Clinical trial NCT02407236
Conditions: Colitis, Ulcerative Inflammatory Bowel Diseases
Keywords: Ustekinumab Inflammatory Bowel Diseases (IBD) Colitis, Ulcerative
Sponsor: Janssen Research & Development, LLC
Start date: 2015-07-10; Completion date: 2021-11-30
Enrollment: 961 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of ustekinumab as intravenous (IV: into the vein) infusion in induction study in participants with moderately to severely active Ulcerative Colitis (UC) and as subcutaneous (SC) administration in maintenance study in participants with moderately to severely active Ulcerative Colitis (UC) who have demonstrated a clinical response to Induction treatment with IV ustekinumab.

Detailed description:
This is a Phase 3, randomized (assignment of study drug by chance), double-blind (neither the participant or study staff will know the identity of study drugs), placebo-controlled (placebo is an inactive substance that is compared with a drug to test whether the drug has a real effect in a clinical trial), parallel-group (a medical research study comparing the response in 2 or more groups of participants receiving different interventions), multi-center (more than one clinical site will work on a medical research study), protocol of ustekinumab. The protocol will consist of 2 studies: an Induction study and a Maintenance study with unique endpoints. Screening period will be up to 8 Weeks. Induction study will be at least 8 weeks duration for each participant. Participant with clinical response in the Induction study will be eligible for the Maintenance study. The Maintenance study will be 44 weeks duration. After completion of the maintenance study, a long term extension will follow eligible participants for an additional 3 years. Clinical remission will be evaluated at Week 8 in the Induction study. Clinical remission among ustekinumab Induction responders will be evaluated at week 44 in the Maintenance study. Participants' safety will be monitored throughout.

Arms: arm 1: Participants will be randomized to receive single dose of placebo as Intravenous (IV: into the vein) infusion at Week 0. Participants with clinical response at Week 8 will be eligible to enter the Maintenance study, but will not be randomized. arm 2: Participants will be randomized to receive single dose of ustekinumab 130 mg as IV infusion at Week 0. Participants with clinical response at Week 8 will be eligible to enter the Maintenance study and will be randomized. arm 3: Participants will be randomized to receive ustekinumab approximating 6 mg/kg of body weight, as intravenous infusion at Week 0. Participants with clinical response at Week 8 will be eligible to enter the Maintenance study and will be randomized. arm 4: Participants without clinical response to placebo at Week 8 will receive a single IV infusion of ustekinumab approximating 6mg/kg along with matching subcutaneous (SC) placebo (to maintain the blind). Participants in clinical response at Week 16 will be eligible to enter Maintenance study and will be randomized. arm 5: Participants without clinical response to ustekinumab (130 mg or 6 mg/kg \[IV\]) at Week 8 will receive a single dose of ustekinumab 90 mg subcutaneously along with matching placebo intravenously (to maintain the blind). Participants in clinical response at Week 16 (that is, delayed responders) will be eligible to enter Maintenance study, but will not be randomized. arm 6: Participants in clinical response (at Week 8 or Week 16) to Induction treatment with single IV infusion of Ustekinumab will be randomized to receive placebo subcutaneously, beginning Week 0 of Maintenance study through Week 44. arm 7: Participants in clinical response (at Week 8 or Week 16) to Induction treatment with single IV infusion of Ustekinumab will be randomized to receive ustekinumab 90 mg subcutaneously every 12 weeks, beginning Week 0 of Maintenance study through Week 44. arm 8: Participants in clinical response (at Week 8 or Week 16) to Induction treatment with single IV infusion of Ustekinumab will be randomized to receive ustekinumab 90 mg subcutaneously every 8 weeks, beginning Week 0 of Maintenance study through Week 44. arm 9: Participants in clinical response to Induction treatment with IV Placebo will receive placebo subcutaneously, beginning Week 0 of Maintenance study through Week 44. Participants are not randomized. arm 10: Participants without clinical response to induction treatment ustekinumab (130 mg or 6 mg/kg \[IV\]) at Week 8 but in clinical response at Week 16 after receiving Induction Ustekinumab at week 8 (delayed responders) will receive ustekinumab 90 mg subcutaneously every 8 weeks, beginning Week 0 of Maintenance study through Week 44. Participants are not randomized.
Interventions: intervention 1: Placebo IV intervention 2: Placebo SC intervention 3: Ustekinumab IV intervention 4: Ustekinumab SC
Intervention descriptions: intervention 1: Placebo will be administered as intravenous infusion. intervention 2: Placebo will be administered Subcutaneously. intervention 3: Ustekinumab will be administered as intravenous infusion at Week 0 or Week 8 in Induction Study. intervention 4: Ustekinumab will be administered as subcutaneously.

