives
Double-blind Acute Phase
The secondary objectives of the Double-blind Acute Phase are to:

Assess clinical and endoscopic response to treatment with MMX mesalamine/mesalazine 
between a low and high dose in children and adolescents aged 5-17 years with mild to 
moderate UC in the Double-blind Acute Phase

Assess changes in the Daily Ulcerative Colitis Scale (DUCS) for children and caregivers 
between a low and high dose of MMX mesalamine/mesalazine in children and adolescents 
aged 5-17 years with mild to moderate UC in the Double-blind Acute Phase

Assess improvement in the Pediatric Ulcerative Colitis Activity Index (PUCAI) score 
between a low and high dose of MMX mesalamine/mesalazine in children and adolescents 
aged 5-17 years with mild to moderate UC in the Double-blind Acute Phase.
Double-blind Maintenance Phase
The secondary objectives of the Double-blind Maintenance Phase are to:

Assess clinical and endoscopic response to treatment with MMX mesalamine/mesalazine 
between a low and high dose in children and adolescents aged 5-17 years who are in 
remission in the Double-blind Maintenance Phase

Assess changes in the DUCS for children and caregivers between a low and high dose of 
MMX mesalamine/mesalazine in children and adolescents aged 5-17 years who are in 
remission in the Double-blind Maintenance Phase

Assess remission using the PUCAI score between a low and high dose of MMX 
mesalamine/mesalazine in children and adolescents aged 5-17 years who are in remission 
in the Double-blind Maintenance Phase.




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In this Open-label Acute Phase, subjects are treated with the high dose of MMX 
mesalamine/mesalazine for their weight group.
Subjects with a clinical response after completion of treatment in either the Double-blind Acute 
Phase or the Open-label Acute Phase will be eligible to enter the Double-blind Maintenance 
Phase based on partial UC-DAI score (ie, without additional endoscopy).  
Subjects without a clinical response after completion of treatment in both the Double-blind 
Acute Phase and the Open-label Acute Phase will not be eligible to enter the Double-blind 
Maintenance Phase and must be withdrawn.
Subjects may enter the Double-blind Maintenance Phase directly following the Baseline Visit 
(Visit 2) if they have a partial UC-DAI ≤1 (with rectal bleeding=0 and stool frequency ≤1 and
PGA=0) and with mucosal appearance (endoscopy score)=0 or 1 at that visit.
MMX mesalamine/mesalazine is dosed once daily by mouth. The selection of doses in this study 
is based on an approximate average of 43mg/kg for the low dose and 85mg/kg for the high dose 
in the 3 lower weight groups (18 to 23kg, >23 to 35kg and >35 to 50kg).  These doses were 
selected based on standard of care dosing for other 5-ASA products in the pediatric population 
and pharmacokinetic dosing results.  The dosing for the highest weight group (>50 to 90kg) is 
based on adult UC experience.
This study will be conducted in children and adolescents (aged 5-17 years) to collect data on the 
safety and efficacy of MMX mesalazine/mesalamine in this population.  This study is a Pediatric 
Research Equity Act post-approval commitment with the US FDA.
Minimum enrollment criteria have been agreed with FDA as follows, based on subject weight 
group; these are summarized in Table 4.
Table 4:
Minimally Required Number of Subjects per Weight Group
Weight Group
Number of Subjects in Combined Low and High Dose a
18 to 23kg
2
>23 to 35kg
12
>35 to 50kg
18
>50 to 90kg
36
a Randomization will be stratified by weight group with the aim of creating balance between the 2 dose groups within a weight 
group.


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Figure 1:
Study Design Flow Chart
PGA=Physician’s Global Assessment; UC-DAI=Ulcerative Colitis Disease Activity Index
a Subjects with partial UC-DAI ≥2 (with a combined rectal bleeding and stool frequency score ≥1 and PGA=1 or 2) and with 
mucosal appearance (endoscopy score)=2 or 3.
b Subjects with partial UC-DAI ≤1 (with rectal bleeding=0 and stool frequency ≤1 and PGA=0) and with mucosal appearance 
(endoscopy score)=0 or 1.
Notes: Solid boxes indicate study phases. Dashed ellipses indicate decision points. 
Subjects will initially be randomized into either the 8-week Double-blind Acute Phase or the 26-week Double-blind Maintenance 
Phase based on partial UC-DAI and mucosal appearance scores as defined in Section 7.1.1.2. Subjects who do not achieve a 
clinical response or who have withdrawn from the Double-blind Acute Phase after a minimum of 2 weeks and, in the 
investigator’s opinion, have not benefited from treatment in the Double-blind Acute Phase may enter the Open-label Phase, see 
Section 7.1.3. Subjects without a clinical response after completion of acute treatment in the Open-label Acute Phase must be 
withdrawn.


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3.2
Duration and Study Completion Definition
The last subject contact for this study is the follow-up assessment (Visit 6).
The maximum duration of participation for a subject following randomization is expected to be 
approximately 42 weeks.  The study will be completed in approximately 5 years.
The Study Completion Date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment.  Please note that this includes the follow-up visit or 
contact, whichever is later.  The Study Completion Date is used to ascertain timing for study 
results posting and reporting.
3.3
Sites and Regions
It is anticipated that sites in approximately 8 countries will participate in this study.  These 
countries are located in North America, Europe, and the Middle East.  Approximately 48 sites 
are expected to enroll subjects into the study.
4.
STUDY POPULATION
Each subject and/or caregiver must participate in the informed consent process and provide 
written informed consent/assent before any procedures specified in the protocol are performed.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below.
General:
1.
Ability to voluntarily provide written, signed, and dated (personally or via a legally 
authorized representative [LAR]) informed consent or assent as applicable to participate in 
the study.
2.
Subject’s parent/LAR demonstrates an understanding, ability, and willingness to fully 
comply with study procedures and restrictions.
3.
Male and female children and adolescents aged 5-17 years, inclusive, at the Baseline Visit 
(Visit 2).
4.
Body weight 18-90 kg at the Screening Visit (Visit 1) and the Baseline Visit (Visit 2).
5.
Male, or non-pregnant, non-lactating female who agrees to comply with any applicable 
contraceptive requirements of the protocol or females of non-childbearing potential.
6.
Diagnosed with mild to moderate UC, established by sigmoidoscopy or colonoscopy with 
compatible histology.  Screened subjects may also have an unconfirmed diagnosis of mild 
to moderate UC; however, the diagnosis of mild to moderate UC must have been 
established by sigmoidoscopy or colonoscopy with compatible histology prior to the 
Baseline Visit (Visit 2).


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7.
Subject is able to swallow the investigational product whole.
Double-blind Acute Phase: 
8.
Partial UC-DAI score ≥2 (with a combined rectal bleeding and stool frequency score ≥1 
and PGA=1 or 2) and with mucosal appearance (endoscopy score)=2 or 3 at the Baseline 
Visit (Visit 2), for which 5-ASA would be used as part of normal treatment. 
9.
If the subject is on 5-ASA treatment prior to study entry, then the dose must be stable.  
Stable therapy is defined as no change in dose, or no initiation of 5-ASA, from the onset of 
the current acute flare through discontinuation of therapy (required at the Baseline Visit; 
Visit 2).  See exclusion criterion 28 for an additional 5-ASA dose-related requirement.
Double-blind Maintenance Phase: 
10.
Partial UC-DAI ≤1 (with rectal bleeding=0 and stool frequency ≤1 and PGA=0) and with 
mucosal appearance (endoscopy score)=0 or 1 at the Baseline Visit (Visit 2). 
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met. 
General:
1.
Severe UC (defined by PGA=3) at the Baseline Visit (Visit 2).
2.
Crohn’s disease, bleeding disorders, and/or active peptic ulcer disease.
3.
Asthma, only if known to be 5-ASA sensitive.
4.
Positive stool culture for enteric pathogens (including Salmonella, Shigella, Yersinia, 
Aeromonas, Plesiomonas, or Campylobacter).  Clostridium difficile toxin, ova, or parasites 
present.
5.
Previous colonic surgery.
6.
History of hepatic impairment that, in the opinion of the investigator, may be incompatible 
with mesalamine treatment.
7.
Moderate to severe renal impairment, in the opinion of the investigator.
8.
Immediate or significant risk of toxic megacolon, in the opinion of the investigator.
9.
History of pancreatitis.
10.
History of Reye’s syndrome.
11.
Systemic or rectal corticosteroid use within 4 weeks prior to the Screening Visit (Visit 1).  
Topical, intranasal, or inhaled use is not exclusionary.
12.
Immunomodulator (eg, 6-mercaptopurine, azathioprine) use within 6 weeks prior to the 
Screening Visit (Visit 1).
13.
History of biologic (eg, anti-tumor necrosis factor agents, integrin receptor antagonists) 
within 1 year prior to the Screening Visit (Visit 1).


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14.
Antibiotic use within 7 days prior to the Screening Visit (Visit 1).  
15.
Any anti-inflammatory drugs, not including 5-ASA treatment but including non-steroidal 
anti-inflammatory drugs such as aspirin, cyclooxygenase-2 inhibitors or ibuprofen, within 
7 days prior to the Screening Visit (Visit 1) unless used at over-the-counter levels for 
<3 days.  However, prophylactic use of a stable dose of aspirin up to 325mg/day for 
cardiac disease is permitted.
16.
Oral anticoagulant use (with the exception of subjects who have been on a stable dose of 
vitamin K antagonists such as warfarin for at least 90 days prior to the Screening Visit 
[Visit 1] and who are medically stable).
17.
Treatment with anti-diarrheals and/or anti-spasmodics within 3 days prior to the Screening 
Visit (Visit 1). 
18.
Vaccination/immunization within 21 days prior to the Screening Visit (Visit 1).
19.
Predisposed to the development of myo- or pericarditis.
20.
Previously been randomized into this study and withdrawn.  
21.
Current or recurrent disease that could affect the action, absorption, or disposition of the 
investigational product, or could affect clinical or laboratory assessments.
22.
Current or relevant history of physical or psychiatric illness, any medical disorder that may 
require treatment, including surgery, or make the subject unlikely to fully complete the 
study, or any condition that presents undue risk from the investigational product or 
procedures.
23.
Current use of any medication (including over-the-counter, herbal, or homeopathic 
preparations) that could affect (improve or worsen) the condition being studied, or could 
affect the action, absorption, or disposition of the investigational product(s), or clinical or 
laboratory assessment.  (Current use is defined as use within 21 days of the Screening Visit 
[Visit 1], or pharmacokinetic equivalent of 5 half-lives, whichever is longer.)  See 
Section 5 (Prior and Concomitant Treatment) for a list of prohibited and restricted 
medications.  
24.
Known or suspected intolerance or hypersensitivity to the investigational product(s) 
(aminosalicylates eg, 5-ASA), closely related compounds (including but not limited to 
salicylates), or any of the stated ingredients. 
25.
Known history of alcohol or other substance abuse within the last year.
26.
Within 30 days prior to the first dose of investigational product:

Have used an investigational product

Have been enrolled in a clinical study (including vaccine studies) that, in the 
investigator’s opinion, may impact this study.


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Double-blind Acute Phase: 
27.
Mucosal appearance (defined by endoscopic score=0 or 1) based on central reading or local 
reading (if central reading is not available) at the Screening Visit (Visit 1) or Baseline Visit 
(Visit 2).
28.
Current relapse on a 5-ASA dose higher than the low dose tested in the study (900mg for 
subjects weighing 18 to 23kg, 1200mg for subjects weighing >23 to 35kg, 1800mg for 
subjects weighing >35 to 50kg, and 2400mg for subjects weighing >50 to 90kg).
29.
Acute flare with onset >6 weeks prior to the Baseline Visit (Visit 2) if being treated with 5-
ASA for the flare.  There is no limit to the onset of flare prior to the Baseline Visit (Visit 2) 
if the flare is untreated.
Double-blind Maintenance Phase: 
30.
Mucosal appearance (endoscopic score)=2 or 3 based on central reading or local reading (if 
central reading is not available) at the Screening Visit (Visit 1) or Baseline Visit (Visit 2).
4.3
Re-randomization
Subjects with a clinical response, ie, partial UC-DAI ≤1 (with rectal bleeding=0 and stool 
frequency ≤1 and PGA=0) after completion of treatment in either the Double-blind or the Open-
label Acute Phases will be eligible for re-randomization into the Double-blind Maintenance 
Phase provided they still meet all Baseline Visit (Visit 2) inclusion and exclusion criteria (where 
re-assessed).  
Note that an additional eligibility endoscopy is not required for entry into the Double-blind 
Maintenance Phase for subjects who achieve a clinical response after completion of treatment in 
either the Double-blind Acute Phase or the Open-label Acute Phase.
Subjects eligible for either the Double-blind Acute or the Double-blind Maintenance Phase can 
be re-randomized if they initially failed randomization for the following reasons: incorrect use of 
IVRS, late or missing central laboratory or endoscopy results, or other reasons of this type as 
long as they meet inclusion and exclusion criteria. Re-randomization can only take place after 
consultation with the medical monitor.
Subjects may be re-randomized into the Double-blind Maintenance Phase if they turned 18 years 
of age during participation in either Acute Phase of the study.
4.4
Reproductive Potential
4.4.1
Female Contraception
Sexually active females of childbearing potential must be using an acceptable form of 
contraception.  Females of childbearing potential must be advised to use acceptable 
contraceptives throughout the study period and for 30 days following the last dose of 
investigational product.  If hormonal contraceptives are used they should be administered 
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Females of childbearing potential who are not currently sexually active must agree to use 
acceptable contraception, as defined below, if they become sexually active during the period of 
the study and 30 days following the last dose of investigational product. 
All female subjects of childbearing potential must have a negative serum beta-human chorionic 
gonadotropin (-HCG) pregnancy test at the Screening Visit (Visit 1) and prior to randomization.  
Female subjects of childbearing potential must abstain from sexual activity that could result in 
pregnancy or agree to use acceptable methods of contraception.  Abstinence can only be 
accepted if this is true abstinence in line with the preferred and usual lifestyle of the subject.
Acceptable methods of contraception are:

Intrauterine devices plus condoms

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam)

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at 
least 30 days prior to the Screening Visit (Visit 1), plus condoms.  Note:  if subject 
becomes sexually active during the study, they must use 1 of the other acceptable methods 
noted above in addition to the hormonal contraceptive until it has been stabilized for 
30 days.
4.5
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution.  The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety).  The investigator is 
encouraged to discuss withdrawal of a subject from investigational product with the medical 
monitor when possible.
If investigational product is discontinued, regardless of the reason, the evaluations listed for the 
Withdrawal Visit (Visits 3.2, 4.2, or 5.2, depending on the phase) are to be performed as 
completely as possible.  Whenever possible, all discontinued subjects should also undergo the 
protocol-specified follow-up.  Comments (spontaneous or elicited) or complaints made by the 
subject must be recorded in the source documents.  The reason for termination, date of stopping 
investigational product, and the total amount of investigational product taken must be recorded in 
source documents.
Subjects who discontinue will not be replaced. 
4.5.1
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and in the electronic case report form (eCRF).  If a subject is withdrawn for more 
than 1 reason, each reason should be documented in the source document and the most clinically 
relevant reason should be entered in the eCRF.


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Reasons for discontinuation include but are not limited to:

Adverse event

Protocol violation

Withdrawal by subject

Lost to follow-up

Lack of efficacy

Other (if “Other” is selected, the investigator must provide further details).
4.5.2
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact).  At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and return any unused investigational product.
In addition to the 3 attempts made to prevent subjects from being lost to follow-up during the 
conduct of the study, Shire’s plan is to regularly evaluate each site for missing data. Any trends 
will be identified and addressed with specific sites should they emerge. Issues leading to missing 
data will be identified and retraining of the site and support for the site will be implemented as 
appropriate. 
5.
PRIOR AND CONCOMITANT TREATMENT
All non-study treatment including but not limited to herbal treatments and vitamins received 
within 21 days prior to the Screening Visit (Visit 1) (or pharmacokinetic equivalent of 
5 half-lives, whichever is longer) and through the final study contact (including protocol-defined 
follow-up period) must be recorded in the appropriate eCRF page.
5.1
Prior Treatment
Prior treatment given for the subject’s UC should be recorded for the year prior to the Screening 
Visit (Visit 1), where available.  All other prior treatment, including but not limited to herbal 
treatments and vitamins, received within 21 days of the date of first dose of investigational 
product must be recorded.
5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product and the end of the follow-up period, inclusive.  Concomitant treatment 
information must be recorded in the appropriate eCRF page.


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During the Screening Visit (Visit 1), the subject must remain on their current 5-ASA medication 
for UC (if applicable) at a stable dose until the Baseline Visit (Visit 2), at which time current 
treatment must be discontinued.
5.3
Prohibited Treatment 
Table 5 details the common prior treatments that are excluded medications for this study. 
Table 5:
Common Prior Excluded Treatments
Minimum Time Before Screening
Treatment
3 days
7 days
21 days
4 weeks
6 weeks
No Use Permitted
Anti-diarrheals and/or 
anti-spasmodicsa
X
Antibioticsa
X
Anti-inflammatory drugsa, b, c
X
Vaccination/immunization
X
Systemic or rectal 
corticosteroids
X
Immunomodulators
X
Oral anticoagulantsb
X
Biologics
1 year
a Non-steroidal anti-inflammatory drugs, anti-diarrheals, laxatives, and antibiotics are permitted for up to 10 consecutive days if 
taken for a condition unrelated to UC
b See Section 4.2 (Exclusion Criteria) for exceptions to these excluded prior medications. 
c Does not include current 5-aminosalicylic acid treatment
Administration of the following medication during the study is not permitted and will result in 
withdrawal of the subject:

Systemic or rectal corticosteroids. 

Other medications containing 5-ASA (eg, sulfasalazine or mesalamine/mesalazine), 
including topical administration

Immunomodulators (eg, 6-mercaptopurine, azathioprine, cyclosporine, methotrexate)

Biologics (eg, anti-tumor necrosis factor agents, such as infliximab).
The following are also prohibited: nicotine patches, any products containing fish oils (fish oils 
are prohibited unless on a stable dose 4 weeks prior to the Screening Visit [Visit 1] and 
throughout study participation), or any investigational or marketed drug that may interfere with 
the evaluation of the investigational product.
In the event of any prohibited UC medication use during the Double-blind Maintenance Phase, 
the subject should notify the investigator who will assess if the subject is experiencing a possible 
acute flare.


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Non-steroidal anti-inflammatory drugs, anti-diarrheals, laxatives, antibiotics, and drugs that 
cause constipation are permitted for up to 10 consecutive days if taken for a condition unrelated 
to UC.  Prophylactic use of a stable dose of aspirin up to 325mg/day for cardiac disease is 
permitted.  For mild, acute pain, acetaminophen is recommended.
Administration of seasonal vaccines is permitted during the study; however, routine vaccinations 
should be deferred until after study completion where possible.
6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is MMX mesalamine/mesalazine, which will be provided in 300, 600, and 
1200mg tablet form.  Matching placebo will also be provided in tablet form.  Additional 
information is provided in the current MMX Mesalazine (Mesalamine) Investigator’s Brochure.
6.1.1
Blinding the Treatment Assignment
This study includes double-blind treatment in the Double-blind Acute Phase and Double-blind 
Maintenance Phase.  The actual double-blind treatment given to individual subjects is 
determined by a randomization schedule which will be automatically assigned by the interactive 
response technology (IRT).  Placebo, which exactly matches the investigational product, will be 
used in the blister packs to provide the same number and size tablets for each of the doses within 
a weight group and maintain the blind between the low and high dose groups.
6.2
Administration of Investigational Product(s)
6.2.1
Interactive Response Technology for Investigational Product Management
Interactive response technology will be used for the following investigational product tasks:

Randomization

Supply management

Inventory management and supply ordering

Expiration tracking

Returns

Emergency unblinding.
6.2.2
Allocation of Subjects to Treatment 
This study includes 2 double-blind phases with low and high-dose MMX 
mesalamine/mesalazine.  The actual double-blind treatment given to individual subjects is 
determined by a randomization schedule stratified by weight group.  Randomization will be a 1:1 
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Subject numbers are assigned to all subjects as they consent to take part in the study.  Within 
each site (numbered uniquely within a protocol), the subject number is assigned to subjects 
according to the sequence of presentation for study participation.  
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined.  
Individual subject doses in the Double-blind Acute Phase are automatically assigned by the IRT 
based on subject weight group at the Baseline Visit (Visit 2).  If the subject is directly entering 
the Double-blind Maintenance Phase, individual doses are also automatically assigned by the 
IRT based on subject weight group at the Baseline Visit (Visit 2).  
Individual subject open-label treatment is automatically assigned by the IRT and will be the high 
dose based on the subject’s weight group at Visit 3.2 (Week 8/Withdrawal of the Double-blind 
Acute Phase).   
Individual subject double-blind doses for subjects being re-randomized to the Double-blind 
Maintenance Phase after completion of treatment at Visit 3.2 (Week 8 of the Double-blind Acute 
Phase) or Visit 4.2 (Week 8 of the Open-label Acute Phase) are automatically assigned by the 
IRT based on subject weight group at the time of re-randomization.  
6.2.3
Dosing
Subjects entering the Double-blind Acute Phase or entering the Double-blind Maintenance Phase 
directly will be randomized to low- or high-dose MMX mesalamine/mesalazine stratified by 
their weight group at the Baseline Visit (Visit 2).  
Subjects entering the Double-blind Maintenance Phase after completing 1 or both of the Acute 
Phases will be re-randomized to low- or high-dose MMX mesalamine/mesalazine at the start of 
the Double-blind Maintenance Phase at Visit 3.2 (Week 8 of the Double-blind Acute Phase) or 
4.2 (Week 8 of the Open-label Acute Phase), as applicable, based on their weight at the time of 
re-randomization.  
Doses will be as follows:

900 or 1800mg/day for subjects weighing 18 to 23kg

1200 or 2400mg/day for subjects weighing >23 to 35kg

1800 or 3600mg/day for subjects weighing >35 to 50kg

2400 or 4800mg/day for subjects weighing >50 to 90kg.
Subjects participating in the Open-label Acute Phase will receive the high dose for their weight 
group.  The subject’s weight at Visit 3.2 (Week 8/Withdrawal of the Double-blind Acute Phase) 
will be used to determine the high dose assigned to the subject.
Investigational product will be administered orally, once daily, in accordance with the MMX 
Mesalazine (Mesalamine) Investigator’s Brochure.  No titration or dose adjustment is allowed.


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Dosing with investigational product will begin the day of the Baseline Visit (Visit 2) if the 
subject’s currently prescribed 5-ASA treatment (if applicable) has not yet been taken that day.  If 
the subject’s currently prescribed 5-ASA treatment (if applicable) has been taken the day of the 
Baseline Visit (Visit 2), dosing with investigational product will begin the day after the Baseline 
Visit (Visit 2).
When proceeding through study phases, dosing with newly prescribed investigational product 
will begin the day of the study visit if the subject’s currently prescribed investigational product 
from the current phase has not yet been taken that day.  If the subject’s currently prescribed 
investigational treatment has been taken the day of the study visit, dosing with newly prescribed 
investigational product will begin the day after the first study visit of the new phase.
6.2.4
Unblinding the Treatment Assignment
The treatment assignment must not be broken during the study except in emergency situations 
where the identification of the investigational product is required for further treatment of the 
subject.  Prior to unblinding, and if the situation allows, the investigator should first contact the 
medical monitor.  
In the event that the treatment assignment is broken, the date, the signature of the person who 
broke the code and the reason for breaking the code are recorded in the IRT and the subject’s 
medical records.  Any code breaks that occur must be reported to the medical monitor/sponsor as 
soon as possible.  
Code break IRT access is held by the pharmacist/designated person at the site and by the medical 
monitor, or designee, for the study.  There will be a provision for unblinding to ensure adequate 
treatment of the subject in the case of an emergency.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
Labels containing study information and pack identification are applied to the investigational 
product(s) packaging. 
All investigational product is labeled with a minimum of the protocol number, medication 
identification number (open-label supplies only), dosage form (including product name and 
quantity in pack), directions for use, storage conditions, expiry), batch number and/or packaging 
reference, the statements ‘For clinical trial use only’, and/or ‘CAUTION: New Drug - Limited by 
Federal (or US) Law to Investigational Use’, and ‘Keep out of reach of children’, and the 
sponsor's name and address.  Any additional labeling requirements for participating countries 
will also be included on the label.
Space is allocated on the label so that the site representative can record a unique subject 
identifier and initials (where permitted by local laws).


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Additional labels may, on a case-by-case basis, be applied to the investigational product in order 
to satisfy local or institutional requirements, but must not:

Contradict the clinical study label

Obscure the clinical study label
Additional labels may not be added without the sponsor’s prior full agreement.
If an investigator site requires a subject’s name to be included on the additional label in order for 
the subject to receive investigational product, the investigator site must ensure that the additional 
label is removed or de-identified before returning investigational product to the sponsor 
nominated contractor for destruction. By removing the label with the subject’s name, the sponsor 
will not have access to the subject’s identity and hence confidentiality will be preserved.
6.3.2
Packaging
Double-blind investigational product is packaged in blister pack wallets containing a 1-week 
supply of product (tablet quantity dependent on weight group).  Placebo, which exactly matches 
the investigational product, will be used in the blister packs to provide the same number and size 
tablets for each of the doses within a weight group and maintain the blind between the low and 
high dose groups.
Open-label investigational product is packaged in 100cc high-density polyethylene bottles in the 
following counts:

600mg=60 tablets/bottle

1200mg=40 tablets/bottle
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storage
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location.  Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.  Investigational products are 
distributed by the pharmacy or nominated member of the study team.  The pharmacist/nominated 
team member will enter the unique subject identifier and initials (where permitted by local law) 
on the investigational product blister pack wallets/bottles as they are distributed.
Investigational product must be stored in accordance with labeled storage conditions.  
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range.  The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required.  