Protocol documents:
Prot_002.pdf: 
1
Approved, Date: 20 April 2016
Janssen Research & Development*
Clinical Protocol
A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter 
Protocol to Evaluate the Safety and Efficacy of Ustekinumab Induction and Maintenance 
Therapy in Subjects with Moderately to Severely Active Ulcerative Colitis
UNIFI
Protocol CNTO1275UCO3001; Phase 3
AMENDMENT 2
Ustekinumab (CNTO1275)
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen 
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc.; Janssen Sciences Ireland UC; or Janssen 
Research & Development, LLC. The term “sponsor” is used throughout the protocol to represent these 
various legal entities; the sponsor is identified on the Contact Information page that accompanies the 
protocol.
This study will be conducted under US Food & Drug Administration IND regulations 
(21 CFR Part 312).
EudraCT NUMBER:
2014-005606-38
Status:
Approved
Date:
20 April 2016
Prepared by:
Janssen Research & Development, LLC 
EDMS number:
EDMS-ERI-93839620
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
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Ustekinumab (CNTO1275)
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Approved, Date: 20 April 2016
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 6
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 6
PROTOCOL AMENDMENTS....................................................................................................................... 7
SYNOPSIS.................................................................................................................................................. 25
TIME AND EVENTS SCHEDULE: INDUCTION STUDY........................................................................... 33
TIME AND EVENTS SCHEDULE: MAINTENANCE STUDY .................................................................... 35
TIME AND EVENTS SCHEDULE: LONG-TERM EXTENSION ................................................................ 37
ABBREVIATIONS ...................................................................................................................................... 38
1.
INTRODUCTION................................................................................................................................ 40
1.1.
Background .................................................................................................................................... 40
1.1.1.
Ustekinumab in Crohn’s Disease ............................................................................................... 41
1.2.
Overall Rationale for the Study...................................................................................................... 42
2.
OBJECTIVES AND HYPOTHESES.................................................................................................. 43
2.1.
Objectives ...................................................................................................................................... 43
2.1.1.
Induction Study........................................................................................................................... 43
2.1.1.1.
Primary Objectives .................................................................................................................. 43
2.1.1.2.
Secondary Objectives.............................................................................................................. 43
2.1.2.
Maintenance Study..................................................................................................................... 44
2.1.2.1.
Primary Objectives .................................................................................................................. 44
2.1.2.2.
Secondary Objectives.............................................................................................................. 44
2.1.3.
Exploratory Objectives................................................................................................................ 44
2.2.
Hypotheses .................................................................................................................................... 45
2.2.1.
Induction Study........................................................................................................................... 45
2.2.2.
Maintenance Study..................................................................................................................... 45
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 45
3.1.
Overview of Study Design.............................................................................................................. 45
3.1.1.
Induction Study........................................................................................................................... 47
3.1.2.
Maintenance Study..................................................................................................................... 50
3.1.2.1.
Management of Clinical Flare and Loss of Response............................................................. 52
3.1.3.
Long-Term Extension ................................................................................................................. 53
3.2.
Study Design Rationale.................................................................................................................. 54
3.2.1.
Study Population......................................................................................................................... 54
3.2.1.1.
Induction .................................................................................................................................. 55
3.2.1.2.
Maintenance ............................................................................................................................ 56
3.2.2.
Endpoints.................................................................................................................................... 56
3.2.2.1.
Induction .................................................................................................................................. 56
3.2.2.2.
Maintenance ............................................................................................................................ 56
3.2.3.
Efficacy Assessments................................................................................................................. 56
3.2.4.
Pharmacokinetic Assessments................................................................................................... 56
3.2.5.
DNA and Biomarker Collection................................................................................................... 57
3.2.6.
Patient-Reported Outcomes on Health-Related Quality of Life.................................................. 57
3.2.7.
Health Economics and Medical Resource Utilization ................................................................. 57
3.2.8.
Control, Randomization, and Blinding in the Induction and Maintenance Studies..................... 57
3.2.9.
Dose Rationale ........................................................................................................................... 58
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3.2.9.1.
Induction .................................................................................................................................. 58
3.2.9.2.
Maintenance ............................................................................................................................ 59
4.
SUBJECT POPULATION.................................................................................................................. 59
4.1.
Inclusion Criteria ............................................................................................................................ 59
4.2.
Exclusion Criteria ........................................................................................................................... 63
4.3.
Prohibitions and Restrictions ......................................................................................................... 67