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Such a device (ie, certified min/max thermometer) would require manual resetting upon each 
recording.  The sponsor must be notified immediately upon discovery of any excursion from the 
established range.  Temperature excursions will require site investigation as to cause and 
remediation.  The sponsor will determine the ultimate impact of excursions on the investigational 
product and will provide supportive documentation as necessary.  Under no circumstances 
should the product be dispensed to subjects until the impact has been determined and the product 
is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
6.4
Drug Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects.  The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition.  Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational product.  
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator.  
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the investigational product only to subjects included 
in this study following the procedures set out in the study protocol.  Each subject will be given 
only the investigational product carrying his/her treatment assignment.  All dispensed medication 
will be documented in the eCRFs and/or other investigational product record.  The investigator is 
responsible for assuring the retrieval of all study supplies from subjects. No investigational 
product stock or returned inventory from a Shire-sponsored study may be removed from the site
where originally shipped without prior knowledge and consent by the sponsor.  If such transfer is 
authorized by the sponsor, all applicable local, state, and national laws must be adhered to for the 
transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records provided that the blind of the study is not compromised.
At the end of the study, or as instructed by the sponsor, all unused stock, subject-returned 
investigational product, and empty/used investigational product packaging are to be sent to a 
nominated contractor on behalf of the sponsor.  Investigational product being returned to the 
sponsor’s designated contractors must be counted and verified by clinical site personnel and the 
sponsor (or designated contract research organization [CRO]).  For unused supplies where the 
original supplied tamper-evident feature is verified as intact, the tamper-evident feature must not 
be broken and the labeled amount is to be documented in lieu of counting.  Shipment return 
forms, when used, must be signed prior to shipment from the site.  


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Validated electronic return systems (ie, IRT) do not require a shipment form.  Returned 
investigational product must be packed in a tamper-evident manner to ensure product integrity.  
Contact the sponsor for authorization to return any investigational product prior to shipment.  
Shipment of all returned investigational product must comply with local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned.  All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.
6.5
Subject Compliance
Subjects must be instructed to bring their unused investigational product and empty/used 
investigational product packaging to every visit.  Investigational product accountability must be 
assessed at the container/packaging level for unused investigational product that is contained 
within the original tamper-evident sealed container (eg, bottles) or at the individual count level 
for opened containers/packaging.  The pharmacist/nominated person will record details on the 
investigational product accountability form.
If investigational product accountability determines that the subject has not taken investigational 
product at the dose prescribed, the subject and/or caregiver will be re-educated as to the protocol 
dosing requirements.
7.
STUDY PROCEDURES
7.1
Study Schedule
See Table 1, Table 2, and Table 3 for study procedures.
7.1.1
Screening Period 
7.1.1.1
Screening Visit (Visit 1)
The Screening Visit (Visit 1) for this study is a period of 3 to 21 days prior to the Baseline Visit 
(Visit 2).  The Screening Visit (Visit 1) date will be considered the date of the first screening 
procedure (eg, informed consent/assent signature, during the Screening Period).  Individual 
screening procedures may be performed at any time during the period of the Screening Visit 
(Visit 1).  All procedures must be completed within this 3- to 21-day period before the Baseline 
Visit (Visit 2).
The Screening Visit (Visit 1) period of 3 to 21 days may be extended if the eligibility endoscopy 
is not adequate for assigning a mucosal appearance score due to inadequate bowel preparation as 
determined by the principal investigator or central endoscopy reader.  In this case, if endoscopy 
is to be repeated during the period of the Screening Visit (Visit 1), the Baseline Visit (Visit 2) 
may occur up to 14 days following initial endoscopy performed during the Screening Visit 
(Visit 1).  The repeat endoscopy must be planned in adequate time to allow the Baseline Visit 
(Visit 2) to occur at a maximum of 14 days following the initial endoscopy.  


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Each subject and/or caregiver will be instructed to continue completion of the electronic-diary 
(e-diary) every night before bedtime during the period of the extended Screening Visit (Visit 1).
During the period of the Screening Visit (Visit 1), the subject must remain on their current 
5-ASA medication for UC (if applicable) at a stable dose until the Baseline Visit (Visit 2), at 
which time current treatment must be discontinued.  If being screened for entry into the 
Double-blind Acute Phase, the current 5-ASA dose must not be higher than the MMX 
mesalamine/mesalazine low dose for the subject’s weight group.  
Subjects should not use any other concomitant medication for their UC during the period of the 
Screening Visit (Visit 1).  Weight will be measured to ensure that this parameter is within 
protocol-defined limits during the period of the Screening Visit (Visit 1).  Weight will be 
re-assessed at the Baseline Visit (Visit 2) for eligible subjects to determine randomization 
stratification. 
Collection of stool samples for all assessments must occur before administration of any bowel 
preparations for endoscopy if samples are collected on the same day as bowel preparation 
administration.  Stool samples collected for culture may be processed by local laboratories; 
however, results from the central laboratory analysis will prevail and will be entered into the 
eCRF.
Subjects without a confirmed diagnosis of UC: 
Endoscopy (flexible sigmoidoscopy or colonoscopy), including biopsies taken for confirmatory 
histology, must be performed during the period of the Screening Visit (Visit 1).  The biopsies 
taken for confirmation of UC diagnosis will be sent to the site’s local laboratory.  Confirmatory 
results to verify the subject’s UC diagnosis must be received prior to the Baseline Visit (Visit 2) 
for randomization.
Subjects with a historical diagnosis of UC: 
Subjects who have been diagnosed with UC (endoscopic and histologic reports of diagnosis are 
available) prior to the Screening Visit (Visit 1) will be considered to have a historical diagnosis 
of UC.  For subjects who have had endoscopy within the 21 days prior to screening, if the 
endoscopy is consistent with UC, the subject may proceed to the Screening Visit (Visit 1) with a 
historical diagnosis of UC.  The subject can be randomized once the endoscopy confirms the 
diagnosis of UC. The histologic confirmation of UC can be available after the Baseline Visit 
(Visit 2).  (See next paragraph below for additional details.)  
Subjects who enter the Double-blind Acute Phase:
If a standard of care endoscopy (flexible sigmoidoscopy or colonoscopy, including biopsy) 
has been performed within 21 days prior to the Screening Visit (Visit 1) and appropriate video 
or photographs of the procedure were obtained, these assessments may be used in lieu of 
performing an endoscopy during the period of the Screening Visit (Visit 1) or at the 
Baseline Visit (Visit 2).  The video or photographs of this endoscopy must be de-identified 
and submitted to the study’s central reader for confirmation of study eligibility after informed 
consent for the study is obtained.  


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The local laboratory histology report confirming the diagnosis of UC may be pending upon entry 
into the study at the Screening Visit (Visit 1); however, the confirmatory histology report must 
be available before randomization at the Baseline Visit (Visit 2). All other protocol-required 
assessments (including all laboratory assessments, ie, blood, urine and stool collection) must be 
performed for the Screening Visit (Visit 1) even if recent results are available.
For subject’s whose historical diagnosis of UC was made more than 21 days prior to the 
Screening Visit (Visit 1), then a study specific endoscopy must be performed during the period 
of the Screening Visit (Visit 1) or at the Baseline Visit (Visit 2).  Biopsies are not required for 
this endoscopy provided that a histology report with results that are compatible with UC is 
present in the subject’s source documents. The confirmatory histology may have been at any 
time in the subject’s history. If histologic confirmation of the previous UC diagnosis is not 
available in source documents, the entry endoscopy and confirmatory histology must be 
performed during the period of the Screening Visit (Visit 1) as for those subjects without a 
confirmed diagnosis of UC.
Subjects who enter the Double-blind Maintenance Phase directly:
All subjects must have a study endoscopy (flexible sigmoidoscopy or colonoscopy) performed 
during the period of the Screening Visit (Visit 1) or at the Baseline Visit (Visit 2).   Biopsies are 
not required for this endoscopy provided that a histology report with results that are compatible 
with UC is present in the subject’s source documents. The confirmatory histology may have 
been at any time in the subject’s history. If histologic confirmation of the previous UC diagnosis 
is not available in source documents, the entry endoscopy and confirmatory histology must be 
performed during the period of the Screening Visit (Visit 1) as for those subjects without a 
confirmed diagnosis of UC.
All subjects: 
Endoscopic video or photographs will be collected and sent to the study’s central endoscopy 
reader for evaluation of mucosal appearance.  
Mucosal appearance (endoscopy score) entry criterion should be assessed based on the central 
reader score, if available.  Only in the event that the central reader score is not available at the 
time of the Baseline Visit (Visit 2) should the local reading be used.  However, the central 
reader’s score will be used for the calculation of the full UC-DAI score.
Please see a description of criteria used for endoscopic scoring in Appendix 2.
Stool collection (for eligibility assessments, 
 
) may occur at any time during the period of the Screening Visit (Visit 1), 
provided that written informed consent/assent has been collected before this procedure.  If a 
standard of care stool sample has been collected within 24 hours prior to the Screening Visit 
(Visit 1), this sample may be used for screening assessments and evaluations provided that 
written informed consent/assent has been collected before the stool is sent for laboratory 
analysis. Stool samples collected for culture may be processed by local laboratories;  however, 
results from the central laboratory analysis will prevail and will be entered into the eCRF.  


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Subjects with positive stool cultures for any enteric pathogen (see Section 4.2) will not be 
eligible for the study.
Results for eligibility assessments must be available and evaluated prior to the end of the period 
of the Screening Visit (Visit 1) and prior to randomization at the Baseline Visit (Visit 2).
Instructions relative to the use of the e-diary for UC-DAI symptoms (rectal bleeding and stool 
frequency), the DUCS, and Overall Current Health entry will be reviewed with the subject and/or 
caregiver, and a training diary entry must be completed prior to live data entry.  Starting from the 
first evening of the period of the Screening Visit (Visit 1), each subject and/or caregiver will be
instructed to complete the e-diary every night before bedtime during the period of the Screening 
Visit (Visit 1). It is recommended that site staff telephone the subject or the subject’s caregiver
approximately 4 to 7 days prior to each visit to remind them to answer the questions in the 
e-diary every night, even if they have no symptoms. It is of particular importance to remind the 
subject at least 3 days prior to the Baseline Visit (Visit 2) to complete the questions in the e-diary 
as this information is required to assess the eligibility of the subject. 
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been randomized or administered 
investigational product(s).  Subjects who do not meet all the eligibility criteria for either the 
Double-blind Acute Phase or the Double-blind Maintenance Phase or who do not have symptom 
score data available (stool frequency and rectal bleeding), (see Section 7.2.1.1 for details), will 
be considered screen failures.  Subjects may be rescreened after consultation with the medical 
monitor.
7.1.1.2
Recommended Telephone Call (Day ⎼7 to ⎼4)
Approximately 4 to 7 days prior to the Baseline Visit (Visit 2), it is recommended that site staff 
telephone the subject or the subject’s caregiver to remind them to enter UC-DAI symptoms 
(rectal bleeding and stool frequency) into the e-diary every night, even if the subject has no 
symptoms.
7.1.1.3
Baseline Visit (Visit 2)
The Baseline visit will take place 3 to 21 days after the first day of the Screening Visit (Visit 1) 
to allow blood and stool tests to be analyzed, and for collection of e-diary data.  An extension to 
this 3- to 21-day period is allowed only in the case where a repeat endoscopy will be performed 
during the period of the Screening Visit (Visit 1) (see Section 7.1.1.1).  
The 3-day visit window which is applicable to other study visits is not applicable to this visit.  
The partial UC-DAI score will be calculated by the site, and the mucosal appearance (endoscopy 
score) will be evaluated separately to determine eligibility for either the Double-blind Acute 
Phase or the Double-blind Maintenance Phase.  The following criteria will determine the study 
phase a subject can be eligible to enter:

Subjects with partial UC-DAI ≥2 (with a combined rectal bleeding and stool frequency 
score ≥1 and PGA=1 or 2) and with mucosal appearance (endoscopy score)=2 or 3 will be
eligible to enter the Double-blind Acute Phase.


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
Subjects with partial UC-DAI ≤1 (with rectal bleeding=0 and stool frequency ≤1 and
PGA=0) and with mucosal appearance (endoscopy score)=0 or 1 will be eligible to enter 
the Double-blind Maintenance Phase. 
Subjects with partial UC-DAI score between 1 and 2 will not be eligible to enter the Double-
blind Acute Phase or the Double-blind Maintenance Phase.
Subjects who do not meet all the eligibility criteria for either the Double-blind Acute Phase or 
the Double-blind Maintenance Phase will be considered screen failures. Subjects may be 
rescreened after consultation with the medical monitor.
A minimum of 1 score each for stool frequency and rectal bleeding must be available in order to 
randomize subjects into either the Double-blind Acute Phase or the Double-blind Maintenance 
Phase (see Section 7.2.1.1 for details). Subjects with no symptom score data available will be 
considered screen failures as these symptom score data are used to calculate the partial UC-DAI 
score needed for enrollment.
Subjects with a historical diagnosis of UC:  
Endoscopy (flexible sigmoidoscopy or colonoscopy) must be performed at the Baseline Visit 
(Visit 2) if not performed at the Screening Visit (Visit 1) or within 21 days prior to the Screening 
Visit (Visit 1) (21 days prior applicable only to subjects entering into the Double-blind Acute 
Phase directly).  Endoscopic video or photographs will be collected and sent to the study’s 
central endoscopy reader for evaluation of mucosal appearance.  
Please see a description of criteria used for endoscopic scoring in Appendix 2.
If the results of blood and stool tests or partial UC-DAI score show that the subject is not eligible 
for the study, he/she will not continue in the study and will be considered a screen failure.  No 
additional data will be captured for these subjects.
Eligible subjects will be randomized to low- or high-dose MMX mesalamine/mesalazine 
stratified by their weight group at the Baseline Visit (Visit 2).  If a subject’s weight changes 
during a study phase, their dose will not change.  
Weight groups have the same absolute low and high doses for both the Double-blind Acute 
Phase and the Double-blind Maintenance Phase (see Section 6.2.3).  
Double-blind investigational product will be dispensed to eligible subjects per the procedures 
detailed in Section 6.
Subjects and/or caregivers will be instructed to collect UC-DAI symptoms (rectal bleeding and
stool frequency) via e-diary once a day before bedtime for 5 days prior to each study visit in the 
Double-blind Acute Phase and/or Double-blind Maintenance Phase as applicable.  The average 
stool frequency and rectal bleeding scores will be calculated and be made available to the 
investigator through a report from the e-diary provider.  The average stool frequency and rectal 
bleeding scores will be added to the PGA score determined by the investigator to calculate the 
partial UC-DAI.  Please see a description of the PGA in Section 7.2.1.1 and the UC-DAI in 
Sections 7.2.1.1 and 7.2.1.2.


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Subjects and/or caregivers will be instructed to complete the DUCS and the Overall Current 
Health e-diary once a day before bedtime for 5 days prior to each study visit in the Double-blind 
Acute Phase or Double-blind Maintenance Phase as applicable.  
The IMPACT III questionnaire will be completed by children aged 8-17 years via paper at the 
Baseline Visit (Visit 2).  Please see a description of the IMPACT III questionnaire in 
Section 7.2.4.1.
The PUCAI score will be calculated by a physician at the site, where applicable.  Please see a 
description of the PUCAI in Section 7.2.4.1.
See Table 1 and Table 3 for a listing of all Baseline Visit (Visit 2) procedures.
7.1.1.4
Subject Visit Schedule Summary Post-baseline
Following the Baseline Visit (Visit 2), subjects will proceed through the study in 1 of 3 ways.
1.
Double-blind Acute Phase → Open-label Acute Phase → Double-blind Maintenance 
Phase.
Visits completed post-Baseline Visit (Visit 2) are as follows: Visit 3, Visit 3.1, Visit 3.2, Visit 4, 
Visit 4.1, Visit 4.2, Visit 5, Visit 5.1, Visit 5.2, and Visit 6.
Note that Visit 3.1 and/or Visit 3.2 may not be completed in the case that a subject enters into the 
Open-label Acute Phase without completing the Double-blind Acute Phase.  See Section 7.1.3
for the criteria for subject eligibility to enter the Open-label Acute Phase.
2.
Double-blind Acute Phase → Double-blind Maintenance Phase.
Visits completed post-Baseline Visit (Visit 2) are as follows: Visit 3, Visit 3.1, Visit 3.2, Visit 5, 
Visit 5.1, Visit 5.2, and Visit 6.
3.
Double-blind Maintenance Phase only.
Visits completed post-Baseline Visit (Visit 2) are as follows: Visit 5, Visit 5.1, Visit 5.2, and 
Visit 6.
7.1.2
Double-blind Acute Phase
7.1.2.1
Recommended Telephone Call (Day ⎼7 to ⎼4)
Approximately 4 to 7 days prior to the Baseline Visit (Visit 2) and prior to each subsequent visit 
(Visits 3, 3.1, and 3.2), it is recommended that site staff telephone the subject or the subject’s 
caregiver to remind them to enter UC-DAI symptoms (rectal bleeding and stool frequency) into 
the e-diary every night, even if the subject has no symptoms.
7.1.2.2
Double-blind Acute Phase Weeks 2 and 4 (Visits 3 and 3.1, respectively) 
Subjects and/or caregivers will collect UC-DAI symptoms (rectal bleeding and stool frequency) 
via e-diary and will complete the DUCS and the Overall Current Health e-diary once a day 
before bedtime for 5 days prior to each study visit in the Double-blind Acute Phase.  


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The PGA score will be determined by the investigator.  Please see a description of the PGA in 
Section 7.2.1.1.
The Global Change in Health questionnaire will be completed via paper at Visits 3 and 3.1.  
Please see a description of the Global Change in Health questionnaire in Section 7.2.4.1.
See Table 1 for a listing of all Visit 3 and Visit 3.1 procedures.
7.1.2.3
Double-blind Acute Phase Week 8/Withdrawal (Visit 3.2)
The Double-blind Acute Phase Withdrawal Visit may occur at any time the subject discontinues 
participation in the Double-blind Acute Phase, or at completion of the study at Week 8 of the 
Double-blind Acute Phase.  No additional Baseline Visit is required for subjects continuing into 
the Open-label Acute Phase or the Double-blind Maintenance Phase from this visit.
Subjects with a clinical response ie, partial UC-DAI ≤1 (with rectal bleeding=0 and stool 
frequency ≤1 and PGA=0) will be weighed and re-randomized into the Double-blind 
Maintenance Phase for treatment with low- or high-dose MMX mesalamine/mesalazine stratified 
by weight group based on current weight.  Please see Section 6.2.3 for weight-stratified 
randomization groups.  Subjects without a clinical response may continue into the Open-label 
Acute Phase and receive MMX mesalamine/mesalazine at the high dose for their weight group, 
based on their weight at Visit 3.2 (Week 8/Withdrawal of the Double-blind Acute Phase).
Collection of stool samples for all assessments must occur before administration of any bowel 
preparations for endoscopy if samples are collected on the same day as bowel preparation 
administration.
Endoscopy (flexible sigmoidoscopy or colonoscopy) should be performed at Visit 3.2 for 
subjects who are not entering into the Open-label Acute Phase.  If performed, endoscopic video 
or photographs will be collected and sent to the study’s central endoscopy reader for evaluation 
of mucosal healing.  Please see a description of criteria used for endoscopic scoring in Appendix 
2.  If endoscopy is not performed at Visit 3.2 and the subject is otherwise eligible, the subject 
may remain in the study.
Subjects and/or caregivers will have collected UC-DAI symptoms (rectal bleeding and stool 
frequency) via e-diary once a day before bedtime for 5 days prior to each study visit in the 
Double-blind Acute Phase.  The average stool frequency and rectal bleeding scores will be 
calculated and be made available to the investigator through a report from the e-diary provider.  
The average stool frequency and rectal bleeding scores will be added to the PGA score 
determined by the investigator to calculate the partial UC-DAI.  Please see a description of the 
PGA in Section 7.2.1.1 and the UC-DAI in Sections 7.2.1.1 and 7.2.1.2.
The IMPACT III (for children aged 8-17 years) and Global Change in Health questionnaires will 
be completed via paper at Visit 3.2.  Please see a description IMPACT III and Global Change in 
Health questionnaires in Section 7.2.4.1.


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The PUCAI score will be calculated by a physician at the site, where applicable.  Please see a 
description of the PUCAI in Section 7.2.4.1.
A pharmacokinetic sample will be taken with the biochemistry and hematology sample from 
subjects at sites qualified for and participating in the pharmacokinetic sampling.  Please see a 
description of the pharmacokinetic sampling in Section 7.2.3.
See Table 1 for a listing of all Visit 3.2 procedures.
7.1.3
Open-label Acute Phase
Subjects may enter the Open-label Acute Phase after completion of the Double-blind Acute 
Phase if they do not meet the requirements for entry into the Double-blind Maintenance Phase ie, 
they do not achieve a clinical response defined as a partial UC-DAI ≤1 (with rectal bleeding=0
and stool frequency ≤1 and PGA=0).  This phase is intended to allow those subjects without 
clinical response in the Double-blind Acute Phase an additional 8 weeks to achieve clinical 
response at the high dose for their weight group.  The subject’s weight at Visit 3.2 
(Week 8/Withdrawal of the Double-blind Acute Phase) will be used to determine the high dose 
assigned to the subject in the Open-label Acute Phase.
Subjects are also eligible for the Open-label Acute Phase provided they have participated in the 
Double-blind Acute Phase for a minimum of 2 weeks and, in the investigator’s opinion, have not 
benefited from treatment in the Double-blind Acute Phase.  In addition, they should not have 
experienced a possibly or probably related severe adverse event (AE) or a serious AE (SAE).  
Due to the delay in onset of action of 5-ASA preparations, investigators should make 
subjects/caregivers aware that they may not benefit from the investigational product within the 
first 2 weeks.  Subjects who withdraw before Visit 3 will not be eligible for the Open-label Acute 
Phase.  
7.1.3.1
Recommended Telephone Call (Days ⎼7 to ⎼4)
Approximately 4 to 7 days prior to Visit 4 and prior to each subsequent visit (Visits 4.1 and 4.2),
it is recommended that site staff telephone the subject or the subject’s caregiver to remind them 
to enter UC-DAI symptoms (rectal bleeding and stool frequency) into the e-diary every night, 
even if the subject has no symptoms.
7.1.3.2
Open-label Acute Phase Weeks 2 and 4 (Visits 4 and 4.1, respectively) 
Subjects and/or caregivers will collect UC-DAI symptoms (rectal bleeding and stool frequency) 
via e-diary and will complete the DUCS and the Overall Current Health e-diary once a day 
before bedtime for 5 days prior to each study visit in the Open-label Acute Phase.  
See Table 2 for a listing of all Visit 4 and 4.1 procedures.
7.1.3.3
Open-label Acute Phase Week 8/Withdrawal (Visit 4.2)
The Open-label Acute Phase Withdrawal Visit may occur at any time the subject discontinues 
participation in the Open-label Acute Phase, or at completion of the study at Week 8 of the 
Open-label Acute Phase.  No additional Baseline Visit is required for subjects continuing into the 
Double-blind Maintenance Phase from this visit.


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Subjects with a clinical response, ie, partial UC-DAI ≤1 (with rectal bleeding=0 and stool 
frequency ≤1 and PGA=0) will be weighed and re-randomized into the Double-blind 
Maintenance Phase of the study for treatment with low- or high-dose MMX 
mesalamine/mesalazine stratified by the weight group based on current weight.  Please see 
Section 6.2.3 for weight-stratified randomization groups.  
Subjects without a clinical response after completion of the Open-label Acute Phase will be 
withdrawn from the study at Visit 4.2.  The Follow-up Visit 6 must be conducted.
Collection of stool samples for all assessments must occur before administration of any bowel 
preparations for endoscopy if samples are collected on the same day as bowel preparation 
administration.
Endoscopy (flexible sigmoidoscopy or colonoscopy) should be performed at Visit 4.2.  If 
performed, endoscopic video or photographs will be collected and sent to the study’s central 
endoscopy reader for evaluation of mucosal healing.  Please see a description of criteria used for 
endoscopic scoring in Appendix 2.  If endoscopy is not performed and the subject is otherwise 
eligible at Visit 4.2, the subject may remain in the study.
Subjects and/or caregivers will have collected UC-DAI symptoms (rectal bleeding and stool 
frequency) via e-diary once a day before bedtime for 5 days prior to each study visit in the Open-
label Acute Phase.  The average stool frequency and rectal bleeding scores will be calculated and 
be made available to the investigator through a report from the e-diary provider.  The average 
stool frequency and rectal bleeding scores will be added to the PGA score determined by the 
investigator to calculate the partial UC-DAI.  Please see a description of the PGA in Section 
7.2.1.1 and the UC-DAI in Sections 7.2.1.1 and 7.2.1.2.
The PUCAI score will be calculated by a physician at the site, where applicable.  Please see a 
description of the PUCAI in Section 7.2.4.1.
A pharmacokinetic sample will be taken with the biochemistry and hematology sample from 
subjects at sites qualified for and participating in the pharmacokinetic sampling.  Please see a 
description of the pharmacokinetic sampling in Section 7.2.3.
See Table 2 for a listing of all Visit 4.2 procedures.
7.1.4
Double-blind Maintenance Phase
7.1.4.1
Recommended Telephone Call (Days ⎼7 to ⎼4)
Approximately 4 to 7 days prior to the Baseline Visit (Visit 2) and prior to each subsequent visit 
(Visits 5, 5.1, and 5.2), it is recommended that site staff telephone the subject or the subject’s 
caregiver to remind them to enter UC-DAI symptoms (rectal bleeding and stool frequency) into 
the e-diary every night, even if the subject has no symptoms.
7.1.4.2
Double-blind Maintenance Phase Weeks 2-4 (Visit 5)
Subjects and/or caregivers will return to the study site once between 2-4 weeks after 
randomization into the Double-blind Maintenance Phase.  