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 67
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 70
6.1.
Induction Study .............................................................................................................................. 70
6.2.
Maintenance Study ........................................................................................................................ 70
7.
TREATMENT COMPLIANCE............................................................................................................ 70
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 70
8.1.1.
Induction Study........................................................................................................................... 71
8.1.1.1.
Restricted or Prohibited Medications/Therapies...................................................................... 71
8.1.1.1.1.
Restricted Medications/Therapies........................................................................................ 71
8.1.1.1.2.
Prohibited Medications/Therapies........................................................................................ 72
8.1.2.
Maintenance Study..................................................................................................................... 72
8.1.2.1.
Rescue Medication on Loss of Response............................................................................... 72
8.1.2.2.
Oral 5-ASA Compounds and Immunomodulators................................................................... 72
8.1.2.3.
Corticosteroids......................................................................................................................... 73
8.1.2.4.
Restricted or Prohibited Medications/Therapies...................................................................... 73
9.
STUDY EVALUATIONS .................................................................................................................... 74
9.1.
Study Procedures........................................................................................................................... 74
9.1.1.
Overview..................................................................................................................................... 74
9.1.2.
Screening Phase ........................................................................................................................ 74
9.1.3.
Induction Study........................................................................................................................... 76
9.1.4.
Maintenance Study..................................................................................................................... 77
9.1.4.1.
Management of Clinical Flare and Loss of Response............................................................. 78
9.1.5.
Long-Term Extension ................................................................................................................. 79
9.1.5.1.
Dose Adjustment During the LTE............................................................................................ 80
9.2.
Efficacy........................................................................................................................................... 80
9.2.1.
Evaluations ................................................................................................................................. 80
9.2.2.
Endpoints.................................................................................................................................... 83
9.2.2.1.
Induction .................................................................................................................................. 83
9.2.2.1.1.
Primary Endpoint.................................................................................................................. 83
9.2.2.1.2.
Major Secondary Endpoints................................................................................................. 84
9.2.2.1.3.
Other Secondary Endpoints................................................................................................. 84
9.2.2.2.
Maintenance ............................................................................................................................ 85
9.2.2.2.1.
Primary Endpoint.................................................................................................................. 85
9.2.2.2.2.
Major Secondary Endpoints................................................................................................. 85
9.2.2.2.3.
Other Secondary Endpoints................................................................................................. 85
9.2.2.3.
Exploratory Endpoints ............................................................................................................. 86
9.2.2.4.
Efficacy Endpoint Definitions................................................................................................... 86
9.3.
Pharmacokinetics and Immunogenicity ......................................................................................... 87
9.3.1.
Evaluations ................................................................................................................................. 87
9.3.1.1.
Endpoints................................................................................................................................. 87
9.3.2.
Analytical Procedures................................................................................................................. 87
9.3.2.1.
Pharmacokinetics .................................................................................................................... 87
9.3.2.2.
Immunogenicity ....................................................................................................................... 88
9.3.3.
Pharmacokinetic Parameters ..................................................................................................... 88
9.3.4.
Immunogenicity Assessments (Antibodies to Ustekinumab)...................................................... 88
9.4.
Biomarkers ..................................................................................................................................... 88
9.4.1.
Serum ......................................................................................................................................... 88
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9.4.2.
Fecal Biomarkers........................................................................................................................ 88
9.4.3.
Mucosal Biopsy RNA and Histology........................................................................................... 89
9.5.
Genetic and Epigenetic (DNA) Evaluations ................................................................................... 89
9.6.
Health Economics and Medical Resource Utilization .................................................................... 89
9.7.
Safety Evaluations ......................................................................................................................... 90
9.8.
Sample Collection and Handling.................................................................................................... 94
10.
SUBJECT COMPLETION/WITHDRAWAL....................................................................................... 94
10.1.
Completion ..................................................................................................................................... 94
10.1.1.
Induction Study........................................................................................................................... 94
10.1.2.
Maintenance Study..................................................................................................................... 94
10.1.3.
Long-Term Extension ................................................................................................................. 94
10.2.
Discontinuation of Study Agent...................................................................................................... 95