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The purpose of this visit is to dispense additional investigational product.  Unused investigational 
product and empty/used investigational product packaging will be collected.  
The subject does not need to be present for this visit; it is sufficient for the caregiver only to 
return to the study site for investigational product dispensation and collection procedures.
No study procedures other than investigational production dispensation and collection are 
performed at Visit 5; however, if information is offered by the subject or caregiver that indicates 
an AE has occurred, the relevant information will be collected and followed up as described in 
Section 8.
See Table 3 for a listing of all Visit 5 procedures.
7.1.4.3
Double-blind Maintenance Phase Week 13 (Visit 5.1)
Subjects and/or caregivers will collect UC-DAI symptoms (rectal bleeding and stool frequency) 
via e-diary and will complete the DUCS and the Overall Current Health e-diary once a day 
before bedtime for 5 days prior to each study visit in the Double-blind Maintenance Phase except 
for Visit 5, which includes collection and dispensation of investigational product only.  
See Table 3 for a listing of all Visit 5.1 procedures.
7.1.4.4
Double-blind Maintenance Phase Week 26/Withdrawal (Visit 5.2)
The Double-blind Maintenance Phase Withdrawal Visit may occur at any time the subject 
discontinues participation in the Double-blind Maintenance Phase, or at completion of the study 
at Week 26 of the Double-blind Maintenance Phase.
Collection of stool samples for all assessments must occur before administration of any bowel 
preparations for endoscopy if samples are collected on the same day as bowel preparation 
administration.
Endoscopy (flexible sigmoidoscopy or colonoscopy) should be performed at Visit 5.2 where 
possible.  If performed, endoscopic videos or photographs will be collected and sent to the 
study’s central endoscopy reader for evaluation of mucosal healing.  Please see a description of 
criteria used for endoscopic scoring in Appendix 2.  
Subjects and/or caregivers will have collected UC-DAI symptoms (rectal bleeding and stool 
frequency) via e-diary once a day before bedtime for 5 days prior to each study visit in the 
Double-blind Maintenance Phase except for Visit 5, which includes collection and dispensation 
of investigational product only.  The average stool frequency and rectal bleeding scores will be 
calculated and made available to the investigator through a report from the e-diary provider.  The 
average stool frequency and rectal bleeding scores will be added to the PGA score determined by 
the investigator to calculate the partial UC-DAI.  Please see a description of the PGA in Section 
7.2.1.1 and the UC-DAI in Sections 7.2.1.1 and 7.2.1.2.


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The IMPACT III (for children aged 8-17 years) and Global Change in Health questionnaires will 
be completed via paper at Visit 5.2.  Please see a description IMPACT III and Global Change in 
Health questionnaires in Section 7.2.4.1.
The PUCAI score will be calculated by a physician at the site, where applicable.  Please see a 
description of the PUCAI in Section 7.2.4.1.
A pharmacokinetic sample will be taken with the biochemistry and hematology sample from 
subjects at sites qualified for and participating in the pharmacokinetic sampling.  Please see a 
description of the pharmacokinetic sampling in Section 7.2.3.
See Table 3 for a listing of all Visit 5.2 procedures.
7.1.5
Follow-up Period (Visit 6)
The follow-up period for this protocol is 7 days following last dose of investigational product.  
All subjects, whether they have completed the study or withdrawn early, must have a follow-up 
contact.
At the end of this period there will be a visit or telephone call initiated by the site staff to query 
for SAEs, AEs, and concomitant treatments.  All AEs and SAEs that are not resolved at the time 
of this contact will be followed to closure (see Section 8).
7.1.6
Additional Care of Subjects After the Study
No additional care is planned after a subject’s participation in this study unless required by local 
laws, ethics committees or competent authorities. The Principal Investigator at each site will be 
responsible for oversight of his or her study participant who continues on MMX 
mesalamine/mesalazine after study completion as a part of the aftercare program.
7.2
Study Evaluations and Procedures
7.2.1
Efficacy
The primary efficacy assessment of the Double-blind Acute Phase is the proportion of subjects 
with a clinical response (defined as partial UC-DAI ≤1 with rectal bleeding=0 and stool 
frequency ≤1 and PGA=0) at Week 8.  The primary efficacy assessment of the Double-blind 
Maintenance Phase is the proportion of subjects with a clinical response at Week 26.  
A secondary efficacy assessment of the Double-blind Acute Phase is the proportion of subjects 
with a clinical and endoscopic response at Week 8 defined as full UC-DAI ≤2 with rectal 
bleeding=0 and stool frequency ≤1 and PGA=0, and with mucosal healing (endoscopy score ≤1) 
based on central reading.  In addition, there must be at least a 1-point reduction in endoscopy
score from baseline.  A secondary efficacy assessment of the Double-blind Maintenance Phase is 
the proportion of subjects with a clinical and endoscopic response at Week 26.




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Did you have blood in your poop? 

I didn’t see any blood in my poop

I saw streaks of blood (a small amount) in my poop

I saw some blood (more than a small amount) in my poop

I saw mostly blood (a lot) in my poop.
Questions and responses for caregivers of children aged 5-10 years:
Based on what you observed, how many more times did your child have a bowel movement than 
they normally do since they went to bed last night?

They didn’t have more bowel movements than they normally do

They had 1 or 2 more bowel movements than normal

They had 3 or 4 more bowel movements than normal 

They had 5 or more bowel movements than normal.
Based on what you observed, did your child have blood in their stool? 

I didn’t see any blood in my child’s stool

I saw streaks of blood (a small amount) in my child’s stool

I saw some blood (more than a small amount) in my child’s stool

I saw mostly blood (a lot) in my child’s stool.
For determination of the partial UC-DAI, the average of the symptom scores of the last available 
3 days within the 5-day period immediately prior to the study visit will be used.  No symptom 
data older than 5 days prior to the study visit will be used.  Data collected on days when bowel 
preparations have been administered or when endoscopy has been performed will be excluded. 
Approximately 4 to 7 days prior to the Baseline Visit (Visit 2) and prior to each subsequent visit, 
it is recommended that site staff telephone the subject or the subject’s caregiver to remind them 
to enter UC-DAI symptoms (rectal bleeding and stool frequency) into the e-diary every night, 
even if the subject has no symptoms.  A missed day’s data may be entered until 12:00 hours the 
following day.
A minimum of 1 score each for stool frequency and rectal bleeding must be available in order to 
randomize subjects into either the Double-blind Acute Phase or the Double-blind Maintenance 
Phase. If no data are available, the average value will be considered missing and the subject will 
be considered a screen failure.


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Calculations of average stool frequency and rectal bleeding scores will proceed as follows:

If symptom scores from the last 3 days are available, average = (x1+x2+x3)/3; the average 
value should be rounded up to 1 decimal place:

For example: (0+1+0)/3 = 0.3333; value = 0.3; (1+0+1)/3=0.666666; value=0.7; 
(2+2+2)/3=2.0

If symptom scores from the last 2 days are available, average = (x1+x2)/2; the average value 
should be rounded up to 1 decimal place.

If symptom scores from only 1 day are available, average = (x1/1) = x1.
The PGA will be performed at all visits where the partial UC-DAI score is calculated by the 
study site, and is scored on a scale from 0-3, where 0=no active disease, 1=mild disease, 
2=moderate disease, and 3=severe disease.  The PGA should be performed by the same 
investigator at all visits, if possible, for consistency in evaluation.
Scoring of the PGA by the investigator should take into account the following parameters:

Rectal bleeding

Stool frequency and consistency

Night-time bowel movements

Abdominal pain

Impact to daily activities

Physical findings

Endoscopic findings (if endoscopy is performed).
The PGA is to be recorded in source documentation and added to the average stool frequency 
and average rectal bleeding scores to calculate the partial UC-DAI score. Sites should not 
perform rounding of partial UC-DAI scores. The average stool frequency and rectal bleeding 
scores will be calculated and available to the investigator through a report from the e-diary 
provider.
7.2.1.2
Modified Full UC-DAI Score
The full UC-DAI is widely used to assess treatment efficacy in subjects with mild to moderate 
UC (Schroeder et al. 1987; Sutherland et al. 1987).  It consists of 4 individual parameters: stool 
frequency, rectal bleeding, endoscopy score (mucosal appearance), and PGA.  For the purpose of 
this study, the standard UC-DAI scale has been modified so that an endoscopy score of mild 
disease does not include friability; instead, friability will be scored as 2: moderate disease.  
Please see a description of stool frequency, rectal bleeding and PGA in Section 7.2.1.1.  


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All 4 parameters will be assessed individually on a scale from 0-3; the maximum total modified 
full UC-DAI score is 12.0.  The modified full UC-DAI score will be calculated at Baseline (Visit 
2), Week 8 of the Double-blind Acute Phase (Withdrawal) for subjects not entering into the 
Open-label Acute Phase, Week 8 of the Open-label Acute Phase (Withdrawal) for subjects who 
have not had endoscopy at the end of the Double-blind Acute Phase, and Week 26 of the Double-
blind Maintenance Phase (Withdrawal) visits.  The total score will be calculated by summing the 
individual scores for the 4 parameters (endoscopy score will be based on the central reader’s 
score).  The site is not required to calculate the full UC-DAI; this will be calculated centrally 
using e-diary and eCRF data.
For determination of the modified full UC-DAI, the average of the symptom scores of the last 
available 3 days within the 5-day period immediately prior to study visits where endoscopic data 
are available, will be used.  No symptom data older than 5 days prior to the study visit will be 
used.  Data collected on days when bowel preparations have been administered or when 
endoscopy has been performed will be excluded. 
An endoscopy must be performed and mucosal appearance scored within 21 days prior to the 
Screening Visit (Visit 1), during the Screening period or at the Baseline Visit (Visit 2) depending 
on the subject’s UC history and phase of the study into which they are entering.  All efforts 
should be made to perform endoscopy at Week 8 of the Double-blind Acute Phase (or Week 8 of 
the Open-label Acute Phase, as applicable), Week 26 of the Double-blind Maintenance Phase, or 
the subject’s withdrawal if different from these visits. 
During this study, an attempt will be made to collect endoscopy data in approximately 30% of 
subjects at the end of the Acute Phase (combined Double-blind and Open-label) and 
approximately 30% at the end of the Double-blind Maintenance Phase.  In addition, data from 
endoscopies performed as a part of routine clinical care during a subject’s participation in the 
study will be collected.
Endoscopies will be centrally read and scored for this study, and endoscopic video or 
photographs must be provided to the central reader for each endoscopy performed.  Video 
images are preferred; however, photographic images will be accepted when video images are not 
of sufficient quality, as determined by the central reader during individual site image evaluation 
prior to enrollment at the site.  Further details of requirements for video and photographic images 
will be provided to study sites under separate cover by the central reader.  All endoscopies 
should be performed by the same investigator/endoscopist, if possible, to ensure consistency in 
endoscopy.
Please see Appendix 2 for the modified full UC-DAI.
7.2.2
Safety
The name and address of each third party vendor (eg, clinical laboratory) used in this study will 
be maintained in the investigator’s and sponsor’s files.


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7.2.2.1
Medical and Medication History
At screening, the subject’s medical history (including UC history) and concomitant medications 
will be reviewed.  Investigator site staff will conduct this review via interview with the subject 
and/or caregiver to determine eligibility.  Any new medical events or changes in intensity from 
the Screening Visit (Visit 1) noted during the study should be evaluated for report as an AE (see 
Section 8).  New medications or changes to existing medications must be added or updated as 
appropriate.
7.2.2.2
Physical Examination 
Abnormalities identified at the Screening Visit (Visit 1) will be documented in the subject’s 
source documents. Changes after the Screening Visit (Visit 1) will be captured as AEs, as 
deemed appropriate by the investigator.
7.2.2.3
Height and Weight
Height will be assessed at the Screening Visit (Visit 1) and at the final visit of each phase.  
Weight will be assessed at the Screening Visit (Visit 1), the Baseline Visit (Visit 2) and at the 
final visit of each phase.  
The collection of height and weight data should be precise. A calibrated stadiometer must be 
used for all height measurements. Height should be measured in stocking feet (without shoes) 
with the subject standing on a flat surface and with chin parallel to the floor. The body should be 
straight but not rigid. The subject’s height should be recorded to the nearest 0.5 inch or 1 cm. 
The same calibrated scale must be used for all weight measurements.  Weight should be 
measured in stocking feet (without shoes) and recorded to the nearest 0.2 kg. 
7.2.2.4
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”).  
Adverse events are collected from the time informed consent is signed.  (Please refer to 
Section 8, Adverse and Serious Adverse Events Assessment.)
In addition, any symptoms/conditions reported during assessments or collected via structured 
data collection will be evaluated by the investigator at each study visit to determine whether 
these are AEs.
7.2.2.5
Vital Signs
Vital signs include blood pressure and pulse.  Blood pressure should be determined by cuff 
(using the same method, the same arm, and in the same position throughout the study).  Any 
clinically significant deviations from the Baseline Visit (Visit 2) vital signs which are deemed 
clinically significant in the opinion of the investigator are to be recorded as an AE.
Measurements of vital signs (blood pressure and pulse) will be performed at all study visits.  
Blood pressure and pulse will be determined in the sitting position (after 5 minutes).


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7.2.2.6
Clinical Laboratory Evaluations
All clinical laboratory assays will be performed according to the laboratory’s normal procedures.  
Reference ranges are to be supplied by the laboratory and will be used to assess the clinical 
laboratory data for clinical significance and out-of-range pathological changes.  The investigator 
should assess out-of-range clinical laboratory values for clinical significance, indicating if the 
value(s) is/are not clinically significant or clinically significant.  Abnormal clinical laboratory 
values, which are unexpected or not explained by the subject’s clinical condition, may, at the 
discretion of the investigator or sponsor, be repeated as soon as possible until confirmed, 
explained, or resolved.
The following routine clinical laboratory assessments will be performed (see Section 8.1.5 for 
additional clinical laboratory assessments that may be performed in the case of elevated liver 
enzymes): 
Biochemistry (approximately 5mL sample)
Alanine aminotransferase
Direct bilirubin 
Albumin
Gamma-glutamyl transferase
Alkaline phosphatase
Glucose random, serum
Aspartate aminotransferase
Lactate dehydrogenase
Bilirubin, total
Magnesium
Bicarbonate
Phosphate
Calcium
Potassium
Chloride
Sodium
Cholesterol, total
Total protein
Creatinine, enzymatic
Triglycerides 
Creatine kinase
Urea (blood urea nitrogen)
C-reactive protein standard
Uric acid 
Hematology (approximately 3mL sample)
Complete blood count (red blood cells,
white blood cells, platelets, hemoglobin)
White blood cell differential
Hematocrit
Urinalysis
pH
Ketones 
Specific gravity
Bilirubin
Protein
Blood 
Glucose


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Microscopic examination will be conducted if protein and/or blood is/are detected during 
urinalysis.  The microscopic examination will consist of red blood cells, white blood cells, casts,
and bacteria.
Please see Table 1, Table 2, and Table 3 for visits requiring biochemistry, hematology and 
urinalysis collection.
7.2.2.7
Pregnancy Test 
A serum -HCG pregnancy test is performed for all females of childbearing potential at the 
following visits as applicable to the subject’s participation in the study: 

Screening Visit (Visit 1)

Double-blind Acute Phase: Week 8 (Visit 3.2)

Open-label Acute Phase: Week 8 (Visit 4.2)

Double-blind Maintenance Phase: Week 26 (Visit 5.2)

If pregnancy is suspected

On withdrawal of the subject from the study.
A urine pregnancy test is performed for all females of childbearing potential at all other visits as 
indicated in Table 1, Table 2, and Table 3.
7.2.2.8
Stool Assessment
Collection of stool samples for all assessments must occur before administration of any bowel 
preparations for endoscopy if samples are collected on the same day as bowel preparation 
administration.
If a standard of care stool sample has been collected within 24 hours prior to the Screening Visit 
(Visit 1), this sample may be used for screening assessments and evaluations provided that 
written informed consent/assent has been collected before the stool is sent for laboratory 
analysis.
Screening Assessments
A stool sample will be collected during the Screening Visit (Visit 1), which is a period of 
3 to 21 days. If a standard of care stool sample was collected within 24 hours prior to the 
Screening Visit (Visit1), this sample may be used for screening assessments and evaluations. 
The sample must be collected in sufficient time to ensure results reporting within the Screening 
Visit (Visit 1) period Stool samples collected for culture may be processed by local laboratories;  
however, results from the central laboratory analysis will prevail and will be entered into the 
eCRF. The following parameters will be assessed:

Culture for enteric pathogens including Salmonella, Shigella, Yersinia, Aeromonas, 
Plesiomonas, and Campylobacter








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PUCAI
The PUCAI is a physician-administered measure that focuses on 6 key signs and symptoms of 
UC and activity limitations (Turner et al. 2007).  The PUCAI yields a total score ranging from 
0-85 with higher scores being worse.  Recommended cut-off scores to differentiate disease 
activity are <10 (remission); 11-30 (mild); 31-64 (moderate) and >65 (severe) (Turner et al. 
2009).  Evaluation of the construct validity of the PUCAI revealed that it was highly correlated 
with physician’s global assessment of disease activity and PUCAI scores were highly predictive 
of the need for escalating medical therapy (Turner et al. 2009).  See Appendix 4.
Only sites who have executed a sublicense with Shire for PUCAI use will be able to collect 
PUCAI data for the study.
IMPACT III
The IMPACT questionnaire is a disease-specific health-related quality-of-life questionnaire 
developed for use in pediatric inflammatory bowel disease through a process of patient 
interviews and analysis of patient responses to an item-reduction questionnaire.  This is a 
self-administered questionnaire, and data will be collected via paper in this study.
The IMPACT questionnaire has been studied to determine its feasibility, reliability, and validity.  
It was found to be a valid and reliable reflection of health-related quality-of-life of older children 
and adolescents with both UC and Crohn's disease (Otley et al. 2002). 
In this study, the IMPACT III will be used.  This is the current version of the questionnaire, 
adapted from IMPACT II, which was developed in 2002.  The original version of IMPACT was 
developed in 1999.  IMPACT III contains 35 items in 6 domains.  The Bowel Symptoms domain 
and the 4 matching symptom items between the IMPACT III and the DUCS will be used to 
evaluate convergent validity of the DUCS.  
The IMPACT is valid for children and adolescents aged 9-17 years old and is completed by the 
subject.  Children/adolescent aged 9-17 years who cannot complete the questionnaire 
independently, may be assisted by an adult who is not the child’s guardian or relative.  Children 
who are 8 years old may complete the IMPACT with assistance from an adult who is not the 
child’s guardian or relative.  Children under the age of 8 years old will not complete the 
IMPACT.  
Global Change in Health
The Global Change in Health item assesses the subject’s (aged 11-17 years) or caregiver’s (for 
children aged 5-10 years) perception of change in health since starting the study and will be 
administered via paper in this study.  This item has been tested in cognitive debriefing interviews 
with the DUCS.  


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7.2.5
Volume of Blood to be Drawn from Each Subject
Table 6:
Volume of Blood to be Drawn From Each Subject
Assessment
Sample 
Volume 
(mL)
Number 
of 
Samples: 
Screening
Number of 
Samples: 
Double-blind 
Acute Phase
Number of 
Samples: 
Open-label 
Acute 
Phase
Number of 
Samples: 
Double-blind 
Maintenance 
Phase
Total 
Volume 
(mL)
Safety
Biochemistry 
and -HCGa
5
1
1
1
1
20
Hematology
3
1
1
1
1
12
Pharmacokinetic samples 
(at participating sites only)
2 
0
1
1
1
6
Total mL
8
8
8
8
32-38
a -HCG testing for females only.
-HCG=beta-human chorionic gonadotropin
It is expected that approximately 32mL of blood will be drawn from subjects who participate in 
every phase of the study, regardless of sex and approximately an additional 6mL will be drawn 
from subjects participating in the pharmacokinetic section of the study.  Blood sampling and 
volume drawn will be less for subjects who do not participate in every phase of the study, in 
accordance with Table 6.
Note: The amount of blood to be drawn for each assessment is an estimate.  The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment; however, the total volume drawn over the course of the study 
should be approximately 32-38mL.  When more than 1 blood assessment is to be done at the 
time point/period, if they require the same type of tube, the assessments may be combined.  
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product 
(International Council for Harmonisation [ICH] Guidance E2A 1995).  
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.5.  This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered.  Where possible, a 
diagnosis rather than a list of symptoms should be recorded.  If a diagnosis has not been made, 
then each symptom should be listed individually.  All AEs should be captured on the appropriate 
AE pages in the eCRF and in source documents.  In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured in the AE eCRF.


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All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study.  Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained.  When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity.  An event that changes in severity should be captured as a new 
event.  Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded in the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention.  The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention.  The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE.  The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product.  If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”.  Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”.  The causality assessment must be 
documented in the source document.


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The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected response 
pattern to that product, and the event cannot be explained by the subject’s medical 
condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the investigational product and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study in the eCRF.  Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae

Recovering/Resolving

Unknown
8.1.4
Symptoms of the Disease Under Study
Symptoms of the disease under study (eg, episodes of diarrhea with blood and mucus, abdominal 
pain, and urgency) should not be classed as AEs as long as they are within the normal day-to-day 
fluctuation or expected progression of the disease and are part of the efficacy data to be collected 
in the study; however, significant worsening of the symptoms should be recorded as an AE.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory, or vital sign, assessment can represent an AE if the 
change is clinically relevant or if, during treatment with the investigational product, a shift of a 
parameter is observed from a normal value to an abnormal value, or a further worsening of an 
already abnormal value.  When evaluating such changes, the extent of deviation from the 
reference range, the duration until return to the reference range, either while continuing treatment 
or after the end of treatment with the investigational product, and the range of variation of the 
respective parameter within its reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, or vital sign, values 
which were not present at the pretreatment value observed closest to the start of study treatment, 
further investigations should be performed until the values return to within the reference range or 
until a plausible explanation (eg, concomitant disease) is found for the abnormal values.


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The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, or vital sign, parameter is clinically significant 
and therefore represents an AE.
Subjects with liver enzymes (alanine aminotransferase, aspartate aminotransferase, gamma-
glutamyl transferase) elevated beyond twice the upper limit of normal will be further evaluated 
with a panel of tests assessing markers of hepatic injury, inflammation, and function.  At a 
minimum, this panel should include the following: repeat alanine aminotransferase, aspartate 
aminotransferase, gamma-glutamyl transferase, total and direct bilirubin, serum albumin, lactate 
dehydrogenase, and prothrombin time.  Consideration should be given as to whether an arterial 
blood sample for serum ammonia should also be obtained based on the magnitude of 
transaminase elevation and the subject’s clinical status (such as presence of mental status 
changes or other findings that might suggest Reye’s syndrome; the Shire Medical Monitor 
should be consulted prior to collection of this specimen).  Subjects should be followed until their 
hepatic enzyme values return to normal ranges.  If abnormal values persist for greater than 1 
week, the Shire Medical Monitor should be contacted for discussion and agreement of additional 
etiology investigation. 
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.5.
Any report of pregnancy for any female study participant must be reported within 24 hours to the 
Shire Pharmacovigilance Department using the Shire Investigational and Marketed Products 
Pregnancy Report Form.  The pregnant female study participant must be withdrawn from the 
study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant.  It is the responsibility of the investigator to obtain this information 
within 30 calendar days after the initial notification and approximately 30 calendar days 
post-partum. 
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Trial Serious Adverse Event 
Form.  Note:  An elective abortion is not considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Trial Serious Adverse Event Form as well 
as the Shire Investigational and Marketed Products Pregnancy Report Form.  The test date of the 
first positive serum/urine -HCG test or ultrasound result will determine the pregnancy onset 
date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2.  Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 


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The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol)

Overdose – Intentional or unintentional intake of a dose of an investigational product 
exceeding a pre-specified total daily dose of 4.8g of the product

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product.  For studies, medication errors are reportable to the sponsor 
only as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of the unassigned treatment is/are always reportable as a 
medication error.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error.
All investigational product provided to pediatric subjects should be supervised by the 
parent/LAR/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the current MMX Mesalazine (Mesalamine) 
Investigator’s Brochure which the sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire 
Pharmacovigilance Department and the CRO Pharmacovigilance Department within 24 hours of 
the first awareness of the event.  Note: The 24-hour reporting requirement for SAEs does not 
apply to reports of abuse, misuse, overdose, or medication errors (see Section 8.1.7) unless they 
result in an SAE. 
The investigator must complete, sign, and date the Shire Clinical Trial Serious Adverse Event 
Form and verify the accuracy of the information recorded on the form with the corresponding 
source documents (Note:  Source documents are not to be sent unless requested) and fax or 
e-mail the form to the Shire Pharmacovigilance Department.  