10.3.
Withdrawal From the Study............................................................................................................ 96
11.
STATISTICAL METHODS................................................................................................................. 97
11.1.
Subject Information ........................................................................................................................ 98
11.2.
Sample Size Determination ........................................................................................................... 98
11.2.1.
Induction Study........................................................................................................................... 98
11.2.2.
Maintenance Study................................................................................................................... 100
11.3.
Efficacy Analyses ......................................................................................................................... 103
11.3.1.
Induction Study......................................................................................................................... 103
11.3.1.1.
Population for Efficacy Analyses ........................................................................................... 103
11.3.1.2.
Primary Analysis.................................................................................................................... 103
11.3.1.3.
Major Secondary Endpoint Analyses .................................................................................... 104
11.3.1.4.
Other Planned Analyses........................................................................................................ 105
11.3.2.
Maintenance Study................................................................................................................... 106
11.3.2.1.
Population for Efficacy Analyses ........................................................................................... 106
11.3.2.2.
Primary Analysis.................................................................................................................... 106
11.3.2.3.
Major Secondary Endpoint Analyses .................................................................................... 108
11.3.2.4.
Other Planned Analyses........................................................................................................ 108
11.3.3.
Exploratory Analyses................................................................................................................ 110
11.3.4.
Criteria for Endpoints................................................................................................................ 110
11.3.4.1.
Induction Study...................................................................................................................... 110
11.3.4.2.
Maintenance Study................................................................................................................ 111
11.4.
Pharmacokinetic Analyses........................................................................................................... 111
11.5.
Immunogenicity Analyses ............................................................................................................ 111
11.6.
Pharmacokinetic/Pharmacodynamic Analyses............................................................................ 112
11.7.
Biomarkers Analysis..................................................................................................................... 112
11.8.
Genetic and Epigenetic (DNA) Analysis ...................................................................................... 112
11.9.
Health Economics and Medical Resource Utilization Analyses................................................... 112
11.10.
Safety Analyses ........................................................................................................................... 112
11.11.
Interim Analysis............................................................................................................................ 113
11.11.1.
Induction Study......................................................................................................................... 113
11.11.2.
Maintenance Study................................................................................................................... 114
11.12.
Data Monitoring Committee ......................................................................................................... 114
12.
ADVERSE EVENT REPORTING .................................................................................................... 114
12.1.
Definitions .................................................................................................................................... 114
12.1.1.
Adverse Event Definitions and Classifications ......................................................................... 114
12.1.2.
Attribution Definitions................................................................................................................ 115
12.1.3.
Severity Criteria ........................................................................................................................ 116
12.2.
Special Reporting Situations........................................................................................................ 116
12.3.
Procedures................................................................................................................................... 117
12.3.1.
All Adverse Events.................................................................................................................... 117
12.3.2.
Serious Adverse Events ........................................................................................................... 117
12.3.3.
Pregnancy................................................................................................................................. 118
12.3.4.
Events of Special Interest......................................................................................................... 119
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12.4.
Contacting Sponsor Regarding Safety......................................................................................... 119
13.
PRODUCT QUALITY COMPLAINT HANDLING............................................................................ 119
13.1.
Procedures................................................................................................................................... 119
13.2.
Contacting Sponsor Regarding Product Quality .......................................................................... 120
14.
STUDY AGENT INFORMATION..................................................................................................... 120
14.1.
Physical Description of Study Agent(s)........................................................................................ 120
14.1.1.
Induction Study......................................................................................................................... 120
14.1.2.
Maintenance Study................................................................................................................... 120
14.2.
Packaging .................................................................................................................................... 120
14.3.
Labeling........................................................................................................................................ 121
14.4.
Preparation, Handling, and Storage............................................................................................. 121
14.5.
Drug Accountability ...................................................................................................................... 121
15.
STUDY-SPECIFIC MATERIALS..................................................................................................... 122
16.