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A copy of the Shire Clinical Trial Serious Adverse Event Form (and any applicable follow-up 
reports) must also be sent to the CRO Pharmacovigilance Department using the details specified 
in the emergency contact information section of the protocol.
8.2.3
Serious Adverse Event Definition
An SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose:

Results in death.

Is life-threatening.  Note: The term “life-threatening” in the definition of “serious” refers to 
an event in which the subject was at risk of death at the time of the event; it does not refer 
to an event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization.  Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not 
be classified as SAEs.  For example, an admission for a previously scheduled ventral 
hernia repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity.

Is a congenital abnormality/birth defect.

Is an important medical event.  Note: Important medical events that may not result in
death, be life-threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent 1 of the outcomes listed in this 
definition.  Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home; blood dyscrasias or convulsions that 
do not result in inpatient hospitalization; or the development of drug dependency or drug 
abuse.  
8.2.4
Serious Adverse Event Collection Timeframe
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.5, and must be reported 
to the Shire Pharmacovigilance Department within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire 
Pharmacovigilance Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria.  The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic.  In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.


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In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date.  
For all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAEs that result in the subject’s death or any ongoing events at the time of death, the 
action taken with the investigational product should be recorded as “dose not changed” or “not 
applicable” (if the subject never received investigational product).
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor and the clinical CRO are responsible for notifying the relevant regulatory 
authorities/US central institutional review boards (IRBs)/European Union (EU) central ethics 
committees (ECs) of related, unexpected SAEs.
In addition the clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SPD476 program.  
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
in the eCRF.  A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy.  Discrepancies 
between source data and data entered in the eCRF will be addressed by qualified site personnel.  
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel.  Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting.  Once a subject is randomized, it is expected that site 
personnel will complete the eCRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management plan.  
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.


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Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures.  Data queries requiring clarification are 
to be communicated to the site for resolution.  Only authorized personnel will make corrections 
to the clinical database, and all corrections are documented in an auditable manner.
9.3
Data Handling Considerations
Data that may potentially unblind the treatment assignment (ie, investigational product serum 
concentrations, treatment allocation, and investigational product preparation/accountability data) 
will be handled with special care during the data cleaning and review process.  These data will be 
handled in such a way that, prior to unblinding, any data that may unblind study team personnel 
will be presented as blinded information or otherwise will not be made available.  If applicable, 
unblinded data may be made available to quality assurance representatives for the purposes of 
conducting independent drug audits. 
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent.  All data analyses will be performed by 
the Biometrics Department of the CRO after the study is completed and unblinded, and the 
database is released for analysis.
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications.  The 
SAP will also include a description of how missing, unused, and spurious data will be addressed.
The SAP will be finalized prior to unblinding to preserve the integrity of the statistical analysis 
and study conclusions.  
All statistical analyses will be performed using SASVersion 8.2 (SAS Institute, Cary, NC 
27513) or later version. 
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
An independent Data Monitoring Committee (DMC) will be established for this study.  The 
purpose of the DMC is to review safety data (eg, AEs, clinical laboratory data).  DMC meetings 
will be held when data is available from specified percentages of subjects who have completed 
or withdrawn from a phase or phases during the study.  The data provided to the DMC will not 
be considered “clean” until the database is locked. Data will be provided to the DMC by an 
independent statistical reporting group not assigned to the project. Further details regarding the 
DMC and meeting frequency can be found in the DMC charter.  


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9.6
Sample Size Calculation and Power Considerations
This will be an estimation study with no formal hypothesis testing; therefore, this study is not 
powered to detect differences between treatment groups. More than 100 subjects will be screened 
and up to 80 subjects will be enrolled in the Double-blind Acute Phase of the study. More than 
65 subjects will be screened (in addition to an expected 28 subjects who will enter the 
Double-blind Maintenance Phase from one of the Acute Phases) and at least 80 subjects will be 
enrolled in the Double-blind Maintenance Phase of the study. The sample size was chosen based 
on practical considerations and on agreement with the US FDA.
9.7
Study Population
The Screened Set will consist of all subjects who have signed an informed consent.
The Double-blind Acute Phase Safety Analysis Set will consist of randomized subjects who 
have taken at least 1 dose of investigational product during the Double-blind Acute Phase.
The Open-label Acute Phase Safety Analysis Set will consist of all subjects who have taken at 
least 1 dose of investigational product during the Open-label Acute Phase.
The Double-blind Maintenance Phase Safety Analysis Set will consist of randomized subjects 
who have taken at least 1 dose of investigational product during the Double-blind Maintenance 
Phase.
9.8
Efficacy Analyses
Baseline is defined as the last observation prior to first dose of investigational product in the 
study.  The Double-blind Acute Phase Week 8/Withdrawal visit (Visit 3.2) is treated as the 
Open-label Acute Phase Week 0 for subjects continuing into the Open-label Acute Phase from 
this visit. The Double-blind Acute Phase Week 8/Withdrawal visit (Visit 3.2) is treated as the 
Double-blind Maintenance Phase Week 0 for subjects continuing into the Double-blind 
Maintenance Phase from this visit. The Open-label Acute Phase Week 8/Withdrawal visit (Visit 
4.2) is treated as the Double-blind Maintenance Phase Week 0 for subjects continuing into the 
Double-blind Maintenance Phase from this visit. For subjects who enter the Double-blind 
Maintenance Phase directly, the Baseline Visit (Visit 2) is treated as the Double-blind 
Maintenance Phase Week 0.
9.8.1
Primary Efficacy Endpoint
The primary endpoints for this study are defined separately for both the Double-blind Acute 
Phase and Double-blind Maintenance Phases and will be conducted using the appropriate Safety 
Analysis Set for the Phase.
9.8.1.1
Double-blind Acute Phase 
The primary efficacy endpoint for the Double-blind Acute Phase is defined as the proportion of 
subjects with a clinical response (defined as partial UC-DAI≤1 with rectal bleeding=0 and stool 
frequency ≤1 and PGA=0) at Week 8.


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Subjects with missing data at Week 8 will be assumed not to have had a clinical response.  The 
primary efficacy endpoint will be compared between treatment arms using a continuity-corrected 
chi-squared test on the Double-blind Acute Phase Safety Analysis Set.  The null hypothesis to be 
tested is that there is no difference in the proportion of subjects with a clinical response at Week 
8 between low and high doses of MMX mesalamine/mesalazine.
9.8.1.2
Double-blind Maintenance Phase 
The primary efficacy endpoint for the Double-blind Maintenance Phase is defined as the 
proportion of subjects who have maintained a clinical response (defined as partial UC-DAI≤1 
with rectal bleeding=0 and stool frequency ≤1 and PGA=0) at Week 26.
Subjects with missing data at Week 26 will be assumed not to have had a clinical response.  The 
primary efficacy endpoint will be compared between treatment arms using a Cochran-Mantel-
Haenszel (CMH) test stratifying for 3 levels of responder status at Week 26 of the Double-blind 
Maintenance Phase (entered Maintenance Phase directly, responder at Week 8 of the Double-
blind Acute Phase, or responder at Week 8 of the Open-label Acute Phase) on the Double-blind 
Maintenance Phase Safety Analysis Set.  The null hypothesis to be tested is that there is no 
difference in the proportion of subjects with a clinical response at Week 26 between low and 
high doses of MMX mesalamine/mesalazine.
9.8.2
Sensitivity Analyses of the Primary Endpoint
The following sensitivity analyses will be performed for both the Double-blind Acute and 
Double-blind Maintenance Phase primary endpoints:

A modified clinical response, defined as partial UC-DAI≤1 with rectal bleeding=0 and stool 
frequency ≤1 will be analyzed in a similar way to the primary endpoint analysis in order to 
investigate the effect of removing the PGA component from the responder definition.

An observed-case analysis will be performed, where data from those who completed Week 
26 and those who withdrew from the study early and are presented and analyzed separately, 
using a similar analysis to the primary endpoint.  

A complete-case analysis, where subjects who withdraw early from the study will be 
excluded, will be performed in a similar way to the primary endpoint analysis.

A last observation carried forward analysis, using data from the final on-treatment 
assessment, will be performed in a similar way to the primary endpoint analysis.

Logistic modeling will be conducted to investigate the effect of doses in mg/kg on the 
clinical response in the Double-blind Acute and Double-blind Maintenance Phases.  
9.8.3
Secondary Efficacy Endpoints
The secondary endpoints for this study are defined separately for both the Double-blind Acute 
and Double-blind Maintenance Phases and will be conducted using the appropriate Safety 
Analysis Set for the Phase.  These endpoints will be described using appropriate summary 
statistics (n [%]) for categorical variables, n, mean, standard deviation, median, minimum and 
maximum for continuous variables).






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9.10 Other Analyses
9.10.1 Health-related Quality-of-Life Analyses
In this study the final validation steps for the PRO instrument, the DUCS, will be performed.  
The psychometric properties of the DUCS, including reliability, validity, and responsiveness, 
will be examined using data from an appropriate number of subjects from the Double-blind 
Acute Phase and an appropriate number of subjects from the Double-blind Maintenance Phase 
prior to unblinding.  To examine convergent validity, the DUCS scores will be correlated with 
the IMPACT III, Overall Current Health and selected clinical data. 
The validation of the DUCS will be described in a separate SAP specific for the DUCS.
10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements.  
The name and address of each third party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1 Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines.  Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study.  The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2 Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines.  If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study.  An insurance certificate is supplied to the CRO/investigator as necessary.


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10.1.3 Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites.  
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities of 
Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP.  This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance.  The sponsor will provide the ECs with a copy of the same summary.
10.1.5 Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason.  
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies, and IRBs/ECs are notified as appropriate.  Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1 Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study.  The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification.  Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.


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A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies.  Agreement with the final clinical study report is documented by the signed 
and dated signature of the coordinating principal investigator, in compliance with Directive 
2001/83/EC as amended by Directive 2003/63/EC and ICH Guidance E3 (1995). 
10.2.2 Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document.  The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria.  Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation.  The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor.  Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure that accurate and timely information is provided 
at all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3 Documentation and Retention of Records
10.2.3.1 Electronic Case Report Forms
Electronic case report forms are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded into eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation.  Electronic case report forms 
must be completed by the investigator or designee as stated in the site delegation log.
All data will have separate source documentation; no data will be recorded directly into the 
eCRF.
All data sent to the sponsor must be endorsed by the investigator.
The clinical research associate/study monitor will verify the contents against the source data per 
the monitoring plan.  If the data are unclear or contradictory, queries are sent for corrections or 
verification of data.
10.2.3.2 Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file including histology reports, subject-completed questionnaires and original 
clinical laboratory reports.


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All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor, the respective national, 
local, or foreign regulatory authorities, the IRB/EC, and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The clinical research associate/study monitor (and auditors, IRB/EC or regulatory inspectors) 
may check the eCRF entries against the source documents.  The consent/assent form includes a 
statement by which the subject/LAR agrees to the monitor/auditor from the sponsor or its 
representatives, national or local regulatory authorities, or the IRB/EC, having access to source 
data (eg, subject’s medical file, appointment books, original laboratory reports, X-rays etc).  
Non-study site personnel will not disclose any personal information or personal medical 
information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
European Medicines Agency, United Kingdom Medicines and Healthcare products Regulatory 
Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3 Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the European Medicines Agency, the United Kingdom 
Medicines and Healthcare products Regulatory Agency, other regulatory authorities, the sponsor 
or its representatives, and the IRB/EC for each site.
10.2.3.4 Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor.  The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in Title 21 of the US Code of 
Federal Regulations Part 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1 Informed Consent/Assent
It is the responsibility of the investigator to obtain written informed consent and assent 
where applicable from all study subjects prior to any study-related procedures including 
screening assessments.  


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All consent and assent documentation must be in accordance with applicable regulations and 
GCP.  Each subject or the subject’s LAR, as applicable, is requested to sign and date the subject 
informed consent/assent form or a certified translation if applicable, after the subject has 
received and read (or been read) the written subject information and received an explanation of 
what the study involves, including but not limited to: the objectives, potential benefits and risk, 
inconveniences, and the subject’s rights and responsibilities.  A copy of the informed consent 
and assent documentation (ie, a complete set of subject information sheets and fully executed 
signature pages) must be given to the subject or the subject’s LAR, as applicable.  This document 
may require translation into the local language.  Signed consent/assent forms must remain in 
each subject’s study file and must be available for verification at any time.
Within the source documents, site personnel should document instruction of and understanding 
by the parent/LAR/caregiver of the safe, responsible storage and administration of 
investigational product to the study subject.
The principal investigator provides the sponsor with a copy of the consent form and assent form 
where applicable which was reviewed by the IRB/EC and which received their favorable 
opinion/approval.  A copy of the IRB/EC’s written favorable opinion/approval of these 
documents must be provided to the sponsor, prior to the start of the study unless it is agreed to 
and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (ie, sponsor or coordinating principal investigator) is responsible for this 
action.  Additionally, if the IRB/EC requires modification of the sample subject information and 
consent document provided by the sponsor, the documentation supporting this requirement must 
be provided to the sponsor.
10.3.2 Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent/assent document (approved by the sponsor or their designee), relevant 
supporting information and all types of subject recruitment information to the IRB/EC for 
review, and all must be approved prior to site initiation.
For sites within the EU, the applicant for an EC opinion can be the sponsor, the investigator, or 
for multicenter studies the coordinating principal investigator or sponsor, according to national 
provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent/assent documents and amendments to the protocol unless there 
is a subject safety issue.
Investigational product supplies will not be released until the sponsor has received written 
IRB/EC approval of and copies of revised documents.




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All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information.  The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study.  To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications.  To the extent that the principal investigator has such sole, 
joint or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts, and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results.  Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication.  If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results.  If such a multicenter publication is not submitted to 
a journal for publication by the sponsor within an 18-month period after conclusion, 
abandonment, or termination of the study at all sites, or after the sponsor confirms there shall be 
no multicenter study publication of the study results, an investigator may individually publish the 
study results from the specific site in accordance with this section.  The investigator must, 
however, acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
current standards.  Participation as an investigator does not confer any rights to authorship of 
publications.


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11.
REFERENCES
Mendeloff AI, Calkins BM 1988.  The epidemiology of idiopathic inflammatory bowel disease.  
In: Kirsner, JB, Shorter, RG (Eds), Inflammatory Bowel Disease.  Lea Febiger, Philadelphia.  
Otley A, Smith C, Nicholas D, Munk M, Avolio J, Sherman PM, et al. 2002.  The IMPACT 
Questionnaire: A valid measure of health-related quality of life in pediatric inflammatory bowel 
disease.  J Pediatr Gastroenterol Nutr; 35(4): 557-63.
Turner D, Otley A, Mack D, Hyams J, De Bruijne J, Uusoue K, et al. 2007.  Development, 
validation, and evaluation of a pediatric ulcerative colitis activity index: a prospective 
multicenter study.  Gastroenterology; 133: 423-32.
Turner D, Hyams J, Markowitz J, Lerer T, Mack DR, Evans J, et al. 2009. Appraisal of the 
Pediatric Ulcerative Colitis Activity Index (PUCAI).  Inflamm Bowel Dis; 15(8): 1218-23.
Turner D, Levine A, Escher JC, Griffiths AM, Russell RK, Dignass A, et al. 2012.  Management 
of pediatric ulcerative colitis: Joint ECCO and ESPGHAN evidence-based consensus guidelines.  
J Pediatr Gastroenterol Nutr; 55(3): 340-61.
Schroeder KW, Tremaine WJ, Ilstrup DM 1987.  Coated oral 5-aminosalicylic acid therapy for 
mildly to moderately active ulcerative colitis.  A randomized study.  N Engl J Med; 317(26): 
1625-9.
Sutherland LR, Martin F, Greer S, Robinson M, Greenberger N, Saibil F, et al. 1987.  
5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and 
proctitis.  Gastroenterology; 92(6): 1894-8.


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12.
APPENDICES


















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APPENDIX 2 THE MODIFIED FULL ULCERATIVE COLITIS DISEASE 
ACTIVITY INDEX (UC-DAI)
The modified full UC-DAI Score is computed as the sum of scores in 4 categories of clinical 
symptoms: stool frequency, rectal bleeding, and mucosal appearance (endoscopy score) and 
PGA.
The 4 components of the modified full UC-DAI are scored in the following way:
Stool frequency Score
Normal
0
1-2 more than normal/day
1
3-4 more than normal/day
2
>4 more than normal/day
3
Rectal bleeding (most severe bleeding of the day)
None
0
Streaks of blood
1
Obvious blood
2
Mostly blood
3
Mucosal appearance (endoscopy score)
Normal (intact vascular pattern; no friability or granulation)
0
Mild 
(erythema, 
decreased 
vascular 
pattern, 
minimal 
granularity)
1
Moderate (marked erythema, granularity, friability, absent 
vascular pattern, bleeding with minimal trauma, no ulcerations)
2
Severe (ulceration, spontaneous bleeding)
3
Physician’s Global Assessment
No active disease
0
Mild disease
1
Moderate disease
2
Severe disease
3


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APPENDIX 3 SUBJECT QUESTIONNAIRES
The following subject completed questionnaires will be utilized in this study:
Daily Ulcerative Colitis Scale for Children and Caregivers
Overall Current Health
Rectal Bleeding
Stool Frequency
Global Change in Health
IMPACT III
A separate master file containing each subject questionnaire listed above will be provided to the 
site.  Updates to subject questionnaires during the study (if applicable) will be documented in the 
table above and a new master file containing the revised subject questionnaire(s) will be 
provided to the site.


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APPENDIX 4 PEDIATRIC ULCERATIVE COLITIS ACTIVITY INDEX





SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Protocol No.:
SPD476-319
Protocol Title:
A Phase 3, Multicenter, Randomized, Double-blind Study 
to Determine the Safety and Efficacy of MMX 
Mesalamine/Mesalazine in Pediatric Subjects with Mild to 
Moderate Ulcerative Colitis, in both Acute and 
Maintenance Phases
Drug:
SPD476, MMX Mesalamine/mesalazine
Sponsor: 
Shire Development LLC. 
300 Shire Way
Lexington, MA 02421
Version No. and Date
Version 4.0, 31 Oct 2018
Version 
No:
Document History
Description of Update
Author(s)
Effective 
Date
0.1
First Draft, with questions for team
19 Feb 2014
0.2
First draft with comments from team, additions, 
updates for handover
25 Feb 2014
0.3
Second Draft
12 Jun 2014
0.4
Second Draft with updates
14 Jul 2014
1.0
Final
17 Jul 2014
1.1
Draft – Added PK summaries, description of 
efficacy and safety variables, section for 
statistical/analytic issues
07 Feb 2016
1.2
Draft – Added analyses to address FDA requests
02 May 2016
2.1
Draft – Added Section 9 for references
19 May 2016
3.0
Final
19 May 2016
3.1
Draft-Updated based on protocol Version 6.0
18 Oct 2018
3.2
Draft-First draft with comments from team
25 Oct 2018
4.0
Final
31 Oct 2018


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Statistical Analysis Plan
SPD476-319
31 Oct 2018
TABLE OF CONTENTS
TABLE OF CONTENTS.................................................................................................................2
LIST OF TABLES...........................................................................................................................5
LIST OF FIGURES .........................................................................................................................5
ABBREVIATIONS .........................................................................................................................6
1.
INTRODUCTION....................................................................................................................7
1.1
Purpose of the Statistical Analysis Plan.....................................................................7
1.2
Background ................................................................................................................7
1.3
Study Rationale ..........................................................................................................7
2.
STUDY OBJECTIVES ............................................................................................................8
2.1
Primary Objectives.....................................................................................................8
2.2
Secondary Objectives.................................................................................................8
2.2.1
Double-blind Acute Phase .......................................................................................8
2.2.2
Double-blind Maintenance Phase ............................................................................8
2.2.3
Safety .......................................................................................................................8
2.3
Exploratory Objectives...............................................................................................9
3.
STUDY DESIGN ...................................................................................................................10
3.1
General Description..................................................................................................10
3.2
Discussion of Study Design, Including the Choice of Control Groups ...................13
3.3
Method of Assigning Subjects to Treatment Groups...............................................13
3.4
Blinding the Treatment Assignment ........................................................................13
3.5
Determination of Sample Size..................................................................................14
4.
EFFICACY AND SAFETY VARIABLES............................................................................15
4.1
Schedule of Assessments .........................................................................................15
4.2
Efficacy Assessments...............................................................................................15
4.2.1
Modified Full UC-DAI Score................................................................................15
4.2.2
Partial UC-DAI Score............................................................................................16
4.3
Other Clinical Outcomes Assessments ....................................................................19
4.3.1
Daily Ulcerative Colitis Scale for Children and Caregivers (DUCS)....................19
4.3.2
Overall Current Health...........................................................................................19
4.3.3
Global Change in Health........................................................................................19
4.3.4
Pediatric Ulcerative Colitis Activity Index............................................................19
4.3.5
IMPACT III ...........................................................................................................20
4.4
Safety Assessments ..................................................................................................21
4.4.1
Medical and Medication History ...........................................................................21
4.4.2
Vital Signs..............................................................................................................22
4.4.3
Height and Weight .................................................................................................22


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4.4.4
Clinical Laboratory Evaluations ............................................................................22
4.4.5
Pregnancy Test.......................................................................................................23
4.4.6
Stool Assessments..................................................................................................24
4.4.7
Physical Examinations...........................................................................................24
4.4.8
Pharmacokinetic Assessments ...............................................................................25
5.
STATISTICAL ANALYSIS ..................................................................................................26
5.1
General Methodology...............................................................................................26
5.2
Subject Population Sets............................................................................................26
5.2.1
Screened Set...........................................................................................................26
5.2.2
Enrolled Set............................................................................................................26
5.2.3
Overall Randomized Analysis Set .........................................................................26
5.2.4
Overall Safety Analysis Set ...................................................................................26
5.2.5
Double-blind Acute Phase Safety Analysis Set.....................................................27
5.2.6
Open-label Acute Phase Safety Analysis Set.........................................................27
5.2.7
Double-blind Maintenance Phase Safety Analysis Set..........................................27
5.3
Subject Disposition ..................................................................................................27
5.4
Protocol Violations and Deviations..........................................................................27
5.5
Demographic and Baseline Characteristics..............................................................28
5.6
Extent of Exposure and Treatment Compliance.......................................................29
5.6.1
Exposure to Investigational Product......................................................................29
5.6.2
Measurement of Treatment Compliance................................................................29
5.7
Prior and Concomitant Medication ..........................................................................30
5.8
Analysis of Efficacy.................................................................................................30
5.8.1
Primary Efficacy Endpoints and Analysis .............................................................31
5.8.1.1
Double-blind Acute Phase......................................................................31
5.8.1.2
Double-blind Maintenance Phase...........................................................31
5.8.2
Secondary Efficacy Endpoints and Analysis .........................................................32
5.8.2.1
Double-blind Acute Phase......................................................................32
5.8.2.2
Double-blind Maintenance Phase...........................................................33
5.8.3
Other Efficacy Endpoint(s) and Analysis ..............................................................33
5.8.3.1
UC-DAI..................................................................................................33
5.8.3.2
PUCAI....................................................................................................34
5.8.3.3
IMPACT III............................................................................................34
5.8.3.4
DUCS .....................................................................................................34
5.8.4
Exploratory Efficacy Endpoint(s) and Analyses....................................................34
5.9
Analysis of Safety ....................................................................................................34
5.9.1
Adverse Events ......................................................................................................35
5.9.2
Clinical Laboratory Variables................................................................................37


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5.9.3
Vital Signs..............................................................................................................39
5.10
Analysis of Pharmacokinetic Data ...........................................................................40
6.
CHANGES TO ANALYSES SPECIFIED IN THE PROTOCOL ........................................41
7.
STATISTICAL/ANALYTIC ISSUES ...................................................................................42
7.1
Adjustment for Covariates .......................................................................................42
7.2
Handling of Dropouts or Missing Data....................................................................42
7.3
Interim Analysis and Data Monitoring.....................................................................42
7.4
Multicenter Studies ..................................................................................................43
7.5
Multiple Comparisons/Multiplicity..........................................................................43
7.6
Examination of Subgroups and Interactions ............................................................43
7.6.1
Weight Group.........................................................................................................43
7.6.2
Prior Response Status ............................................................................................43
7.7
Sensitivity Analyses .................................................................................................43
7.7.1
Sensitivity Analyses of the Primary Endpoint.......................................................43
8.
DATA HANDLING CONVENTIONS..................................................................................45
8.1
General Data Reporting Conventions ......................................................................45
8.2
Derived Efficacy Endpoints .....................................................................................45
8.3
Repeated or Unscheduled Assessments of Safety Parameters.................................46
8.4
Incomplete Date of Diagnosis..................................................................................46
8.5
Missing Date of Investigational Product..................................................................46
8.6
Missing Date Information for Prior or Concomitant Medications...........................46
8.6.1
Incomplete Start Date ............................................................................................46
8.6.2
Incomplete Stop Date.............................................................................................47
8.7
Missing Date Information for Adverse Events ........................................................48
8.7.1
Incomplete Start Date ............................................................................................48
8.7.2
Incomplete Stop Date.............................................................................................48
8.8
Missing Severity Assessment for Adverse Events...................................................48
8.9
Missing Relationship to Investigational Product for Adverse Events......................48
8.10
Character Values of Clinical Laboratory Variables .................................................48
9.
REFERENCES .......................................................................................................................50
10. TABLE OF CONTENTS FOR TABLES,FIGURES AND LISTINGS ................................51
11. SCHEDULE OF EVENTS.....................................................................................................67


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LIST OF TABLES
Table 1: 
Minimally Required Number of Subjects per Weight Group .......................11
Table 2:
Criteria for Potentially Clinically Important Laboratory Tests .....................38
Table 3:
Criteria for Potentially Clinically Significant Vital Signs.............................40
Table 4:
Examples for Coding of Special Character Values for Clinical 
Laboratory Variables.....................................................................................49
Table 5:
Double-blind Acute Phase.............................................................................68
Table 6:
Open-label Acute Phase ................................................................................72
Table 7:
Double-blind Maintenance Phase..................................................................74
LIST OF FIGURES
Figure 1:
Study Design Flow Chart ..............................................................................12


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ABBREVIATIONS
5-ASA
5-aminosalicylic acid
AE
adverse event
ATC
anatomical therapeutic class
BMI
body mass index
CMH
Cochran-Mantel-Haenszel
DUCS
Daily Ulcerative Colitis Scale
DMC
data monitoring committee
eCRF
electronic case report form
e-diary
electronic diary
FDA
Food and Drug Administration
FoTA
Final on Treatment Assessment
IRT
interactive response technology
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
MMX
Multi Matrix System
PCI
potentially clinically important
PGA
Physician’s Global Assessment
PRO
patient reported outcome
PUCAI
Pediatric Ulcerative Colitis Activity Index
SAE
serious adverse event
SAP
statistical analysis plan
SOC
system organ class
TEAE 
treatment-emergent adverse event
UC
ulcerative colitis
UC-DAI
Ulcerative Colitis Disease Activity Index
WHO-DRUG
World Health Organization Drug Dictionary


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1.
INTRODUCTION
1.1
Purpose of the Statistical Analysis Plan
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of efficacy and safety data as described in the final study protocol 
SPD476-319 Version 6.0 dated 10 Apr 2017.  Specifications for tables, figures, and listings 
are contained in a separate document.
1.2
Background
This is a phase 3, multicenter, randomized, double blind study to determine the safety and 
efficacy of Multi Matrix System (MMX) mesalamine/mesalazine in pediatric subjects (aged 
5-17 years) with mild to moderate ulcerative colitis (UC). This study is comprised of an 8-week 
Double-blind Acute Phase and a 26-week Double-blind Maintenance Phase. Each phase 
includes 2 arms, and subjects will be randomized to 1 of 2 doses (low or high) of MMX 
mesalamine/mesalazine (900-4800mg/day, given once daily) at the beginning of each phase.
Randomization will be in a 1:1 ratio stratified by body weight group. 
The data from this study will:

Aid in selection of appropriate doses in the pediatric population

Determine whether MMX mesalamine/mesalazine is safe and effective for use in children 
and adolescents (aged 5-17 years) with mild to moderate UC or who are in remission.
The study allows all subjects to receive active MMX mesalamine/mesalazine. The doses for the 
study were determined from pharmacokinetic modeling using data from the SPD476-112 study, 
a pharmacokinetic study in children and adolescents with mild to moderate UC.
1.3
Study Rationale
MMX mesalamine/mesalazine is approved for both the induction of remission in adult patients 
with mild to moderate UC and for maintenance of remission of UC. Currently, limited data are 
available on the safety and efficacy of MMX mesalamine/mesalazine in children and adolescents 
with UC.
This study, a PREA post approval commitment with FDA, is designed to determine the 
appropriate dosage of MMX mesalamine/mesalazine for once-daily dosing across a range of 
weight groups, in children and adolescents aged 5-17 years with mild to moderate UC or who are 
in remission.