ETHICAL ASPECTS ....................................................................................................................... 122
16.1.
Study-Specific Design Considerations......................................................................................... 122
16.2.
Regulatory Ethics Compliance..................................................................................................... 123
16.2.1.
Investigator Responsibilities ..................................................................................................... 123
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................. 123
16.2.3.
Informed Consent ..................................................................................................................... 124
16.2.4.
Privacy of Personal Data .......................................................................................................... 125
16.2.5.
Long-Term Retention of Samples for Additional Future Research .......................................... 126
16.2.6.
Country Selection ..................................................................................................................... 126
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 126
17.1.
Protocol Amendments.................................................................................................................. 126
17.2.
Regulatory Documentation .......................................................................................................... 127
17.2.1.
Regulatory Approval/Notification .............................................................................................. 127
17.2.2.
Required Prestudy Documentation........................................................................................... 127
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 128
17.4.
Source Documentation................................................................................................................. 128
17.5.
Case Report Form Completion .................................................................................................... 129
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 129
17.7.
Record Retention ......................................................................................................................... 130
17.8.
Monitoring .................................................................................................................................... 130
17.9.
Study Completion/Termination..................................................................................................... 131
17.9.1.
Study Completion ..................................................................................................................... 131
17.9.2.
Study Termination..................................................................................................................... 131
17.10.
On-Site Audits .............................................................................................................................. 131
17.11.
Use of Information and Publication.............................................................................................. 132
REFERENCES.......................................................................................................................................... 134
ATTACHMENTS....................................................................................................................................... 136
INVESTIGATOR AGREEMENT ............................................................................................................... 147
LAST PAGE.............................................................................................................................................. 147
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LIST OF ATTACHMENTS
Attachment 1:
Definition of Inadequate Initial Response, Loss of Response, or Intolerance to 
TNF Antagonist Therapies (Infliximab, Adalimumab, Golimumab, or Approved 
Biosimilars for Infliximab or Adalimumab) or Vedolizumab .................................................... 136
Attachment 2:
Definition of Inadequate Response to or Intolerance of Corticosteroids or 
AZA/6-MP and Corticosteroid Dependence ........................................................................... 141
Attachment 3:
QuantiFERON-TB Gold Testing .................................................................................. 142
Attachment 4:
Tuberculin Skin Testing ............................................................................................... 144
Attachment 5:
Mayo Score.................................................................................................................. 145
Attachment 6:
Anticipated Events ....................................................................................................... 146
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Schedule of events: Induction study......................................................................................... 33
Table 2:
Schedule of events: Maintenance study................................................................................... 35
Table 3:
Schedule of events: Long-term extension study....................................................................... 37
Table 4:
Power for detecting a treatment effect based on different proportions of subjects in 
clinical remission at Week 8 (global definition) with a fixed sample size of 951 subjects 
(317 per treatment group)......................................................................................................... 99
Table 5:
Power for detecting a treatment effect based on different proportions of subjects in 
clinical remission at Week 8 (US-specific definition) with a fixed sample size of 951 
subjects (317 per treatment group)........................................................................................... 99
Table 6:
Power for detecting a treatment effect based on different proportions of subjects in 
clinical remission (both global and US definitions) at Week 44 with a fixed sample size 
of 327 subjects (109 in each treatment group) ....................................................................... 101
Table 7:
Power for detecting a treatment effect for each of the major secondary endpoints with 
327 subjects in the primary population (109 in each treatment group) .................................. 102
Table 8:
Projected number of subjects in the primary population of the maintenance study  with 
a sample size of 951 subjects (317 per treatment group) in the induction study ................... 102
FIGURES
Figure 1:
Overall schema for CNTO1275UCO3001 protocol .................................................................. 46
Figure 2:
Schema for the CNTO1275UCO3001 induction study............................................................. 48
Figure 3:
Treatment of subjects who are not in clinical response to induction in 
CNTO1275UCO3001................................................................................................................ 49
Figure 4:
Schema for the CNTO1275UCO3001 maintenance study....................................................... 50
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PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
17 March 2015
Amendment 1
14 July 2015
Amendment 2
20 April 2016
Amendments below are listed beginning with the most recent amendment.
Amendment 2 (20 April 2016)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union. 
The overall reason for the amendment: To address health authority requests for additional data collection as well 
as to address investigator feedback and to provide further clarifications on the protocol.
Rationale: The text was corrected to clarify that the US-specific definition of clinical remission will be used to
support the US submission only, and a line was added to indicate that each definition will be applied to all subjects 
in the analysis population.
Synopsis; 
9.2.2, Endpoints