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2.
STUDY OBJECTIVES
2.1
Primary Objectives
The primary objective of the Double-blind Acute Phase of the study is to assess clinical response 
to MMX mesalamine/mesalazine between a low and high dose in children and adolescents aged 
5-17 years with mild to moderate UC.
The primary objective of the Double-blind Maintenance Phase of the study is to assess clinical 
response to MMX mesalamine/mesalazine between a low and high dose in children and 
adolescents aged 5-17 years who are in remission.
2.2
Secondary Objectives
2.2.1
Double-blind Acute Phase

To assess clinical and endoscopic response to treatment with MMX mesalamine/mesalazine 
between a low and high dose in children and adolescents aged 5-17 years with mild to 
moderate UC in the Double-blind Acute Phase.

To assess changes in the Daily Ulcerative Colitis Scale (DUCS) for children and caregivers 
between a low and high dose of MMX mesalamine/mesalazine in children and adolescents 
aged 5-17 years with mild to moderate UC in the Double-blind Acute Phase.

To assess improvement in Pediatric Ulcerative Colitis Activity Index (PUCAI) score between 
a low and high dose of MMX mesalamine/mesalazine in children and adolescents aged 
5-17 years with mild to moderate UC in the Double-blind Acute Phase.
2.2.2
Double-blind Maintenance Phase

To assess clinical and endoscopic response to treatment with MMX mesalamine/mesalazine 
between a low and high dose in children and adolescents aged 5-17 years who are in 
remission in the Double-blind Maintenance Phase.

To assess changes in the DUCS for children and caregivers between a low and high dose of 
MMX mesalamine/mesalazine in children and adolescents aged 5-17 years who are in 
remission in the Double-blind Maintenance Phase.

To assess remission using the PUCAI score between a low and high dose of MMX 
mesalamine/mesalazine in children and adolescents aged 5-17 years who are in remission in 
the Double-blind Maintenance Phase.
2.2.3
Safety
To evaluate the safety and tolerability of a low and high dose of MMX mesalamine/mesalazine 
in children and adolescents aged 5-17 years with mild to moderate UC, in the Double-blind 
Acute Phase, the Open-label Acute Phase, and the Double-blind Maintenance Phase.




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3.
STUDY DESIGN
3.1
General Description
This study will be conducted in children and adolescents (aged 5-17 years) to collect data on the 
safety and efficacy of MMX mesalazine/mesalamine in this population. This study is a PREA 
post-approval commitment with the US FDA and is intended to provide estimates of clinical 
response for 2 doses (low and high) across a range of weight groups.
This study will enroll male and female children and adolescents aged 5-17 years. This is a 
prospective, parallel-group study with an 8-week Double-blind Acute Phase, and a 26-week 
Double-blind Maintenance Phase. More than 100 subjects will be screened, and up to 80 subjects 
will be enrolled in the Double-blind Acute Phase of the study. After agreement with FDA, the 
sample size for the Double-blind Acute Phase has been reduced to 53 subjects due to difficulties 
with recruitment.
More than 65 subjects will be screened (in addition to an expected 28 subjects who will enter the 
Double-blind Maintenance Phase from one of the Acute Phases) and at least 80 subjects will be 
enrolled in the Double-blind Maintenance Phase of the study.   
Each phase includes 2 treatment arms, and subjects will be randomized at the beginning of each 
phase to 1 of 2 doses (low and high dose) of MMX mesalamine/mesalazine (900-4800mg/day, 
given once daily), stratified by weight group. There is an additional 8-week, Open-label Acute 
Phase for subjects who do not achieve a clinical response or who have withdrawn from the 
Double-blind Acute Phase and have met certain criteria (see Figure 1). Clinical response is 
defined as partial Ulcerative Colitis Disease Activity Index (UC-DAI) ≤1 (with rectal 
bleeding=0 and stool frequency ≤1 and Physician’s Global Assessment [PGA] =0) at the end of 
the Double-blind Acute Phase.  In this Open-label Acute Phase, subjects are treated with the high 
dose of MMX mesalamine/mesalazine for their weight group.
Subjects with a clinical response after completion of treatment in either the Double-blind Acute 
Phase or the Open-label Acute Phase will be eligible to enter the Double-blind Maintenance 
Phase based on partial UC-DAI score (i.e., without additional endoscopy).
Subjects without a clinical response after completion of acute treatment in the Open-label Acute 
Phase must be withdrawn.
Subjects may enter the Double-blind Maintenance Phase directly following the Baseline Visit 
(Visit 2) if they have a partial UC-DAI ≤1 (with rectal bleeding=0 and stool frequency ≤1 and 
PGA=0) and with mucosal appearance (endoscopy score) = 0 or 1 at that visit.
MMX mesalamine/mesalazine is dosed once daily by mouth. The selection of doses in this study 
is based on an approximate average of 43mg/kg for the low dose and 85mg/kg for the high dose 
in the 3 lower weight groups (18 to 23kg, >23 to 35kg and >35 to 50kg).  These doses were 
selected based on standard of care dosing for other 5-ASA products in the pediatric population 
and pharmacokinetic dosing results.  The dosing for the highest weight group (>50 to 90kg) is 
based on adult UC experience.


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Minimum enrollment criteria have been agreed with FDA as follows, based on subject weight 
group:
Table 1: 
Minimally Required Number of Subjects per Weight Group
Weight Group
Low Dose
(mg/day)
High Dose
(mg/day)
Number of Subjects 
in Combined Low 
and High Dosea
18 to 23kg
900
1800
2
>23 to 35kg
1200
2400
12
>35 to 50kg
1800
3600
18
>50 to 90kg
2400
4800
36
a Randomization will be stratified by weight group with the aim of creating balance between the 2 dose groups within a weight 
group


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Figure 1:
Study Design Flow Chart
PGA=Physician’s Global Assessment; UC-DAI=Ulcerative Colitis Disease Activity Index.
a Subjects with partial UC-DAI ≥2 (with a combined rectal bleeding and stool frequency score ≥1 and PGA=1 or 2) and with 
mucosal appearance (endoscopy score)=2 or 3.
b Subjects with partial UC-DAI ≤1 (with rectal bleeding=0 and stool frequency ≤1 and PGA=0) and with mucosal appearance 
(endoscopy score)=0 or 1.
Notes: Solid boxes indicate study phases. Dashed ellipses indicate decision points. 
Subjects will initially be randomized into either the 8-week Double-blind Acute Phase or the 26-week Double-blind Maintenance 
Phase based on partial UC-DAI and mucosal appearance scores. Subjects who do not achieve a clinical response or who have 
withdrawn from the Double-blind Acute Phase after a minimum of 2 weeks and, in the investigator’s opinion, have not benefited 
from treatment in the Double-blind Acute Phase may enter the Open-label Phase. Subjects without a clinical response after 
completion of acute treatment in the Open-label Acute Phase must be withdrawn.


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3.2
Discussion of Study Design, Including the Choice of Control Groups
The inclusion of placebo and standard of care arms were considered in the design of this study. 
The use of placebo was considered not feasible given the alternative treatments currently 
available to children and adolescents with UC. As standard of care varies and there is no 
standard formulation or dose of 5-ASA licensed and approved across regions, a standard of 
care/comparator arm was not included.
3.3
Method of Assigning Subjects to Treatment Groups 
This study includes 2 double-blind phases with low- and high-dose MMX 
mesalamine/mesalazine.  The actual double-blind treatment given to individual subjects is 
determined by a randomization schedule stratified by weight group.  Randomization will be a 
1:1 ratio between low and high doses.
Subject numbers are assigned to all subjects as they consent to take part in the study.  Within 
each site (numbered uniquely within a protocol), the subject number is assigned to subjects 
according to the sequence of presentation for study participation.
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined.
Subjects eligible for either the Double-blind Acute or the Double-blind Maintenance Phase can 
be re-randomized if they initially failed randomization for the following reasons: incorrect use of 
IVRS, late or missing central laboratory or endoscopy results, or other reasons of this type as 
long as they meet inclusion and exclusion criteria. Re-randomization can only take place after 
consultation with the medical monitor.
Individual subject doses in the Double-blind Acute Phase are automatically assigned by the 
interactive response technology (IRT) based on subject weight group at the Baseline Visit 
(Visit 2).  If the subject is directly entering the Double-blind Maintenance Phase, individual 
doses are also automatically assigned by the IRT based on subject weight group at the Baseline 
Visit (Visit 2).
Individual subject open-label treatment is automatically assigned by the IRT and will be the high 
dose based on the subject’s weight group at Visit 3.2 (Week 8/Withdrawal of the Double-blind 
Acute Phase).
Individual subject double-blind doses for subjects being re-randomized to the Double-blind 
Maintenance Phase after completion of treatment at Visit 3.2 (Week 8 of the Double-blind Acute 
Phase) or Visit 4.2 (Week 8 of the Open-label Acute Phase) are automatically assigned by the 
IRT based on subject weight group at the time of re-randomization.
3.4
Blinding the Treatment Assignment
This study includes double-blind treatment in the Double-blind Acute Phase and Double-blind 
Maintenance Phase.  


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The actual double-blind treatment given to individual subjects is determined by a randomization 
schedule which will be automatically assigned by the interactive response technology (IRT).  
Placebo, which exactly matches the investigational product, will be used in the blister packs to 
provide the same number and size tablets for each of the doses within a weight group and 
maintain the blind between the low and high dose groups.
3.5
Determination of Sample Size
This will be an estimation study with no formal hypothesis testing; therefore, this study is not 
powered to detect differences between treatment groups. More than 100 subjects will be screened 
and up to 80 subjects will be enrolled in the Double-blind Acute Phase of the study. After 
agreement with FDA, the sample size for the Double-blind Acute Phase has been reduced to 
53 subjects due to difficulties with recruitment.
More than 65 subjects will be screened (in addition to an expected 28 subjects who will enter the 
Double-blind Maintenance Phase from one of the Acute Phases) and at least 80 subjects will be 
enrolled in the Double-blind Maintenance Phase of the study.
The sample size was chosen based on practical considerations and on agreement with the US 
FDA.


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4.
EFFICACY AND SAFETY VARIABLES
4.1
Schedule of Assessments 
Table 5, Table 6, and Table 7 in Section 11 present schematics of the study separately for each 
treatment phase.
4.2
Efficacy Assessments
4.2.1
Modified Full UC-DAI Score
The full UC-DAI is widely used to assess treatment efficacy in subjects with mild to moderate 
UC (Schroeder et al., 1987; Sutherland et al., 1987).  It consists of 4 individual parameters: stool 
frequency, rectal bleeding, endoscopy score (mucosal appearance), and PGA.  For the purpose of 
this study, the standard UC-DAI scale has been modified so that an endoscopy score of mild 
disease does not include friability; instead, friability will be scored as 2: moderate disease.
Please see a description of stool frequency, rectal bleeding and PGA in Section 4.2.2.
All 4 parameters will be assessed individually on a scale from 0-3; the maximum total modified 
full UC-DAI score is 12.0.  
Stool Frequency Score:

0 = Normal

1 = 1-2 more than normal/day

2 = 3-4 more than normal/day

3 = >4 more than normal day
Rectal bleeding (most severe bleeding of the day) Score:

0 = None

1 = Streaks of blood

2 = Obvious blood

3 = Mostly blood
Mucosal Appearance (endoscopy score):

0 = Normal (intact vascular pattern; no friability or granulation)

1 = Mild (erythema, decreased vascular pattern, minimal granularity)

2 = Moderate (marked erythema, granularity, friability, absent vascular pattern, bleeding 
with minimal trauma, no ulcerations)

3 = Severe (ulceration, spontaneous bleeding)
Physician’s Global Assessment:

0 = No active disease

1 = Mild disease

2 = Moderate disease

3 = Severe disease


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The modified full UC-DAI score will be calculated at Baseline (Visit 2), Week 8 of the 
Double-blind Acute Phase (Withdrawal) for subjects not entering into the Open-label Acute 
Phase, Week 8 of the Open-label Acute Phase (Withdrawal) for subjects who have not had 
endoscopy at the end of the Double-blind Acute Phase, and Week 26 of the Double-blind 
Maintenance Phase (Withdrawal) visits.  The total score will be calculated by summing the 
individual scores for the 4 parameters (endoscopy score will be based on the central reader’s 
score).  The site is not required to calculate the full UC-DAI; this will be calculated centrally 
using e-diary and eCRF data.
For determination of the modified full UC-DAI, the average of the symptom scores of the last 
available 3 days within the 5-day period immediately prior to study visits where endoscopic data 
are available, will be used.  No symptom data older than 5 days prior to the study visit will be 
used.  Data collected on days when bowel preparations have been administered or when 
endoscopy has been performed will be excluded.
An endoscopy must be performed and mucosal appearance scored within 21 days prior to the 
Screening Visit (Visit 1), during the Screening period or at the Baseline Visit (Visit 2) depending 
on the subject’s UC history and phase of the study into which they are entering.  All efforts 
should be made to perform endoscopy at Week 8 of the Double-blind Acute Phase (or Week 8 of 
the Open-label Acute Phase, as applicable), Week 26 of the Double-blind Maintenance Phase, or 
the subject’s withdrawal if different from these visits.
Endoscopies will be centrally read and scored for this study and endoscopic video or 
photographs must be provided to the central reader for each endoscopy performed.  Video 
images are preferred; however, photographic images will be accepted when video images are not 
of sufficient quality, as determined by the central reader during individual site image evaluation 
prior to enrollment at the site.  Further details of requirements for video and photographic images 
will be provided to study sites under separate cover by the central reader.  All endoscopies 
should be performed by the same investigator/endoscopist, if possible, to ensure consistency in 
endoscopy.
4.2.2
Partial UC-DAI Score
The partial UC-DAI score is based on the individual parameters of the modified full UC-DAI 
without the endoscopic component.  (Please see Section 4.2.1 for a description of the modified 
full UC-DAI.)  It includes stool frequency, rectal bleeding, and PGA only.  All 3 parameters will 
be assessed individually on a scale from 0-3; the maximum total partial UC-DAI score is 9.0.
Subjects’ symptoms (rectal bleeding and stool frequency) will be reported by the 
subjects/caregivers in the e-diary once a day before bedtime starting from the evening of the 
Screening Visit (Visit 1) through the Baseline Visit (Visit 2).  Subjects’ symptoms are completed 
once a day before bedtime for the 5 days immediately prior to Visits 3, 3.1, and 3.2 of the 
Double-blind Acute Phase, Visits 4, 4.1, 4.2 of the Open-label Acute Phase and Visits 5.1 and 
5.2 of the Double-blind Maintenance Phase.  Symptom data should also be reported as soon as a 
subject’s symptoms suggest that they might be experiencing an acute flare during the 
Double-blind Maintenance Phase, and they should contact the site to arrange for an unscheduled 
visit.  In this case, symptoms should be entered for 5 days immediately prior to the unscheduled 
visit, if possible.


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Stool frequency and rectal bleeding will be assessed on a scale from 0-3.  Scores will be based 
on 1 of 2 versions of e-diary questions.  One version is for children and adolescents aged 
11-17 years and the other is for caregivers of children aged 5-10 years.  Subject age at the 
beginning of their current study phase will determine which version of the e-diary will be 
completed for the entire phase; the version being completed will not change from caregiver to 
subject completion during a phase.  However, the version should change from caregiver 
completion to subject completion for the next phase, if applicable based on a subject’s age 
change. 
Questions and responses for children and adolescents aged 11-17 years:
How many more times did you poop than you normally do since you went to bed last night?
I didn’t poop more than I normally do
I pooped 1 or 2 more times than normal
I pooped 3 or 4 more times than normal 
I pooped 5 or more times than normal.
Did you have blood in your poop? 
I didn’t see any blood in my poop
I saw streaks of blood (a small amount) in my poop
I saw some blood (more than a small amount) in my poop
I saw mostly blood (a lot) in my poop.
Questions and responses for caregivers of children aged 5-10 years:
Based on what you observed, how many more times did your child have a bowel movement than 
they normally do since they went to bed last night?
They didn’t have more bowel movements than they normally do
They had 1 or 2 more bowel movements than normal
They had 3 or 4 more bowel movements than normal 
They had 5 or more bowel movements than normal
Based on what you observed, did your child have blood in their stool? 
I didn’t see any blood in my child’s stool
I saw streaks of blood (a small amount) in my child’s stool
I saw some blood (more than a small amount) in my child’s stool
I saw mostly blood (a lot) in my child’s stool.


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For determination of the partial UC-DAI, the average of the symptom scores of the last available 
3 days within the 5-day period immediately prior to the study visit will be used.  No symptom 
data older than 5 days prior to the study visit will be used.  Data collected on days when bowel 
preparations have been administered or when endoscopy has been performed will be excluded. 
Approximately 4 to 7 days prior to the Baseline Visit (Visit 2) and prior to each subsequent visit, 
it is recommended that site staff telephone the subject or the subject’s caregiver to remind them 
to enter UC-DAI symptoms (rectal bleeding and stool frequency) into the e-diary every night, 
even if the subject has no symptoms.  A missed day’s data may be entered until 12:00 hours the 
following day. 
A minimum of 1 score each for stool frequency and rectal bleeding must be available in order to 
randomize subjects into either the Double-blind Acute Phase or the Double-blind Maintenance 
Phase. If no data are available, the average value will be considered missing and the subject will 
be considered a screen failure.
Calculations of average stool frequency and rectal bleeding scores will proceed as follows:
If symptom scores from the last 3 days are available, average = (x1+x2+x3)/3; the average 
value should be rounded up to 1 decimal place:

For example: (0+1+0)/3 = 0.3333; value = 0.3; (1+0+1)/3=0.666666; value=0.7; 
(2+2+2)/3=2.0
If symptom scores from the last 2 days are available, average = (x1+x2)/2; the average 
value should be rounded up to 1 decimal place.
If symptom scores from only 1 day are available, average = (x1/1) = x1.
The PGA will be performed at all visits where the partial UC-DAI score is calculated by the 
study site, and is scored on a scale from 0-3, where 0=no active disease, 1=mild disease, 
2=moderate disease, and 3=severe disease.  The PGA should be performed by the same 
investigator at all visits, if possible, for consistency in evaluation.
Scoring of the PGA by the investigator should take into account the following parameters:
Rectal bleeding
Stool frequency and consistency
Night-time bowel movements
Abdominal pain
Impact to daily activities
Physical findings
Endoscopic findings (if endoscopy is performed).


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The PGA is to be recorded in source documentation and added to the average stool frequency 
and average rectal bleeding scores to calculate the partial UC-DAI score.  Sites should not 
perform rounding of partial UC-DAI scores.  The average stool frequency and rectal bleeding 
scores will be calculated and available to the investigator through a report from the e-diary 
provider.
4.3
Other Clinical Outcomes Assessments
4.3.1
Daily Ulcerative Colitis Scale for Children and Caregivers (DUCS)
Shire has developed an electronic daily sign and symptom diary, the DUCS. Two versions have 
been developed: 1 PRO to be self-completed by children aged 8-17 years and 1 ObsRO to be 
completed by caregivers of children aged 5-10 years. Both the PRO and ObsRO will be 
completed by children aged 8-10 years; however, the ObsRO will be used for the secondary 
endpoint analysis. The data obtained from the PRO in this age group will provide information for 
future use to determine if children/adolescents can reliably complete the PRO.
A separate SAP has been developed for DUCS.
4.3.2
Overall Current Health
An Overall Current Health item will be included in the e-diary. The Overall Current Health item 
has been tested in cognitive debriefing interviews with the DUCS.
4.3.3
Global Change in Health
The Global Change in Health item assesses the subject’s (aged 11-17 years) or caregiver’s (for 
children aged 5-10 years) perception of change in health since starting the study and will be 
administered via paper in this study. This item has been tested in cognitive debriefing interviews 
with the DUCS.
4.3.4
Pediatric Ulcerative Colitis Activity Index
The PUCAI is a physician-administered measure that focuses on 6 key signs and symptoms of 
UC and activity limitations (Turner et al., 2007). The PUCAI yields a total score ranging from 
0-85 with higher scores being worse. Recommended cut-off scores to differentiate disease 
activity are <10 (remission); 11-30 (mild); 31-64 (moderate) and >65 (severe) (Turner et al., 
2009). Evaluation of the construct validity of the PUCAI revealed that it was highly correlated 
with physician’s global assessment of disease activity and PUCAI scores were highly predictive 
of the need for escalating medical therapy (Turner et al., 2009). 
Only sites who have executed a sub-license with Shire for PUCAI use will be able to collect 
PUCAI data for the study.


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4.3.5
IMPACT III
The IMPACT questionnaire is a disease-specific health-related quality-of-life questionnaire 
developed for use in pediatric inflammatory bowel disease through a process of patient 
interviews and analysis of patient responses to an item-reduction questionnaire. This is a 
self-administered questionnaire, and data will be collected via paper in this study.
The IMPACT questionnaire has been studied to determine its feasibility, reliability, and validity. 
It was found to be a valid and reliable reflection of health-related quality of life of older children 
and adolescents with both UC and Crohn's disease (Otley et al., 2002).


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In this study, the IMPACT III will be used. This is the current version of the questionnaire, 
adapted from IMPACT II, which was developed in 2002. The original version of IMPACT was 
developed in 1999. IMPACT III contains 35 items in 6 domains. The Bowel Symptoms domain 
and the 4 matching symptom items between the IMPACT III and the DUCS will be used to 
evaluate convergent validity of the DUCS.
The IMPACT III questionnaire has 35 questions, each with 5 Likert responses that are scored 1, 
2, 3, 4, or 5, such that a higher score corresponds to a better quality of life.  The questions are 
grouped into 5 domains, each of which is scored by adding the scores of the questions therein.  
A total score is obtained by adding the scores of all of the questions.  The total score and the 
domain scores are computed only if the number of missing responses is no more than the 
maximum number in the table below.  
Domain Name (range of scores)
Question numbers 
(Maximum number of missing responses)
Body Image (3 – 15)
7, 15, 33
(0)
Bowel Symptoms (7 – 35)
1, 3, 10, 19, 21, 25, 31
(1)
Emotional Functioning (7 – 35)
4, 5, 11, 12, 13, 16, 29
(1)
Social Functioning (12 – 60)
8, 9, 14, 17, 18, 20, 23, 26, 27, 30, 34, 35
(1)
Systemic Symptoms (3 – 15)
6, 28, 32
(0)
Treatment/Interventions (3 - 15)
2, 22, 24
(0)
Total Score (35 – 175)
1 – 35
(3)
The IMPACT is valid for children and adolescents aged 9-17 years old and is completed by the 
subject. Children/adolescent aged 9-17 years who cannot complete the questionnaire 
independently, may be assisted by an adult who is not the child’s guardian or relative. Children 
who are 8 years old may complete the IMPACT with assistance from an adult who is not the 
child’s guardian or relative. Children under the age of 8 years old will not complete the 
IMPACT. 
4.4
Safety Assessments
4.4.1
Medical and Medication History
At screening, the subject’s medical history (including UC history) and concomitant medications 
will be reviewed.  Any new medical events or changes in intensity from the Screening Visit 
(Visit 1) noted during the study should be evaluated for report as an AE.  New medications or 
changes to existing medications must be added or updated as appropriate. Adverse Event 
Assessments


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At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (e.g., “Have you had any health problems since your last 
visit?”). Adverse events are collected from the time informed consent is signed.
In addition, any symptoms/conditions reported during assessments or collected via structured 
data collection will be evaluated by the investigator at each study visit to determine whether 
these are AEs.
4.4.2
Vital Signs
Vital signs include blood pressure and pulse. Blood pressure should be determined by cuff (using 
the same method, the same arm, and in the same position throughout the study). Any clinically 
significant deviations from the Baseline Visit (Visit 2) vital signs which are deemed clinically 
significant in the opinion of the investigator are to be recorded as an AE.
Measurements of vital signs (blood pressure and pulse) will be performed at all study visits. 
Blood pressure and pulse will be determined in the sitting position (after 5 minutes).
4.4.3
Height and Weight
Height will be assessed at the Screening Visit (Visit 1) and at the final visit of each phase.  
Weight will be assessed at the Screening Visit (Visit 1), the Baseline Visit (Visit 2) and at the 
final visit of each phase.  
4.4.4
Clinical Laboratory Evaluations
All clinical laboratory assays will be performed according to the laboratory’s normal procedures. 
Reference ranges are to be supplied by the laboratory and will be used to assess the clinical 
laboratory data for clinical significance and out-of-range pathological changes.
The investigator should assess out-of-range clinical laboratory values for clinical significance, 
indicating if the value(s) is/are not clinically significant or clinically significant. Abnormal 
clinical laboratory values, which are unexpected or not explained by the subject’s clinical 
condition, may, at the discretion of the investigator or sponsor, be repeated as soon as possible 
until confirmed, explained, or resolved.


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The following routine clinical laboratory assessments will be performed: 
Biochemistry
ALT
Albumin
Alkaline phosphatase
AST
Bilirubin, total
Bicarbonate
Calcium
Chloride
Cholesterol, total
Creatinine, enzymatic
CK (creatine kinase)
CRP standard (C-reactive protein)
Direct bilirubin
Gamma GT
Glucose random, serum
Lactate dehydrogenase
Magnesium
Phosphate
Potassium
Sodium
Total protein
Triglycerides
Urea (BUN, blood urea nitrogen)
Uric acid
Hematology
Complete blood count (RBC [red blood 
cells], WBC [white blood cells], platelets, 
HGB [hemoglobin])
HCT (hematocrit)
White blood cell differential
Urinalysis
pH
Specific gravity
Protein
Glucose
Ketones
Bilirubin
Blood
Microscopic examination will be conducted if protein and/or blood is/are detected during 
urinalysis. The microscopic examination will consist of red blood cells, white blood cells, casts, 
and bacteria.
4.4.5
Pregnancy Test
A serum β-HCG pregnancy test is performed for all females of childbearing potential at the 
following visits as applicable to the subject’s participation in the study:

Screening Visit (Visit 1)

Double-blind Acute Phase: Week 8 (Visit 3.2)

Open-label Acute Phase: Week 8 (Visit 4.2)

Double-blind Maintenance Phase: Week 26 (Visit 5.2)

If pregnancy is suspected

On withdrawal of  the  subject from the study




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4.4.8
Pharmacokinetic Assessments
Blood samples will be collected at the times specified in Table 5, Table 6, and Table 7 to allow 
measurement of plasma concentrations of 5-ASA and its major metabolite Ac-5-ASA.  
Pharmacokinetic sampling will occur only at participating sites that have been appropriately 
assessed and qualified for pharmacokinetic sampling.


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5.
STATISTICAL ANALYSIS
5.1
General Methodology
All statistical analyses will be performed using SAS® Version 9.2 or higher (SAS Institute, 
Cary, North Carolina, USA).
Unless otherwise specified, summary tabulations using the Double-blind Acute Phase and 
Double-blind Maintenance Phase Safety Analysis Sets will be presented by treatment arm and 
overall.  Summary tabulations using the Open-label Acute Phase Safety Analysis Set will be 
presented by high-dose only. Summary tabulations using the Overall will be presented by overall 
only.
For categorical variables, the number and percentage of subjects within each category (with a 
category for missing data as needed) of the parameter will be presented. For continuous 
variables, the number of subjects, mean, median, standard deviation (SD), Q1, Q3, minimum, 
and maximum values will be presented. 
This is an estimation study intended to provide estimates of clinical response for 2 doses (low 
and high) across a range of weight groups and not powered to detect differences between 
treatment groups.  P-values will be presented as descriptive statistics.
All statistical tests will be 2-sided hypothesis tests performed at the 5% level of significance for 
main effects.  All confidence intervals will be 2-sided 95% confidence intervals, unless stated 
otherwise.
5.2
Subject Population Sets
Note that as the efficacy analysis sets are identical to the safety sets for this study, only one set of 
definitions will be used.  All efficacy analyses will be based on the Safety Analysis Sets.
5.2.1
Screened Set
The Screened Set will consist of all subjects who have signed an informed consent.
5.2.2
Enrolled Set
The enrolled Set will consist of all subjects who have signed informed consent and also passed 
inclusion/exclusion criteria.
5.2.3
Overall Randomized Analysis Set
The Overall Randomized Analysis Set will consist of randomized subjects.
5.2.4
Overall Safety Analysis Set
The Overall Safety Analysis Set will consist of randomized subjects who have taken at least 
1 dose of investigational product.


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5.2.5
Double-blind Acute Phase Safety Analysis Set
The Double-blind Acute Phase Safety Analysis Set will consist of randomized subjects who have 
taken at least 1 dose of investigational product during the Double-blind Acute Phase.
5.2.6
Open-label Acute Phase Safety Analysis Set
The Open-label Acute Phase Safety Analysis Set will consist of all subjects who have taken at 
least 1 dose of investigational product during the Open-label Acute Phase.
5.2.7
Double-blind Maintenance Phase Safety Analysis Set
The Double-blind Maintenance Phase Safety Analysis Set will consist of randomized subjects 
who have taken at least 1 dose of investigational product during the Double-blind Maintenance 
Phase. 
5.3
Subject Disposition
A listing of all Screen Failures (i.e., subjects who were screened but not randomized) will be 
presented along with reasons for screen fail and details of any adverse events (AEs).
The number of subjects included in each analysis set (i.e., Screened Set, Enrolled Set, Overall 
Randomized Analysis Set, Overall Safety Analysis Set, Double-blind Acute Phase Safety 
Analysis Set, Open-label Acute Phase Safety Analysis Set, and Double-blind Maintenance Phase 
Safety Analysis Set) will be summarized as a whole.  For the Double-blind Maintenance Phase 
Safety Analysis Set, this will also include the subjects who entered directly, and subjects who 
entered via the Acute Phase (Double-blind/Open-label) as well as the total.
For Double-blind Acute Phase and Double-blind Maintenance Phase Safety Analysis Sets, the 
number and percentage of subjects who completed, and discontinued from the phase will be 
presented by treatment arm and overall. For the Open-label Acute Phase Safety Analysis Set, the 
number and percentage of subjects who completed, and discontinued from the phase will be 
presented by high dose only. The Primary reasons for discontinuation as recorded on the 
termination page of the electronic case report form (eCRF) will also be summarized (number and 
percentage) by treatment arm, separately for each phase. All subjects who discontinued will be 
listed by discontinuation reason, separately for each phase.
The number of subjects enrolled, randomized, received at least 1 dose of investigational product 
and completed will be tabulated by site and country for the Overall Randomized Analysis Set.  In 
addition, the duration of enrollment in days, will be summarized for each site, country, and 
overall.  Duration of enrollment will be calculated as (last date of contact for any subject at that 
site - the first date of informed consent for any subject at that site + 1).
5.4
Protocol Violations and Deviations
Protocol major/minor deviations will be recorded by the site separately from the clinical 
database.  The Shire study team will review and classify all protocol deviations and violations 
into categories before database lock.


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Protocol deviations will be summarized by site for Overall Safety Analysis Set and Open-Label 
Acute Phase Safety Analysis Set. Protocol deviations will also be summarized by site and 
treatment arm for the Double-blind Acute Phase Safety Analysis Set and the Double-blind 
Maintenance Phase Safety Analysis Set separately. Protocol major/minor deviations will be also 
listed.
5.5
Demographic and Baseline Characteristics
Descriptive summaries of demographic and baseline characteristics will be presented separately 
for each Safety Analysis Set (Overall, Double-blind Acute Phase, Open-label Acute Phase and 
Double-blind Maintenance Phase).  For the Double-blind Acute Phase and Double-blind 
Maintenance Phase Safety Analysis Sets, summaries will be presented by treatment arm and 
overall. For the Overall Safety Analysis Set, summaries will be presented by overall, and for the 
Open-label Acute Phase Safety Analysis Set, summaries will be presented for high-dose only.
Demographic characteristics include age, age group (5-10 years and 11-17 years), sex, ethnicity, 
and race. Baseline characteristics include weight, weight group (18 to 23kg, >23 to 35kg, 
>35 to 50kg and >50 to 90kg), height, and body mass index (BMI). Height will be presented 
in cm and weight will be presented in kg.  Any height measurements recorded in the CRF in 
inches will be multiplied by 2.54 to convert to cm.  Body mass index will be presented in kg/m2.
Ulcerative colitis history will be presented separately for each Safety Analysis Set (Overall, 
Double-blind Acute Phase, Open-label Acute Phase, and Double-blind Maintenance Phase).  For 
the Double-blind Acute Phase and Double-blind Maintenance Phase Safety Analysis Sets, 
summaries will be presented by treatment arm and overall. For the Overall Safety Analysis Set, 
summaries will be presented overall only, and for the Open-label Acute Phase, summaries will 
be presented for high-dose only.
The following parameters will be summarized:

Time (in months) since diagnosis ([screening date - diagnosis date] +1 / 30)

Method of diagnosis

Diagnosis state (i.e., is the subject newly diagnosed) 
For subjects who are not newly diagnosed:

Number of acute episodes of UC in the last year 

Number of acute episodes of UC since diagnosis 

Typical duration of past acute episodes (days [where this is recorded in weeks the value 
will be multiplied by 7]) 

Time (in days) since current acute episode of UC ([screening date - onset date] +1)

Full extent of disease measured from anal margin (cm) at the time of the most recent 
endoscopy

The classification of the extent of disease at the most recent endoscopy

Subjects with rectal involvement

Subjects with extra-intestinal manifestations

Subjects with any history of significant GI surgery
Medical history will be listed.


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5.6
Extent of Exposure and Treatment Compliance
For the Double-blind Acute and Double-blind Maintenance Phase, summaries will be presented 
by treatment arm and overall.  For the Open-label Acute Phase, summaries will be presented by 
treatment arm only.
5.6.1
Exposure to Investigational Product 
Exposure to investigational product will be summarized separately for each of the three Safety 
Analysis Sets (Double-blind Acute Phase, Open-label Acute Phase and Double-blind 
Maintenance Phase).  Summary statistics (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) for the duration of treatment exposure will also be presented.
Exposure will be summarized in terms of total dose, average daily dose, and length of exposure 
for each phase, calculated for each subject as:

Total Dose (mg) = sum of doses within phase of interest

Average Daily Dose (mg/day) = Total Dose / total days of dosing within phase of interest

Length of Exposure (weeks) = (Date of last dose within phase of interest – date of first 
dose within phase of interest + 1) / 7
Additionally, to examine subject-level exposure across study phases, these parameters will be 
listed by subject and phase.
5.6.2
Measurement of Treatment Compliance
Summaries of compliance will be produced for each of the three Safety Analysis Sets 
(Double-blind Acute Phase, Open-label Acute Phase and Double-blind Maintenance Phase).
Frequencies and percentages of subjects will be presented for the following categories:  <80%, 
80-120%, and >120%.  Any treatment compliance calculations conducted at the site will be used 
for study management purposes.  Therefore, those values will not be reconciled with values 
calculated during data analysis. Summary statistics (n, mean, SD, median, Q1, Q3, minimum, 
maximum) will also be presented.
Compliance is calculated for each phase and defined as: 
%
100
x 
Day
Per 
Tablets
of
Number 
 x 
1]
Dose
First 
of
Date
  -
  
Dose
Last 
of
[Date
returned
 tablets
of
Number 
Overall
  -
  
dispensed
 tablets
of
Number 
Overall

The number of tablets per day is 4 for subjects in the weight groups of 18 to 23kg, >23 to 
35kg, and >50 to 90kg regardless of treatment arm or phases.  The number of tablets per day 
is 6 for subjects in the >35 to 50kg weight group regardless of treatment arm or phases.
Additionally, to examine subject-level compliance across study phases, these parameters will be 
listed by subject and phase.


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5.7
Prior and Concomitant Medication 
World Health Organization Drug Dictionary (WHO-DRUG) 2013SEP01 (or newer) and the 
Anatomical Therapeutic Chemical (ATC) classification system will be used to classify prior and 
concomitant medications by therapeutic class.  
Prior medication is defined as any medication with the start date prior to the date of the first dose 
of investigational product.  Prior treatment given for the subject’s UC was recorded for the year 
prior to the Screening Visit, where available. All other prior treatment, including but not limited 
to herbal treatments and vitamins, received within 21 days of the date of first dose of 
investigational product was recorded.
Concomitant medication is defined as any medication with a start date prior to the date of the 
first dose of investigational product and continuing after the first dose of investigational product 
or with a start date between the dates of the first dose of investigational product and the end of 
the follow-up period, inclusive.  Any medication with a start date after the date of the end of the 
follow-up period will not be considered a concomitant medication.
Both prior and concomitant medication usage will be summarized by the number and proportion 
of subjects receiving each medication within each therapeutic class and preferred term.  
Medications can be counted both as prior and concomitant medication.  Multiple medication 
usage by a subject in the same category will be counted only once.
Separate summaries for both prior and concomitant medication usage will be produced for both 
the Double-blind Acute and Double-blind Maintenance Phase Safety Analysis Sets by treatment 
arm and overall.  For the Overall Safety Analysis Set, summaries for both prior and concomitant 
medication usage will be presented overall only. For the Open-label Acute Phase Safety Set, 
summaries for concomitant medication usage will be presented by high-dose.
All prior and concomitant medication will be listed.
5.8
Analysis of Efficacy
All efficacy analyses will be based on the Safety Analysis Set specific to the study phase.  
Baseline is defined as the last observation prior to first dose of investigational product in the 
study.  The Double-blind Acute Phase Week 8/Withdrawal visit (Visit 3.2) is treated as the 
Open-label Acute Phase Week 0 for subjects continuing into the Open-label Acute Phase from 
this visit.  The Double-blind Acute Phase Week 8/Withdrawal visit (Visit 3.2) is treated as the 
Double-blind Maintenance Phase Week 0 for subjects continuing into the Double-blind 
Maintenance Phase from this visit.  The Open-label Acute Phase Week 8/Withdrawal visit 
(Visit 4.2) is treated as the Double-blind Maintenance Phase Week 0 for subjects continuing into 
the Double-blind Maintenance Phase from this visit.  For subjects who enter the Double-blind 
Maintenance Phase directly, the Baseline Visit (Visit 2) is treated as the Double-blind 
Maintenance Phase Week 0.


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The final on treatment assessment (FoTA) for the Double-blind Acute phase is defined as data 
from the Double-blind Acute phase Week 8, or early withdrawal visit if subject withdrew prior to 
Week 8. The FoTA for the Open-label Acute phase is defined as data from the Open-label Acute 
phase Week 8, or early withdrawal visit if subject withdrew prior to Week 8. The FoTA for the 
Double-blind Maintenance phase is defined as data from the Double-blind Maintenance phase
Week 26, or early withdrawal visit if subject withdrew prior to Week 26.
Details of the derivation of the composite endpoints (partial and full UC-DAI scores) are 
included in Section 8.2.
5.8.1
Primary Efficacy Endpoints and Analysis 
The primary endpoints for this study are defined separately for both the Double-blind Acute 
Phase and Double-blind Maintenance Phases and will be conducted using the appropriate Safety 
Analysis Set for the phase:
5.8.1.1
Double-blind Acute Phase 
The primary efficacy endpoint for the Double-blind Acute Phase is defined as the proportion of 
subjects with a clinical response (defined as partial UC-DAI≤1 with rectal bleeding=0, stool 
frequency ≤1, and PGA=0) at Week 8.

Subjects with missing data at Week 8 will be assumed not to have had a clinical response.  
The primary efficacy endpoint will be compared between treatment arms using a 
continuity corrected chi-squared test on the Double-blind Acute Phase Safety Analysis 
Set. If any of the expected cell counts are very low (i.e., less than 5), then Fisher’s Exact 
Test will be used as an alternative analysis method. 

The null hypothesis to be tested is that there is no difference in the proportion of subjects 
with a clinical response at Week 8 between low and high doses of MMX 
mesalamine/mesalazine.

The number (n, %) of subjects with a clinical response at Week 8 and the difference 
between treatment arms, together with the 95% CI (2-sided), and associated p-value will 
be presented. The odds ratio comparing the two treatments, together with the 95% CI 
(2-sided) will also be presented.
5.8.1.2
Double-blind Maintenance Phase 
The primary efficacy endpoint for the Double-blind Maintenance Phase is defined as the 
proportion of subjects who have maintained a clinical response (defined as partial UC-DAI≤1 
with rectal bleeding=0 and stool frequency ≤1 and PGA=0) at Week 26.

Subjects with missing data at Week 26 will be assumed not to have had a clinical 
response.  The primary efficacy endpoint will be compared between treatment arms using 
a Cochran-Mantel-Haenszel (CMH) test stratifying for 3 levels of Week 8 responder 
status (entered Maintenance Phase directly, responder at Week 8 of the Double-blind 
Acute Phase, or responder at Week 8 of the Open-label Acute Phase) on the Double-blind 
Maintenance Phase Safety Analysis Set.


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
The null hypothesis to be tested is that there is no difference in the proportion of subjects 
with a clinical response at Week 26 between low and high doses of MMX 
mesalamine/mesalazine.

The number (n, %) of subjects with a clinical response at Week 26 and the difference 
between treatment arms, together with the 95% CI (2-sided), and associated p-value will 
be presented. The odds ratio comparing the two treatments, together with the 95% CI 
(2-sided) will also be presented.
5.8.2
Secondary Efficacy Endpoints and Analysis 
The secondary endpoints for this study are defined separately for both the Double-blind Acute 
and Double-blind Maintenance Phases and will be conducted using the appropriate Safety 
Analysis Set for the phase.  
5.8.2.1
Double-blind Acute Phase 

The proportion of subjects with a clinical and endoscopic response at Week 8, defined as 
UC-DAI ≤2 with rectal bleeding=0 and stool frequency ≤1 and PGA=0, and with mucosal 
healing (endoscopy score ≤1) based on central reading. In addition, there must be at least a 
1-point reduction in endoscopy score from baseline. This endpoint will be compared between 
treatment arms using a continuity corrected chi-squared test. If any of the expected cell 
counts are very low (i.e., less than 5), then Fisher’s Exact Test will be used as an alternative 
analysis method. Subjects with missing data at Week 8 will be assumed not to have had a
clinical response. Subjects who completed week 8 but who did not have central reading 
endoscopies at both baseline and week 8 will be excluded.

The proportion of subjects with a clinical and endoscopic response at Week 8, defined as 
UC-DAI ≤2 with rectal bleeding=0 and stool frequency ≤1 and PGA=0, and with mucosal 
healing (endoscopy score ≤1) based on local reading. In addition, there must be at least a 
1-point reduction in endoscopy score from baseline. This endpoint will be compared between 
treatment arms using a continuity corrected chi-squared test. If any of the expected cell 
counts are very low (i.e., less than 5), then Fisher’s Exact Test will be used as an alternative 
analysis method. Subjects with missing data at Week 8 will be assumed to be treatment 
failures.  Subjects with missing data at Week 8 will be assumed not to have had a clinical 
response.  Subjects who completed week 8 but who did not have local reading endoscopies at 
both baseline and week 8 will be excluded.

The change in the DUCS score from baseline to Week 8 of the Double-blind Acute Phase.  
This endpoint will be compared between treatment arms using an analysis of covariance
(ANCOVA), including treatment arm as a factor and the baseline DUCS score as a covariate 
in the model.

The percentage of subjects with an improvement (change of ≥20 points) in PUCAI score 
from baseline to Week 8 of the Double-blind Acute Phase. This endpoint will be compared 
between treatment arms using a continuity corrected chi-squared test. If any of the expected 
cell counts are very low (i.e., less than 5), then Fisher’s Exact Test will be used as an 
alternative analysis method. Subjects with missing data at Week 8 will be assumed not to 
have had a clinical response.  


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5.8.2.2
Double-blind Maintenance Phase 

The proportion of subjects who have maintained a clinical and endoscopic response at 
Week 26, defined as UC-DAI ≤2 with rectal bleeding=0 and stool frequency ≤1 and PGA=0 
and with mucosal healing (endoscopy score ≤1) based on central reading.  This endpoint will 
be compared between treatment arms using a CMH test stratifying by Week 8 responder 
status Subjects with missing data at Week 26 will be assumed not to have had a clinical 
response.  If there are an insufficient number of subjects with central reading endoscopy data, 
then the CMH test will not be performed.  The number and percentage of subjects with 
clinical and endoscopic response – based on central response will be presented by treatment 
arm.

The proportion of subjects who have maintained a clinical and endoscopic response at 
Week 26, defined as UC-DAI ≤2 with rectal bleeding=0 and stool frequency ≤1 and PGA=0, 
and with mucosal healing (endoscopy score ≤1) based on local reading.  This endpoint will 
be compared between treatment arms using a CMH test stratifying by Week 8 responder 
status.  Subjects with missing data at Week 26 will be assumed not to have had a clinical 
response.   If there are an insufficient number of subjects with central reading endoscopy 
data, then the CMH test will not be performed.  The number and percentage of subjects with 
clinical and endoscopic response – based on local response will be presented by treatment 
arm.

The change in the DUCS score from Double-blind Maintenance Phase Week 0 to Week 26.  
This endpoint will be compared between treatment arms using an analysis of covariance, 
including treatment arm as a factor, the DUCS score at Double-blind Maintenance Phase 
Week 0 and Week 8 responder status as covariates in the model.

The percentage of subjects in remission (PUCAI <10) at Double-blind Maintenance Phase 
Week 26.  This endpoint will be compared between treatment arms using a CMH test 
stratifying by Week 8 responder status. Subjects with missing data at Week 26 will be 
assumed not to have had a clinical response. 
5.8.3
Other Efficacy Endpoint(s) and Analysis 
Other efficacy endpoints will be summarized by study phase (Double-blind Acute Phase, 
Open-label Acute Phase, and Double-blind Maintenance Phase) using the appropriate Safety 
Analysis Set for that phase.
5.8.3.1
UC-DAI 

The partial UC-DAI (continuous version, calculated as the sum of symptoms plus PGA 
score) and the full UC-DAI (continuous version, calculated as the sum of partial UC-DAI 
plus endoscopy) will be summarized by visit and treatment arm (as applicable) for each study 
phase. These tables will include both continuous and categorical summaries.  Separate 
summaries will be produced for the full UC-DAI using endoscopy results from central and 
local readings.

The components of the UC-DAI (average stool frequency score, average rectal bleeding 
score, PGA score and endoscopy score) will be summarized individually as continuous and 
categorical variables by visit and treatment arm (as applicable) for each study phase. 