The following US-specific definition of clinical remission will be used in the United 
States:  an absolute stool number ≤3, a rectal bleeding subscore of 0, and a Mayo 
endoscopy subscore of 0 or 1.
Each definition of clinical remission will be applied to all subjects in the analysis 
population.
11.3.1.2, (Induction) 
Primary Analysis
The primary endpoint is clinical remission at Week 8. The definition of clinical remission 
(as well as the testing procedure) will be different for countries outside the United States 
and for the United States, as described below. Each definition of clinical remission will 
be based on all randomized subjects.
11.3.2.2, (Maintenance) 
Primary Analysis 
The primary endpoint is clinical remission at Week 44. The definition of clinical 
remission is different for countries outside the United States and for the United States, as 
described below. Each definition of clinical remission will be based on the primary 
population.
Rationale:  At the request of a health authority, collection of stool consistency data using the Bristol Stool Form 
Scale has been added as an exploratory analysis.
Synopsis (Objectives 
and Hypotheses); 
2.1.3, Exploratory 
Objectives
An exploratory objective for the Bristol Stool Form Scale was added:

To evaluate the data based on the Bristol Stool Form Scale score in the induction 
study.
Synopsis (Efficacy 
Evaluations/Endpoints); 
9.2.1, Evaluations
The Bristol Stool Form Scale was added to the bulleted list of efficacy evaluations in the 
Synopsis and at the start of Section 9.2.1, and a paragraph describing it was added to the 
text following the bullets in Section 9.2.1: 
The Bristol Stool Form Scale is a medical aid to classify the form (or consistency) of 
human feces into 7 categories.22 It has been used as a research tool to evaluate the 
effectiveness of treatments for various diseases of the bowel (eg, irritable bowel 
syndrome [IBS]).12 The daily average of the same 3-day period used to calculate the 
stool frequency and rectal bleeding subscores of the Mayo score will be used to 
calculate the average Bristol Stool Form Scale score for the visit.
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Table 1, Time and 
Events Schedule: 
Induction Study
The Bristol Stool Form Scale was added to the Time and Events Schedule: Induction, 
under the Efficacy assessments subhead, with data collection at Weeks I-0, I-2, I-4, I-8, 
and I-16.
9.1.2, Screening Phase
Text about the Bristol Stool Form Scale was added to the Screening Phase subsection:
Bristol Stool Form Scale diaries will also be provided to subjects to classify the form (or 
consistency) of their stools during the induction study (Section 9.2.1). 
Subjects will be instructed to complete Mayo diary cards and Bristol Stool Form Scale 
diaries 7 days immediately before each visit and bring them to every visit for data 
collection and review by the investigator/study coordinator. Bristol Stool Form Scale 
diaries are required only during the induction study.
9.2.2.3, Exploratory 
Endpoints
The section was updated to include an exploratory endpoint based on data collected using 
the Bristol Stool Form Scale (only in the induction study):