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Baseline is defined as the last observation prior to first dose of investigational product in the 
study.  If an assessment occurs on same day as the first dose of investigational product, the 
assessment will be considered the Baseline assessment. The Double-blind Acute Phase 
Week 8/Withdrawal visit (Visit 3.2) is treated as the Open-label Acute Phase Week 0 for subjects 
continuing into the Open-label Acute Phase from this visit.  The Double-blind Acute Phase 
Week 8/Withdrawal visit (Visit 3.2) is treated as the Double-blind Maintenance Phase Week 0 
for subjects continuing into the Double-blind Maintenance Phase from this visit.  The Open-label 
Acute Phase Week 8/Withdrawal visit (Visit 4.2) is treated as the Double-blind Maintenance 
Phase Week 0 for subjects continuing into the Double-blind Maintenance Phase from this visit.  
For subjects who enter the Double-blind Maintenance Phase directly, the Baseline Visit (Visit 2) 
is treated as the Double-blind Maintenance Phase Week 0.
Safety variables include AEs, clinical laboratory variables and vital signs variables.  For each 
safety variable, the last value collected prior to the first dose of investigational product (during 
phase of interest) will be used as baseline/Week 0 for the analyses of that safety variable.  A 
Final on-Treatment Assessment (FoTA) will be defined as the last valid assessment obtained 
after baseline/Week 0 and whilst on investigational product.
5.9.1
Adverse Events
Adverse events will be coded using Version 16.1 (or newer) of Medical Dictionary for 
Regulatory Activities (MedDRA).  The number and percentage of subjects with an event, as well 
as the number of events will be reported for each summary.  
An AE (classified by preferred term) that occurs during the study will be considered a 
treatment-emergent AE (TEAE) if it has a start date on or after the first dose of investigational 
product or if it has a start date before the date of the first dose of investigational product, but 
increases in severity on or after the date of the first dose of investigational product.  If more than 
1 AE with the same preferred term is reported before the date of the first dose of investigational 
product, then the AE with the greatest severity will be used as the benchmark for comparison to 
the AEs occurring during the study under the preferred term.  An AE that occurs more than 
7 days after the date of the last dose of investigational product of that phase will not be counted 
as a TEAE.
An overall summary of the number of subjects with TEAEs and number of TEAEs will be 
presented overall for the Overall Safety Analysis Set, an overall summary of the number of 
subjects with TEAEs and number of TEAEs will be presented for High-dose MMX only for 
Open Label Acute Phase Safety Analysis Set, and by treatment group and overall for the 
Double-blind Acute and Double-blind Maintenance Phase Safety Analysis Sets. The summary 
will include the number and percentage of subjects with any TEAEs, serious TEAEs, TEAEs 
related to investigational product, TEAEs leading to discontinuation of investigational product
and TEAEs leading to death.
The number and percentage of subjects reporting TEAEs, as well as the number of events, will 
be tabulated by system organ class (SOC) and preferred term for Overall Safety Analysis set, the 
Double-blind Acute and Double-blind Maintenance Phase Safety Analysis Sets, and also for 
Open-label Acute Phase Safety Analysis Set. 


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The number and percentage of subjects reporting TEAEs will also be tabulated by SOC, 
preferred term, and maximum severity for Overall Safety Analysis set, Double-blind Acute and 
Double-blind Maintenance Phase Safety Analysis Sets, and also for Open-label Acute Phase 
Safety Analysis Set. 
Treatment-emergent adverse events considered related to investigational product will also be 
summarized by SOC and preferred term for Overall Safety Analysis set, Double-blind Acute and 
Double-blind Maintenance Phase Safety Analysis Sets, and also for Open-label Acute Phase 
Safety Analysis Set.
If more than 1 AE occurs with the same preferred term for the same subject, then the subject will 
be counted only once for that preferred term using the most severe and most related occurrence 
for the summarization by severity and by relationship to investigational product.
The incidence of frequently occurring TEAEs (5% of subjects in any treatment arm) will be 
summarized by preferred term for Overall Safety Analysis set, the Double-blind Acute and 
Double-blind Maintenance Phase Safety Analysis Sets, and also for Open-label Acute Phase 
Safety Analysis Set. 
TEAEs related to investigational product, serious TEAEs, TEAEs leading to discontinuation of 
investigational product, and serious TEAEs leading to death will be summarized by SOC and 
preferred term.
Treatment-emergent adverse events of special interest (including renal toxicity, hepatic toxicity, 
pericarditis, myocarditis, pancreatitis, gastritis, and cholecystitis) will also be summarized by 
SOC and preferred term for Overall Safety Analysis set, Double-blind Acute and Double-blind 
Maintenance Phase Safety Analysis Sets, and also for Open-label Acute Phase Safety Analysis 
Set. 
Renal Toxicity

Acute renal failure - (SMQ- Broad)

Chronic kidney disease – (SMQ- Broad)
Hepatic Toxicity

Drug related hepatic disorders- comprehensive search – (SMQ)  

Cholestasis and jaundice of hepatic origin (SMQ)

Drug related hepatic disorders – severe events only (SMQ)

Liver related investigations, signs and symptoms (SMQ)

Liver related coagulation and bleeding disturbances (SMQ)
Pericarditis

Pericarditis (PT)

Pleuropericarditis (PT)


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Myocarditis

Myocarditis (PT)

Allergic Myocarditis (PT)

Eosinophilic myocarditis (PT)
Pancreatitis

Acute pancreatitis (SMQ)
Gastritis

Gastrointestinal nonspecific inflammation (SMQ)

Gastrointestinal nonspecific dysfunction (SMQ)
Cholecystitis

Cholecystitis (PT)

Cholecystitis acute (PT)

Cholecystitis chronic (PT)

Cholecystectomy (PT)

Cholecystocholangitis (PT)
Subject listings will be presented for all deaths, serious AEs (SAEs), and subjects withdrawn due 
to AEs.
5.9.2
Clinical Laboratory Variables 
Descriptive statistics for clinical laboratory values (in SI units) and changes from baseline at 
each assessment time point as well as shift tables from baseline/week 0 to each visit for 
quantitative variables will be presented for the following clinical Hematology and Biochemistry 
laboratory variables (Note: Urinalysis is only collected at screening and will be listed but not 
summarized) for Double-blind Acute and Double-blind Maintenance Phase Safety Analysis Sets, 
and also for Open-label Acute Phase Safety Analysis Set .
Hematology
Complete blood count (RBC [red blood cells], WBC [white blood cells], 
platelets, HGB [hemoglobin]), HCT (hematocrit), white blood cell differential
Biochemistry
ALT, albumin, alkaline phosphatase, AST, bilirubin (total), bicarbonate, 
calcium, chloride, cholesterol (total), creatinine (enzymatic), CK (creatine 
kinase), CRP standard (C-reactive protein), direct bilirubin, gamma glutamyl 
transpeptidase (GGT), glucose random (serum), lactate dehydrogenase, 
magnesium, phosphate, potassium, sodium, total protein, triglycerides, urea 
(BUN, blood urea nitrogen), uric acid
Urinalysis
Bilirubin, blood, glucose, ketones, pH, protein, specific gravity
Clinical laboratory test values are potentially clinically important (PCI) if they meet either the 
low or high PCI criteria listed in Table 2.  The number and percentage of subjects with 
post-baseline/Week 0 PCI values during phase of interest will be tabulated.  The percentages will 
be calculated relative to the number of subjects with available baseline/Week 0 values and at 
least 1 post-baseline/Week 0 assessment during phase of interest.  


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The numerator is the total number of subjects with at least 1 post-baseline/Week 0 PCI value 
during phase of interest.  A supportive listing of subjects with post-baseline PCI values will be 
provided including the subject number, site, baseline/Week 0, and post-baseline/Week 0 values.
Table 2:
Criteria for Potentially Clinically Important Laboratory Tests
Parameter
SI Unit
Lower Limit
Higher Limit
Biochemistry
Sodium
mmol/L
<130 
>150 
Potassium
mmol/L
<3.0
>5.5
Glucose
mmol/L
<3.1
>8.6
Blood Urea Nitrogen
mmol/L
-
>1.5 x ULN
Creatinine
µmol/L
-
>1.5 x ULN
Calcium
mmol/L
<2.20 (2-11 yrs)
<2.10 (12-17 yrs)
<2.00 (>17 yrs)
>2.82 (2-11 yrs)
>2.67 (12-17 yrs)
>2.87 (>17 yrs)
Total Protein
g/L
<54
>86
Albumin 
g/L
<33 (5-14 yrs)
<33 (15-17  yrs, F)
<30 (15-17 yrs, M)
<30 (>17 yrs)
-
Aspartate Transaminase (AST)
U/L
-
>1.5 x ULN
Alanine Transaminase (ALT)
U/L
-
>1.5 x ULN
Gamma Glutamyl Transferase 
(GGT)
U/L
-
>1.5 x ULN
Alkaline Phosphatase
U/L
-
>1.5 x ULN
Total Bilirubin
µmol/L
-
>1.5 x ULN
Bicarbonate
mmol/L
<16
>30
Chloride
mmol/L
<90
>115
Uric acid
µmol/L
-
>532 (F)
>591 (M)
Phosphate
mmol/L
<1.01 (3-9 yrs)
<1.04 (10-15 yrs)
<0.75 (>15 yrs)
>2.06 (3-9 yrs)
>1.93 (10-15 yrs)
>1.61 (>15 yrs)
Triglycerides
U/L
-
>2.5 x ULN
Lactate dehydrogenase (LDH)
U/L
-
>2.5 x ULN
Creatine kinase
U/L
-
>1.5 x ULN
Magnesium
mmol/L
<0.74
-


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Table 2:
Criteria for Potentially Clinically Important Laboratory Tests
Parameter
SI Unit
Lower Limit
Higher Limit
Cholesterol
mmol/L
-
>7.77
Hematology
White Blood Cell Count – Total 
(WBC)
109/L
<4.10 (3-4 yrs)
<3.60 (5-6 yrs)
<3.10 (7-8 yrs)
<3.00 (>8 yrs)
>19.20 (3-4 yrs)
>18.00 (5-6 yrs)
>17.00 (7-8 yrs)
>16.50 (9-10 yrs)
>16.20 (11-15 yrs)
>16.00 (>15 yrs)
Red Blood Cells (RBC) 
1012/L
<3.0
-
Hemoglobin
g/L
<100
-
Hematocrit
L/L
<0.32
>0.50
Platelet Count
109/L
<75
>500
Neutrophils/Leukocytes
%
<20 (2-5 yrs)
<25 (6-11 yrs)
<30 (12-17 yrs)
<40 (>17 yrs)
>65 (2-11 yrs)
>70 (12-17 yrs)
>75 (>17 yrs)
Lymphocytes/ Leukocytes
%
<12 (2-17 yrs)
<15 (>17 yrs)
>63 (2-5 yrs)
>57 (6-11 yrs)
>52 (12-17 yrs)
>47 (>17 yrs)
Monocytes/Leukocytes
%
-
> 15
Eosinophils/Leukocytes
%
-
> 10
Basophils/Leukocytes
%
-
> 10
LLN:  Lower limit of normal value provided by the laboratory
ULN:  Upper limit of normal value provided by the laboratory
5.9.3
Vital Signs
Descriptive statistics for vital signs (e.g., systolic and diastolic blood pressure, and pulse rate) 
and their changes from baseline/Week 0 at each post-baseline/Week 0 visit will be presented for 
Double-blind Acute and Double-blind Maintenance Phase Safety Analysis Sets, and also for 
Open-label Acute Phase Safety Analysis Set.
Vital sign values will be considered PCI if they meet either the low or high PCI criteria listed in 
Table 3.  The number and percentage of subjects with PCI post-baseline values will be tabulated. 
The percentages will be calculated relative to the number of subjects with baseline and at least 
1 post-baseline/Week 0 assessment during phase of interest.  The numerator is the total number 
of subjects with at least 1 PCI post-baseline/Week 0 vital sign value during phase of interest.  


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A supportive listing of subjects with post-baseline/Week 0 PCI values will be provided including 
the subject number, site, baseline/Week 0, and post-baseline/Week 0 PCI values.
Table 3:
Criteria for Potentially Clinically Significant Vital Signs
Vital Sign Parameter
Age (yrs)
Lower Limit
Upper Limit
Systolic blood pressure
(mmHg)
5 - 6
<89
>125
7 – 12
<92
>135
≥13
<100
>140
Diastolic blood pressure
(mmHg)
5 - 6
<50
>84
7 – 12
<55
>90
≥13
<60
>90
Pulse rate
(beats per minute)
5 - 6
<50
>130
7 – 12
<50
>125
≥13
<50
>120
5.10
Analysis of Pharmacokinetic Data
Blood samples will be collected for determination of 5-ASA and Ac-5-ASA plasma 
concentrations, and the plasma samples will be assayed for 5-ASA and Ac-5-ASA using 
validated analytical methods.
Plasma concentrations reported as BLQ (below the limit of quantification) of the assay will be 
reported as zero on the data listings, and BLQ concentrations are treated as zero in the 
calculation of summary statistics.
The plasma concentrations of 5-ASA and Ac-5-ASA will be summarized by treatment and visit 
using descriptive statistics (number of observations, mean, standard deviation, coefficient of 
variation, median, Q1, Q3, maximum, and minimum) using the Safety Analysis Set for each 
study phase.
A population pharmacokinetic model was developed based on the 5-ASA and Ac-5-ASA plasma 
concentration data (full pharmacokinetic profiles) from SPD476-112.  The plasma concentration 
data from this study (sparse pharmacokinetic sampling) will be pooled with the plasma 
concentration data from SPD476-112 to update the original population pharmacokinetic analysis.  
The population pharmacokinetic methods will be described in a separate document from this 
statistical analysis plan.


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6.
CHANGES TO ANALYSES SPECIFIED IN THE PROTOCOL

Changes to the analyses specified in the protocol are as follows: The observed-case 
sensitivity analysis has been removed from the SAP, since the observed-case analysis would 
be identical to the complete-case analysis. The model-based imputation method sensitivity 
analysis has been omitted from the SAP as this study is not powered to detect differences 
between treatment groups and other sensitivity analysis (LOCF and complete case) intended 
to examine the robustness of the treatment estimate (under the assumption that the subjects 
with missing Week 8 or Week 26 results are treatment failures) have been included.

Statements were added to the SAP to clarify that this is an estimation study intended to 
provide estimates of clinical response for 2 doses (low and high) across a range of weight 
groups and not powered to detect differences between treatment groups.

After agreement with FDA, the sample size for the Double-blind Acute Phase has been 
reduced to 53 subjects due to difficulties with recruitment.

Subgroup analyses for the primary endpoint were added to the SAP to explore efficacy by 
weight group and Week 8 responder status.  

For maintenance phase secondary endpoints, the proportion of subjects who have maintained 
a clinical and endoscopic response at Week 26, using central reading and using local reading 
endoscopies, if there are an insufficient number of subjects with central reading endoscopy 
data, then the CMH test will not be performed.  The number and percentage of subjects with 
clinical and endoscopic response will be presented by treatment arm.

To conduct psychometric analysis of the DUCS would require more data, and thus will be 
considered in the future.


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7.
STATISTICAL/ANALYTIC ISSUES
7.1
Adjustment for Covariates
The analysis of the primary efficacy endpoint for the Double-blind Acute Phase does not include 
adjustment for covariates.
The analysis of the primary efficacy endpoint for the Double-blind Maintenance Phase includes 
adjustment for prior response status (entered Maintenance Phase directly, responder at Week 8 in 
Double-blind Acute Phase, responder at Week 8 in Open-label Acute Phase).   
The analysis of the secondary efficacy endpoint, change in DUCS score from baseline to Week 8 
for the Double-blind Acute Phase includes adjustment for the baseline DUCS score.
The analysis of the secondary efficacy endpoint, change in DUCS score from Week 0 to 
Week 26 for the Double-blind Maintenance Phase includes adjustment for the baseline DUCS 
score and prior response status (entered Maintenance Phase directly, responder at Week 8 in 
Double-blind Acute Phase, responder at Week 8 in Open-label Acute Phase). 
7.2
Handling of Dropouts or Missing Data
For the primary analysis of the primary efficacy endpoint, subjects with missing data at Week 8 
or Week 26 for the Double-blind Acute Phase or Double-blind Maintenance Phase, respectively, 
will be assumed not to have had a clinical response and will be considered treatment failures.  
Sensitivity analyses to examine the handling of missing data for the primary efficacy endpoint 
include complete-case analysis and last observation carried forward.  These are described in 
Section 7.7.  
7.3
Interim Analysis and Data Monitoring
A safety review team will review safety data twice a year according to the Data Review Plan.
There is no interim efficacy analysis planned for this study. An independent Data Monitoring 
Committee (DMC) will monitor safety data generated by the study at regular intervals for the 
duration of the study. Their role is to protect the interests of subjects in the study and of future 
subjects who may enroll, by reviewing the accumulating safety and tolerability data generated in 
this study. DMC meetings will be held on 3 occasions—the first time after one-fourth of the 
targeted sample size is evaluable for analysis, the second time after two-fourth are evaluable, and 
third time after three-fourth are evaluable. The data provided to the DMC will not be considered 
‘clean’ until the database is locked. Data will be provided to the DMC by an independent 
statistical reporting group not assigned to the project.
Further details regarding the DMC and meeting frequency can be found in the DMC charter.  
The DMC charter will define the primary responsibilities of the DMC, guide its activities, its 
relationship with other trial components, its membership, and the purpose and timing of its 
meetings.  It will provide the procedures for ensuring confidentiality, formal communication, an 
outline of the content of the Open and Closed Reports that will be provided to the DMC.


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7.4
Multicenter Studies
Data from all centers that participate in this protocol will be combined so that an adequate 
number of subjects will be available for analysis.
7.5
Multiple Comparisons/Multiplicity
This is an estimation study intended to provide estimates of clinical response for 2 doses (low 
and high) across a range of weight groups and not powered to detect differences between 
treatment groups. No adjustment for multiplicity will be performed.
7.6
Examination of Subgroups and Interactions
As indicated for each subgroup analysis, efficacy endpoints will be summarized by study phase 
(Double-blind Acute Phase, Open-label Acute Phase, and Double-blind Maintenance Phase) 
using the appropriate Safety Analysis Set for that phase.
7.6.1
Weight Group
The primary efficacy endpoint will be summarized for each study phase by weight group 
(18 to 23kg, >23 to 35kg, >35 to 50kg and >50 to 90kg).  
7.6.2
Prior Response Status
The primary and secondary efficacy endpoints will be summarized for the Double-blind 
Maintenance Phase by prior response status (entered Maintenance Phase directly, responder at 
Week 8 in Double-blind Acute Phase, responder at Week 8 in Open-label Acute Phase).  This 
analysis will provide information on the durability of response with respect to the prior treatment 
with either MMX or other 5-ASA treatment.  
In addition, the primary and secondary efficacy endpoints will be summarized for the 
Double-blind Maintenance Phase by prior response status (entered Maintenance Phase directly, 
responder at Week 8 in Double-blind Acute Phase, responder at Week 8 in Open-label Acute 
Phase) and prior treatment (low-dose MMX, high-dose MMX, and 5-ASA by medication 
preferred term).  This analysis will provide information on the durability of response with respect 
to the prior MMX dose group or other 5-ASA treatments by preferred term. 
The number (n, %) of subjects with a clinical response at Week 26 and difference between 
treatment arms for each stratum, together with the 95% CI (2-sided), and associated p-value will 
be presented.
7.7
Sensitivity Analyses
7.7.1
Sensitivity Analyses of the Primary Endpoint
The following sensitivity analyses will be performed for both the Double-blind Acute and 
Double-blind Maintenance Phase primary endpoint:
A modified clinical response, defined as partial UC-DAI≤1 with rectal bleeding=0 and stool 
frequency ≤1 will be analyzed in a similar way to the primary endpoint analysis in order to 
investigate the effect of removing the PGA component from the responder definition.


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A modified clinical response, defined as partial UC-DAI≤1 with rectal bleeding=0 and stool 
frequency=0, and PGA=0 will be analyzed in a similar way to the primary endpoint to 
support extrapolation to adult efficacy.
A complete-case analysis (where subjects who withdraw early from the study are excluded) 
will be performed in a similar way to the primary endpoint analysis.
A last observation carried forward analysis (LOCF), using data from the final on-treatment 
assessment (FoTA) for the appropriate phase, will be performed in a similar way to the 
primary endpoint analysis. Specifically, the values of the individual components of the 
partial UC-DAI (rectal bleeding, stool frequency and PGA scores) will be imputed using the 
last observation carried forward (LOCF) method.
Logistic modeling will be conducted to investigate the effect of doses in mg/kg on the 
clinical response in the Double-blind Acute and Double-blind Maintenance Phases.  The 
logistic regression model will adjust for doses in mg/kg, sex, and age.  For the Double-blind 
Maintenance Phase primary endpoint, the logistic regression model will also adjust for 
Week 8 responder status.


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8.
DATA HANDLING CONVENTIONS
8.1
General Data Reporting Conventions
Continuous variables will be summarized using the following descriptive statistics: n, mean, 
median, standard deviation, Q1, Q3, minimum, maximum.  Categorical and count variables will 
be summarized by the number of subjects (n) and the percent of subjects in each category.
See TFLs4Shire for rules on the number of decimal places to present data and p-values.
8.2
Derived Efficacy Endpoints 

Stool frequency and rectal bleeding score:
o
For both stool frequency and rectal bleeding, the symptom score (collected via the 
electronic diary [e-diary]) is defined as the average of the scores from the last available 
3 days from the 5 days immediately prior to the visit (days -1 to -5).  If there are fewer 
than 3 days of data available during days -1 to -5, the average will be calculated from 
any available days within the period.  If there are no available days during the period, 
then the symptom score will be missing for that visit.  Data collected on days when 
bowel preparations have been administered or when endoscopy has been performed 
will be excluded.
o
For stool frequency and rectal bleeding, the symptom score will be grouped into a 
category (0, >0 - <1, 1 - <2, 2 - <3, and 3).

Partial UC-DAI score:
o
Sum of rectal bleeding score, stool frequency score and PGA score

Full UC-DAI score:
o
Sum of rectal bleeding score, stool frequency score, PGA score and endoscopy score 

Clinical response: partial UC-DAI ≤1 (rectal bleeding=0 and stool frequency ≤1 and 
PGA=0) 

Clinical and endoscopic response: UC-DAI ≤2 with rectal bleeding=0 and stool frequency 
≤1 and PGA=0, and mucosal healing (endoscopy score ≤1) based on central reading

Week 8 responder status is defined based on clinical response: entered Maintenance Phase 
directly, responder at Week 8 of the Double-blind Acute Phase, or responder at Week 8 of 
the Open-label Acute Phase.


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8.3
Repeated or Unscheduled Assessments of Safety Parameters 
If a subject has repeated assessments before the start of investigational product, then the results 
from the final assessment made prior to the start of investigational product during phase of 
interest will be used as baseline/Week 0.  If end of phase assessments are repeated or 
unscheduled, the last post-baseline/Week 0 assessment will be used as the end of phase 
assessment for generating descriptive statistics.  However, all post-baseline/Week 0 assessments 
will be used for PCI value determination and all assessments will be presented in the data 
listings. 
8.4
Incomplete Date of Diagnosis
When computing the time since diagnosis, any missing days (of month) will be imputed as the 
15th for diagnosis dates that precede screening. If imputed date is after screening, then screening 
date will be used as imputed diagnosis date.
8.5
Missing Date of Investigational Product 
When the date of the last dose of investigational product is missing for a subject in the Safety Set 
for the acute or maintenance phases, all efforts should be made to obtain the date from the 
investigator.  If it is still missing after all efforts, then the last visit date when investigational 
product was returned will be used in the calculation of treatment duration.
8.6
Missing Date Information for Prior or Concomitant Medications 
For prior or concomitant medications, incomplete (i.e., partially missing) start date and/or stop 
date will be imputed.  When the start date and the stop date are both incomplete for a subject, the 
start date will be imputed first.
8.6.1
Incomplete Start Date 
The following rules will be applied to impute the missing numerical fields.  If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date.
Missing day and month

If the year of the incomplete start date is the same as the year of the date of the first dose of 
investigational product, then the day and month of the date of the first dose of 
investigational product will be assigned to the missing fields.

If the year of the incomplete start date is before the year of the date of the first dose of 
investigational product, then December 31 will be assigned to the missing fields.

If the year of the incomplete start date is after the year of the date of the first dose of 
investigational product, then 01 January will be assigned to the missing fields.


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Missing month only

The day will be treated as missing and both month and day will be replaced according to 
the above procedure.
Missing day only

If the month and year of the incomplete start date are the same as the month and year of the 
date of the first dose of investigational product, then the day of the date of the first dose of 
investigational product will be assigned to the missing day.

If either the year is before the year of the date of the first dose of investigational product or 
if both years are the same but the month is before the month of the date of the first dose of 
investigational product, then the last day of the month will be assigned to the missing day.

If either the year is after the year of the date of the first dose of investigational product or if 
both years are the same but the month is after the month of the date of the first dose of 
investigational product, then the first day of the month will be assigned to the missing day.
8.6.2
Incomplete Stop Date 
The following rules will be applied to impute the missing numerical fields.  If the date of the last 
dose of investigational product is missing, then the last visit date will be imputed.  If the imputed 
stop date is before the start date (imputed or non-imputed start date), then the imputed stop date 
will be equal to the start date.
Missing day and month

If the year of the incomplete stop date is the same as the year of the date of the last dose of 
investigational product, then the day and month of the date of the last dose of 
investigational product will be assigned to the missing fields.

If the year of the incomplete stop date is before the year of the date of the last dose of 
investigational product, then 31 December will be assigned to the missing fields.

If the year of the incomplete stop date is after the year of the date of the last dose of 
investigational product, then 01 January will be assigned to the missing fields.
Missing month only

The day will be treated as missing and both month and day will be replaced according to 
the above procedure.
Missing day only

If the month and year of the incomplete stop date are the same as the month and year of the 
date of the last dose of investigational product, then the day of the date of the last dose of 
investigational product will be assigned to the missing day.


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
If either the year is before the year of the date of the last dose of investigational product or 
if both years are the same but the month is before the month of the date of the last dose of 
investigational product, then the last day of the month will be assigned to the missing day.

If either the year is after the year of the last dose of investigational product or if both years 
are the same but the month is after the month of the date of the last dose of investigational 
product, then the first day of the month will be assigned to the missing day.
8.7
Missing Date Information for Adverse Events 
For AEs, only incomplete (i.e., partially missing) start dates will be imputed, to determine if the 
event is treatment emergent.
8.7.1
Incomplete Start Date 
Follow same rules as in Section 8.6.1.
8.7.2
Incomplete Stop Date 
Not applicable as duration of AEs is not presented.
8.8
Missing Severity Assessment for Adverse Events
If severity is missing for an AE starting prior to the date of the first dose of investigational 
product, then a severity of “Mild” will be assigned. If the severity is missing for a TEAE starting 
on or after the date of the first dose of investigational product, then a severity of “Severe” will be 
assigned. The imputed values for severity assessment will be used for incidence summaries, 
while the actual values will be used in data listings.
8.9
Missing Relationship to Investigational Product for Adverse Events
If the relationship to investigational product is missing for a TEAE starting on or after the date of 
the first dose of investigational product, a causality of “Related” will be assigned. The imputed 
values for relationship to double-blind investigational product will be used for incidence 
summaries, while the actual values will be presented in data listings.
8.10
Character Values of Clinical Laboratory Variables 
If the reported value of a clinical laboratory variable cannot be used in a statistical analysis (e.g., 
if a character string is reported for a numerical variable), then the appropriately determined 
coded value will be used in the statistical analysis.  However, the actual values as reported in the 
database will be presented in data listings.


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Table 4:
Examples for Coding of Special Character Values for Clinical Laboratory 
Variables
Clinical Laboratory Test
Possible Results (in SI units)
Coded Value for 
Analysis
Chemistry:  ALT
<5
0
Chemistry:  AST
<5
0
Chemistry:  Total Bilirubin
<2
0
Urinalysis:  Glucose
55
Positive
0
Negative
Urinalysis:  pH
8.0
8.0


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9.
REFERENCES
Otley, A., Smith, C., Nicholas, D., Munk, M., Avolio, J., Sherman, P. M.and Griffiths, A. M. 
2002. The IMPACT Questionnaire: A Valid Measure of Health-Related Quality of Life 
in Pediatric Inflammatory Bowel Disease. Journal of Pediatric Gastroenterology and 
Nutrition, 35, 557-563.
Schroeder, K. W., Tremaine, W. J.and Ilstrup, D. M. 1987. Coated oral 5-aminosalicylic acid 
therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J 
Med, 317, 1625-9.
Sutherland, L. R., Martin, F., Greer, S., Robinson, M., Greenberger, N., Saibil, F., Martin, T., 
Sparr, J., Prokipchuk, E.and Borgen, L. 1987. 5-Aminosalicylic acid enema in the 
treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis. Gastroenterology,
92, 1894-8.
Turner, D., Hyams, J., Markowitz, J., Lerer, T., Mack, D. R., Evans, J., Pfefferkorn, M., Rosh, J., 
Kay, M., Crandall, W., Keljo, D., Otley, A. R.and Kugathas 2009. Appraisal of the 
pediatric ulcerative colitis activity index (PUCAI). Inflammatory Bowel Diseases, 15, 
1218-1223.
Turner, D., Otley, A. R., Mack, D., Hyams, J., de Bruijne, J., Uusoue, K., Walters, T. D., Zachos, 
M., Mamula, P., Beaton, D. E., Steinhart, A. H.and Griffiths, A. M. 2007. Development, 
Validation, and Evaluation of a Pediatric Ulcerative Colitis Activity Index: A Prospective 
Multicenter Study. Gastroenterology, 133, 423-432.










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Table Number
Table Title
14.2.2.1.11
Proportion of Subjects with a Clinical and Endoscopic Response at Week 
26 of Double-Blind Maintenance Phase by Treatment Arm, Prior Response 
Status and Prior Treatment – Based on Local Reading [Double-Blind
Maintenance Phase Safety Analysis Set]
14.2.2.1.12
Proportion of Subjects with a Clinical and Endoscopic Response at Week 
26 of Double-Blind Maintenance Phase by Treatment Arm and Prior 
Treatment (Preferred Term) – Based on Local Reading [Double-Blind
Maintenance Phase Safety Analysis Set – Subjects who Entered the 
Maintenance Phase Directly]
14.2.2.1.13
Change in the DUCS Score from Week 0 to Week 26 of Double-Blind 
Maintenance Phase by Treatment Arm - Using Analysis of Covariance 
[Double-Blind Maintenance Phase Safety Analysis Set]
14.2.2.1.14
Change in the DUCS Score from Week 0 to Week 26 of Double-Blind 
Maintenance Phase by Treatment Arm and Prior Response Status [Double-
Blind Maintenance Phase Safety Analysis Set]
14.2.2.1.15
Change in the DUCS Score from Week 0 to Week 26 of Double-Blind 
Maintenance Phase by Treatment Arm, Prior Response Status and Prior 
Treatment [Double-Blind Maintenance Phase Safety Analysis Set]
14.2.2.1.16
Change in the DUCS Score from Week 0 to Week 26 of Double-Blind 
Maintenance Phase by Treatment Arm and Prior Treatment (Preferred 
Term) [Double-Blind Maintenance Phase Safety Analysis Set – Subjects 
who Entered the Maintenance Phase Directly]
14.2.2.1.17
Proportion of Subjects in Remission  (<10 Points) PUCAI Score from 
Week 0 to Week 26 of Double-Blind Maintenance Phase by Treatment 
Arm [Double-Blind Maintenance Phase Safety Analysis Set]
14.2.2.1.18
Proportion of Subjects in Remission  (<10 Points) PUCAI Score from 
Week 0 to Week 26 of Double-Blind Maintenance Phase by Treatment 
Arm and Prior Response Status [Double-Blind Maintenance Phase Safety 
Analysis Set]
14.2.2.1.19
Proportion of Subjects in Remission  (<10 Points) PUCAI Score from 
Week 0 to Week 26 of Double-Blind Maintenance Phase by Treatment 
Arm, Prior Response Status and Prior Treatment [Double-Blind
Maintenance Phase Safety Analysis Set]
14.2.2.1.20
Proportion of Subjects in Remission  (<10 Points) PUCAI Score from 
Week 0 to Week 26 of Double-Blind Maintenance Phase by Treatment 
Arm and Prior Treatment (Preferred Term) [Double-Blind Maintenance 
Phase Safety Analysis Set – Subjects who Entered the Maintenance Phase 
Directly]








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Table Number
Table Title
14.3.1.2.1
Treatment-emergent Adverse Events (TEAEs) by System Organ Class, 
Preferred Term [Overall Safety Analysis Set]
14.3.1.2.2
Treatment-emergent Adverse Events (TEAEs) during Double-Blind Acute 
Phase by System Organ Class, Preferred Term and Treatment Arm 
[Double-Blind Acute Phase Safety Analysis Set]
14.3.1.2.3
Treatment-emergent Adverse Events (TEAEs) during Open-Label Acute 
Phase by System Organ Class, Preferred Term and High-Dose MMX
[Open-Label Acute Phase Safety Analysis Set]
14.3.1.2.4
Treatment-emergent Adverse Events (TEAEs) during Double-Blind 
Maintenance Phase by System Organ Class, Preferred Term and Treatment 
Arm [Double-Blind Maintenance Phase Safety Analysis Set]
14.3.1.3.1
Frequently Occurring (>=5%) Treatment-emergent Adverse Events 
(TEAEs) by Preferred Term [Overall Safety Analysis Set]
14.3.1.3.2
Frequently Occurring (>=5%) Treatment-emergent Adverse Events 
(TEAEs) during Double-Blind Acute Phase by Preferred Term and 
Treatment Arm [Double-Blind Acute Phase Safety Analysis Set]
14.3.1.3.3
Frequently Occurring (>=5%) Treatment-emergent Adverse Events 
(TEAEs) during Open-Label Acute Phase by Preferred Term and High-
Dose MMX [Open-Label Acute Phase Safety Analysis Set]
14.3.1.3.4
Frequently Occurring (>=5%) Treatment-emergent Adverse Events 
(TEAEs) during Double-Blind Maintenance Phase by Preferred Term and 
Treatment Arm [Double-Blind Maintenance Phase Safety Analysis Set]
14.3.2.1.1
Treatment-emergent Adverse Events (TEAEs) by Maximum Severity, 
System Organ Class, Preferred Term and Treatment Arm [Overall Safety 
Analysis Set]
14.3.2.1.2
Treatment-emergent Adverse Events (TEAEs) during Double-Blind Acute 
Phase by Maximum Severity, System Organ Class, Preferred Term and 
Treatment Arm [Double-Blind Acute Phase Safety Analysis Set]
14.3.2.1.3
Treatment-emergent Adverse Events (TEAEs) during Open-Label Acute 
Phase by Maximum Severity, System Organ Class, Preferred Term and 
High-Dose MMX [Open-Label Acute Phase Safety Analysis Set]
14.3.2.1.4
Treatment-emergent Adverse Events (TEAEs) during Double-Blind 
Maintenance Phase by Maximum Severity, System Organ Class, Preferred 
Term and Treatment Arm [Double-Blind Maintenance Phase Safety 
Analysis Set]
14.3.2.2.1
Treatment-emergent Adverse Events (TEAEs) Considered Related to 
Investigational Product by System Organ Class, Preferred Term and 
Treatment Arm [Overall Safety Analysis Set]


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Table Number
Table Title
14.3.2.2.2
Treatment-emergent Adverse Events (TEAEs) Considered Related to 
Investigational Product during Double-Blind Acute Phase by System 
Organ Class, Preferred Term and Treatment Arm [Double-Blind Acute 
Phase Safety Analysis Set]
14.3.2.2.3
Treatment-emergent Adverse Events (TEAEs) Considered Related to 
Investigational Product during Open-Label Acute Phase by System Organ 
Class and Preferred Term [Open-Label Acute Phase Safety Analysis Set]
14.3.2.2.4
Treatment-emergent Adverse Events (TEAEs) Considered Related to 
Investigational Product during Double-Blind Maintenance Phase by 
System Organ Class, Preferred Term and Treatment Arm [Double-Blind
Maintenance Phase Safety Analysis Set]
14.3.3.1.1
Serious Treatment-emergent Adverse Events (TEAEs) Leading to Death 
by System Organ Class, Preferred Term and Treatment Arm [Overall 
Safety Analysis Set]
14.3.3.1.2
Serious Treatment-emergent Adverse Events (TEAEs) Leading to Death 
during Double-Blind Acute Phase by System Organ Class, Preferred Term 
and Treatment Arm [Double-Blind Acute Phase Safety Analysis Set]
14.3.3.1.3
Serious Treatment-emergent Adverse Events (TEAEs) Leading to Death 
during Open-Label Acute Phase by System Organ Class, Preferred Term 
and High-Dose MMX [Open-Label Acute Phase Safety Analysis Set]
14.3.3.1.4
Serious Treatment-emergent Adverse Events (TEAEs) Leading to Death 
during Double-Blind Maintenance Phase by System Organ Class, Preferred 
Term and Treatment Arm [Open-Label Acute Phase Safety Analysis Set]
14.3.3.2.1
Treatment-emergent Adverse Events (TEAEs) Leading to Discontinuation 
of Investigational Product by System Organ Class, Preferred Term and 
Treatment Arm [Overall Safety Analysis Set]
14.3.3.2.2
Treatment-emergent Adverse Events (TEAEs) Leading to Discontinuation 
of Investigational Product during Double-Blind Acute Phase by System 
Organ Class, Preferred Term and Treatment Arm [Double-Blind Acute 
Phase Safety Analysis Set]
14.3.3.2.3
Treatment-emergent Adverse Events (TEAEs) Leading to Discontinuation 
of Investigational Product during Open-Label Acute Phase by System 
Organ Class, Preferred Term and High-Dose MMX [Open-Label Acute 
Phase Safety Analysis Set]
14.3.3.2.4
Treatment-emergent Adverse Events (TEAEs) Leading to Discontinuation 
of Investigational Product during Double-Blind Maintenance Phase by 
System Organ Class, Preferred Term and Treatment Arm [Double-Blind
Maintenance Phase Safety Analysis Set]












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Listing 
Number
Title
 
16.2.8.1.2.5
Clinical Laboratory Test Results: Stool Sample Culture [Enrolled Set]
16.2.8.1.2.6
Clinical Laboratory Test Results: Stool Sample for Microbiome Analysis 
[Enrolled Set]
16.2.8.1.3.1
Subjects with Potentially Clinical Important (PCI) Laboratory Test Results: 
Hematology [Enrolled Set]
16.2.8.1.3.2
Subjects with Potentially Clinical Important (PCI) Laboratory Test Results: 
Biochemistry [Enrolled Set]
16.2.8.2.1
Vital Signs [Enrolled Set]
16.2.8.2.2
Subjects with Potentially Clinical Important (PCI) Vital Signs [Enrolled Set]


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11.
SCHEDULE OF EVENTS




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Table 5:
Double-blind Acute Phase
Visit
1
(Screening)
Recommended 
Telephone calla
2
(Baseline)
3b
3.1
3.2c, d, e, f
6g
Week/Monthh
Day –21 to –3
Day –7 to ⎼4
Week 0
Week 2
Week 4
Week 8/Withdrawal
Follow-up
Review DUCS instructions, 
ability to read and 
understand e-diary with 
subject/caregiver

Subject/caregiver e-diary 
entry: rectal bleeding, stool 
frequency, DUCS, and
Overall Current Healthm





Assessment of e-diary 
compliancea

Global Change in Healthl



IMPACT IIIn


PUCAI (where applicable)


Average stool frequencyo, p, q




Average rectal bleedingo, p, q




PGAp, q




Endoscopy (flexible 
sigmoidoscopy or 
colonoscopy) for study 
eligibilityh, q, r


Endoscopy (flexible 
sigmoidoscopy or 
colonoscopy), where 
possible for subjects who are 
not entering into the Open-
label Acute Phase)q

Calculate partial UC-DAI


IRT entry





Investigational product 
dispensed



s


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Table 5:
Double-blind Acute Phase
Visit
1
(Screening)
Recommended 
Telephone calla
2
(Baseline)
3b
3.1
3.2c, d, e, f
6g
Week/Monthh
Day –21 to –3
Day –7 to ⎼4
Week 0
Week 2
Week 4
Week 8/Withdrawal
Follow-up
Investigational product 
collected and compliance 
calculated



Adverse events







Concomitant medication






Re-randomization (subjects 
entering Double-blind 
Maintenance Phase only)

Abbreviations: DUCS=Daily Ulcerative Colitis Scale for children and caregivers; eCRF=electronic case report form; e-diary=electronic diary; IRT= interactive response 
technology; PGA=Physician’s Global Assessment; PUCAI=Pediatric Ulcerative Colitis Activity Index; UC-DAI=Ulcerative Colitis Disease Activity Index.
a Approximately 4 to 7 days prior to the Baseline Visit (Visit 2) and prior to each subsequent visit (Visits 3, 3.1, and 3.2), it is recommended that site staff telephone the subject or 
the subject’s caregiver to remind them to enter UC-DAI symptoms (rectal bleeding and stool frequency) into the e-diary every night, even if the subject has no symptoms.
b Subjects may enter into the Open-label Acute Phase beginning at Visit 3 (after a minimum of 2 weeks double-blind treatment) and at any time until the end of the Double-blind 
Acute Phase provided all criteria have been met.
c Subjects will continue into the Open-label Acute Phase if they have not met the criteria to enter the Double-blind Maintenance Phase and are eligible to continue into the 
Open-label Acute Phase.
d Subjects will continue into the Double-blind Maintenance Phase if partial UC-DAI ≤1 (with rectal bleeding=0 and stool frequency ≤1 and PGA=0) and with mucosal healing 
(endoscopy score)=0 or 1, and are eligible to continue into the Double-blind Maintenance Phase.
e This will be the final visit for subjects not entering the Open-label Acute Phase or the Double-blind Maintenance Phase.
f The Baseline Visit (Visit 2) does not need to be repeated for subjects entering the Double-blind Maintenance Phase at the end of the Double-blind Acute Phase.  Visit 3.2 will be 
considered the Week 0 visit for the next phase into which subjects are continuing.
g Follow-up assessment in this phase applies only to subjects who are discontinuing the study; may be performed via telephone call within 7 days of the last dose of investigational 
product.
h A visit window of 3 days is permitted for all study visits except for the Screening Visit (Visit 1) and the Baseline Visit (Visit 2), which must occur 3 to 21 days following the 
Screening Visit (Visit 1).  If the initial endoscopy is not adequate for mucosal healing score assignment due to inadequate bowel preparation, to allow for a repeat endoscopy to be 
conducted, the period of the Screening Visit (Visit 1) can be extended by an additional 14 days from the date of the initial endoscopy.
i The serum pregnancy test will be performed for all female subjects of childbearing potential at the screening visit (Visit 1) and Week 8/Withdrawal (Visit 3.2). Urine pregnancy 
tests will be performed at all other visits.
j Urinalysis performed at this visit only for subjects who are not continuing into the Open-label Acute Phase.
 
l Stool samples collected for culture may be processed by local laboratories;  however, results from the central laboratory analysis will prevail and will be entered in the eCRF.
m Rectal bleeding, stool frequency, DUCS, and Overall Current Health e-diary entry is completed once a day before bedtime every day from the evening of the Screening Visit 


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Table 5:
Double-blind Acute Phase
Visit
1
(Screening)
Recommended 
Telephone calla
2
(Baseline)
3b
3.1
3.2c, d, e, f
6g
Week/Monthh
Day –21 to –3
Day –7 to ⎼4
Week 0
Week 2
Week 4
Week 8/Withdrawal
Follow-up
(Visit 1), preferably for at least the 3 days immediately prior to the Baseline Visit (Visit 2).  Rectal bleeding, stool frequency, DUCS and Overall Current Health e-diary entry is 
completed once a day before bedtime for the 5 days immediately prior to Visits 3, 3.1, and 3.2 of the Double-blind Acute Phase.
n Global Change in Health to be completed by caregivers of children aged 5-10 years and by children aged 11-17 years; IMPACT III to be completed by children aged 8-17 years 
only (see Section 4.3).
o The average stool frequency and rectal bleeding scores will be calculated and available to the investigator through a report from the e-diary provider.
p Components of the partial UC-DAI.
q Components of the modified full UC-DAI.
r For subjects entering the Double-Blind Acute Phase only: Subjects with an unconfirmed diagnosis of UC must have endoscopy performed during the Screening Visit (Visit 1).  
Subjects with a previously confirmed diagnosis must have endoscopy at the Screening Visit (Visit 1) or at the Baseline Visit (Visit 2) if endoscopy has not been performed within 
21 days prior to the Screening Visit (Visit 1).
s Only for subjects continuing into the Open- label Acute or Double- blind Maintenance Phase.




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Table 6:
Open-label Acute Phase
Visit
Recommended 
Telephone calla
4
4.1
4.2b, c, d, e
6f
Weekg
Day ⎼7 to ⎼4
Week 2
Week 4
Week 8/Withdrawal
Follow-up
Investigational product 
dispensed


m
Investigational product collected 
and compliance calculated



Adverse events





Concomitant medication




Re-randomization (subjects 
entering Double-blind 
Maintenance Phase only)

Abbreviations: DUCS=Daily Ulcerative Colitis Scale for children and caregivers; e-diary=electronic diary; IRT= interactive response technology; PGA=Physician’s Global 
Assessment; PUCAI=Pediatric Ulcerative Colitis Activity Index; UC-DAI=Ulcerative Colitis Disease Activity Index.
a Approximately 4 to 7 days prior to Visit 4 and prior to each subsequent visit (Visits 4.1 and 4.2), it is recommended that site staff telephone the subject or the subject’s caregiver 
to remind them to enter UC-DAI symptoms (rectal bleeding and stool frequency) into the e-diary every night, even if the subject has no symptoms.
b Subjects will continue into the Double-blind Maintenance Phase if partial UC-DAI ≤1 (with rectal bleeding=0 and stool frequency ≤1 and PGA=0) and are eligible to continue 
into the Double-blind Maintenance Phase.
c Subjects will be withdrawn from the study if they have not achieved a partial UC-DAI ≤1 (with rectal bleeding=0 and stool frequency ≤1 and PGA=0).
d This will be the final visit for subjects not continuing into the Double-blind Maintenance Phase.
e The Baseline Visit (Visit 2) does not need to be repeated for subjects entering the Double-blind Maintenance Phase at the end of the Open-label Acute Phase.  Visit 4.2 will be 
considered the Week 0 visit for the Double-blind Maintenance Phase.
f Follow-up assessment in this phase applies only to subjects who are discontinuing the study; may be performed via telephone call within 7 days of the last dose of investigational 
product.
g A visit window of 3 days is permitted for all study visits.
h The serum pregnancy test will be performed for all female subjects of childbearing potential at Week 8/Withdrawal (Visit 4.2). Urine pregnancy tests will be performed at all 
other visits.
i Rectal bleeding, stool frequency, DUCS, and Overall Current Health e-diary entry is completed once a day before bedtime every day for 5 days immediately prior to Visits 4, 4.1 
and 4.2 of the Open-label Acute Phase.
j The average stool frequency and rectal bleeding scores will be calculated and available to the investigator through a report from the e-diary provider.
k Components of the partial UC-DAI.
l Components of the modified full UC-DAI.
m Only for subjects continuing into the Double-blind Maintenance Phase.




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Table 7:
Double-blind Maintenance Phase
Visit
1
(Screening)a
Recommended 
Telephone callb
2
(Baseline)a
5
5.1
5.2
6c
Day/Monthd
Day –21 to –3
Day ⎼7 to ⎼4
Week 0
Weeks 2-4
Week 13
Week 26/ 
Withdrawal
Follow-up
Global Change in Healthi

IMPACT IIIi


PUCAI (where applicable)


Average stool frequency j, k, l



Average rectal bleeding j, k, l



PGA k, l


Endoscopy (flexible sigmoidoscopy or 
colonoscopy) for study eligibilityd, l, m


Endoscopy (flexible sigmoidoscopy or 
colonoscopy), where possiblel

IRT entry





Calculate partial UC-DAI


Investigational product dispensed



Investigational product collected and 
compliance calculated



Adverse events







Concomitant medication





Abbreviations: DUCS=Daily Ulcerative Colitis Scale for children and caregivers; eCRF=electronic case report form; e-diary=electronic diary; IRT= interactive response 
technology; PGA=Physician’s Global Assessment; PUCAI=Pediatric Ulcerative Colitis Activity Index; UC-DAI=Ulcerative Colitis Disease Activity Index.
a The Screening Visit (Visit 1) and the Baseline Visit (Visit 2) in Table 7 apply only to subjects entering directly into the Double-blind Maintenance Phase.  
b Approximately 4 to 7 days prior to the Baseline Visit (Visit 2) and prior to each subsequent visit (Visits 5, 5.1, and 5.2), it is recommended that site staff telephone the subject or 
the subject’s caregiver to remind them to enter UC-DAI symptoms (rectal bleeding and stool frequency) into the e-diary every night, even if the subject has no symptoms.
c Follow-up assessment may be performed via telephone call within 7 days of the last dose of investigational product.
d A visit window of 3 days is permitted for all study visits except for the Screening Visit (Visit 1) (must be 3 to 21 days) and the Baseline Visit (Visit 2), which must occur 3 to 
21 days following the Screening Visit (Visit 1).  If the initial endoscopy is not adequate for mucosal healing score assignment due to inadequate bowel preparation, to allow for a 
repeat endoscopy to be conducted, the period of the Screening Visit (Visit 1) can be extended by an additional 14 days from the date of the initial endoscopy.
e The serum pregnancy test will be performed for all female subjects of childbearing potential at the screening visit (Visit 1) and Week 26/Withdrawal (Visit 5.2). Urine pregnancy 
tests will be performed at all other visits.
 


Shire
CONFIDENTIAL
Page 76
Statistical Analysis Plan
SPD476-319
31 Oct 2018
Table 7:
Double-blind Maintenance Phase
Visit
1
(Screening)a
Recommended 
Telephone callb
2
(Baseline)a
5
5.1
5.2
6c
Day/Monthd
Day –21 to –3
Day ⎼7 to ⎼4
Week 0
Weeks 2-4
Week 13
Week 26/ 
Withdrawal
Follow-up
.
g Stool samples collected for culture may be processed by local laboratories in addition to the assessment by the central laboratory. Central laboratory results will prevail and, as 
such, they will be the data entered into the eCRF.
h Rectal bleeding, stool frequency, DUCS and Overall Current Health e-diary entry is completed once a day before bedtime every day during the Screening Visit (Visit 1), 
preferably for at least the 3 days immediately prior to the Baseline Visit (Visit 2).  Rectal bleeding, stool frequency, DUCS and Overall Current Health e-diary entry is completed 
once a day before bedtime for the 5 days immediately prior to Visit 5.1 and Visit 5.2.
i Global Change in Health to be completed by caregivers of children aged 5-10 years and by children aged 11-17 years; IMPACT III to be completed by children aged 8-17 years 
only.
j The average stool frequency and rectal bleeding scores will be calculated and available to the investigator through a report from the e-diary provider.
k Components of the partial UC-DAI.
l Components of the modified full UC-DAI.
m For subjects entering the Double-blind Maintenance Phase directly: Subjects with a previously confirmed diagnosis must have endoscopy at the Screening Visit (Visit 1) or at the 
Baseline Visit (Visit 2).  If the initial endoscopy is not adequate for mucosal healing score assignment due to inadequate bowel preparation, to allow for a repeat endoscopy to be 
conducted, the period of the Screening Visit (Visit 1) can be extended by an additional 14 days from the date of the initial endoscopy.