Average Bristol Stool Form Scale score over time in induction. 
11.3.3, Exploratory 
Analyses
A sentence about the Bristol Stool Form Scale was added to the Exploratory Analyses 
section:
Analyses of the average Bristol Stool Form Scale score over time in the induction 
study will be conducted.
References
Two references for the Bristol Stool Form Scale (Dove et al 2013 and Lewis/Heaton 
1997) were added to the References and other references were renumbered accordingly.
Rationale:  Because an exploratory objective was added for the Bristol Stool Form Scale evaluation in induction, 
the wording for the header and the existing objective was changed.
Synopsis (Objectives 
and Hypotheses); 
2.1.3, Exploratory 
Objectives
(2.1.3) Exploratory Objectives

To evaluate response using the Mayo score without the physician's global 
assessment (PGA) subscore in both induction and maintenance.

To evaluate the performance of the Bristol Stool Form Scale score in the induction 
study.
9.2.2.3, Exploratory 
Endpoints
9.2.2.3.
Exploratory Endpoints

Response using the Mayo score without the PGA subscore in both induction and 
maintenance. 

Average Bristol Stool Form Scale score over time in induction.
Rationale: If tuberculin is unavailable for the skin test, this method of testing will be considered not required for 
Ukrainian study centers. QuantiFERON-TB Gold and chest radiograph must still be done if tuberculosis (TB) is 
suspected, along with referral to a TB specialist if possible.
Table 1, Time and 
Events Schedule:
Induction, footnote h
h. All subjects will undergo QuantiFERON-TB Gold testing. In countries where the 
QuantiFERON-TB Gold test is not registered/approved, TB skin testing will also be 
required (recommended but not required for study centers in Ukraine if tuberculin is not 
available).
Table 1, Time and 
Events Schedule:
Induction, and Table 3, 
Time and Events 
Schedule: Long-Term 
Extension, footnote m; 
Table 2, Time and 
Events Schedule: 
Maintenance Study,
footnote k
The following footnote was revised in each of the three Time and Events Schedules:
If TB is suspected at any time, a chest radiograph and QuantiFERON-TB Gold test 
should be performed. In countries where the QuantiFERON-TB Gold test is not 
registered/approved, TB skin testing should also be performed (recommended but not 
required for study centers in Ukraine if tuberculin is not available). 
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Ustekinumab (CNTO1275)
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4.1, Inclusion Criteria, 
10d
The following sentence was added at the end of Inclusion Criterion 10d: 
A tuberculin skin test is recommended but not required for study centers in Ukraine if
tuberculin is not available.
9.1.2, Screening Phase
The following paragraph was revised:
Subjects with a negative QuantiFERON-TB Gold test result (and a negative tuberculin 
skin test result in countries in which the QuantiFERON-TB Gold test is not 
approved/registered or the tuberculin skin is mandated by local health authorities) are 
eligible to continue with prerandomization procedures. A tuberculin skin test is 
recommended but not required for study centers in Ukraine if tuberculin is not available. 
Subjects with a newly identified positive QuantiFERON-TB Gold (or tuberculin skin) 
test result must undergo an evaluation to rule out active TB and initiate appropriate 
treatment for latent TB. Appropriate treatment for latent TB is defined according to local
country guidelines for immunocompromised patients. If no local country guidelines for 
immunocompromised patients exist, US guidelines must be followed, or the subject will 
be excluded from the study. 
9.7 Safety Evaluations, 
Early Detection of 
Active Tuberculosis
The last paragraph was revised as follows:
Subjects who experience close contact with an individual with active TB during the 
conduct of the study must have a repeat chest radiograph, a repeat QuantiFERON®-TB 
Gold test, a repeat tuberculin skin test (Attachment 4) in countries in which the 
QuantiFERON-TB Gold test is not approved/registered or tuberculin skin testing is 
mandated by local health authorities, and, if possible, referral to a physician specializing 
in TB to determine the subject’s risk of developing active TB and whether treatment for 
latent TB is warranted. A tuberculin skin test is recommended but not required for study 
centers in Ukraine if tuberculin is not available. If the QuantiFERON-TB Gold test result 
is indeterminate, the test should be repeated as outlined in Section 9.1.2.  Subjects should 
be encouraged to return for all subsequent scheduled study visits as specified in the Time 
and Events Schedules. 
10.2, Discontinuation 
of Study Agent

A subject undergoing evaluation has a chest radiograph with evidence of 
current active TB and/or a positive QuantiFERON-TB Gold test result (and/or 
a positive tuberculin skin test result in countries in which the QuantiFERON-
TB Gold test is not approved/registered or the tuberculin skin test is mandated 
by local health authorities [recommended but not required for study centers in 
Ukraine if tuberculin is not available]), unless active TB can be ruled out and 
appropriate treatment for latent TB can be initiated before the next 
administration of study agent and continued to completion. Indeterminate 
QuantiFERON-TB Gold test results should be handled as described in 
Section 9.1.2. Subjects with persistently indeterminate QuantiFERON-TB 
Gold test results may continue without treatment for latent TB, if active TB is 
ruled out, their chest radiograph shows no abnormality suggestive of TB 
(active or old, inactive TB) and the subject has no additional risk factors for 
TB as determined by the investigator. This determination must be promptly 
reported to the sponsor’s medical monitor and recorded in the subject's source 
documents and initialed by the investigator.
Attachment 3, 
QuantiFERON-TB 
Gold Testing: 
Adherence to Local 
Guidelines
A sentence was added to the second (and final) paragraph: 
In countries in which the QuantiFERON®-TB Gold test is not considered 
approved/registered, a tuberculin skin test is additionally required.  In Ukraine, the 
tuberculin skin test is recommended but not required if tuberculin is not available.
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Attachment 4, 
Tuberculin Skin 
Testing: Treatment of 
Latent Tuberculosis
The following sentence was added as the second (and final) paragraph: 
In Ukraine, the tuberculin skin test is recommended but not required if tuberculin is not 
available.
Rationale:  To be consistent with Table 2 (Time and Events Schedule: Maintenance), in which study agent 
administrations at Weeks 20 and 28 were removed with Protocol Amendment 1, the corresponding marks for those 
administrations were deleted from Figure 1.
3.1 (Figure 1)
Study agent administration marks were deleted for Weeks 20 and 28 of the maintenance 
study. 
Rationale:  Respiratory rate was added in the appropriate footnotes in each of the Time and Events Schedules and in 
text to clarify that it is among the vital signs to be collected during the study.
Table 1, footnote n; 
Table 2, footnote i; 
Table 3, footnote k
Temperature, pulse/heart rate, respiratory rate, and blood pressure.
9.7, Safety Evaluations
Vital Signs
Vital signs (including temperature, pulse/heart rate, respiratory rate, and blood pressure) 
will be obtained…
Rationale:  The order of the third and fourth secondary objectives/major secondary endpoints in the maintenance 
study has been reversed. In addition, the analysis population for the objective/endpoint of corticosteroid-free 
remission at Week 44 (now the third secondary objective/major secondary endpoint) has been updated to include all 
subjects randomized into the maintenance study regardless of corticosteroid use at the M-0 visit (instead of being 
limited to only subjects who were receiving corticosteroids at the M-0 visit). This analysis will thereby evaluate the 
overall impact of ustekinumab maintenance therapy on achieving clinical remission while either eliminating or 
preventing the use of corticosteroids in subjects induced into clinical response with ustekinumab. The previous 
endpoint of corticosteroid-free remission at Week 44 in subjects induced into clinical response with ustekinumab 
and receiving corticosteroids at Week 0 of maintenance has been moved to the Other Secondary Endpoints section. 
Maintaining clinical remission in subjects induced into clinical remission with ustekinumab (now the fourth 
secondary objective/major secondary endpoint) has been retained, reflecting its significance as a desired treatment 
effect. In recognition of this objective/endpoint as a subgroup analysis, however, it has been moved to follow the 
corticosteroid-free remission objective/endpoint discussed above.
Synopsis (Maintenance 
Study, Secondary 
Objectives); 
2.1.2.2, Secondary 
Objectives 
(Maintenance Study)
(2.1.2.2) Secondary Objectives

To evaluate the efficacy of ustekinumab in maintaining clinical response in subjects 
induced into clinical response with ustekinumab.

To evaluate endoscopic healing (ie, improvement in the endoscopic appearance of 
the mucosa) in subjects induced into clinical response with ustekinumab.

To evaluate the efficacy of ustekinumab in achieving corticosteroid-free clinical 
remission in subjects induced into clinical response with ustekinumab.

To evaluate the efficacy of ustekinumab in maintaining clinical remission in 
subjects induced into clinical remission with ustekinumab. 
… (additional secondary objectives)
Synopsis (Maintenance 
Endpoints)
The following are the major secondary endpoints in the maintenance study, presented 
in the order in which they will be tested:  maintenance of clinical response through 
Week 44; endoscopic healing at Week 44; clinical remission and not receiving 
concomitant corticosteroids at Week 44; and maintenance of clinical remission through 
Week 44 among the subjects who had achieved clinical remission at maintenance 
baseline.
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3.1.2, Maintenance 
Study
The primary endpoint of the maintenance study is clinical remission at Week 44 among 
subjects who were responders to IV ustekinumab induction. The major secondary 
endpoints of the maintenance study are maintenance of clinical response through 
Week 44; endoscopic healing at Week 44; clinical remission and not receiving 
concomitant corticosteroids at Week 44; and maintenance of clinical remission through 
Week 44 among the subjects who had achieved clinical remission at maintenance 
baseline.
9.2.2.2.2, Major 
Secondary Endpoints
The following are the major secondary endpoints, which are presented in the order in 
which they will be tested:

Maintenance of clinical response through Week 44. 

Endoscopic healing at Week 44. 

Clinical remission and not receiving concomitant corticosteroids at Week 44.

Maintenance of clinical remission through Week 44 among the subjects who had 
achieved clinical remission at maintenance baseline. 
9.2.2.2.3, Other 
Secondary Endpoints; 
11.3.2.4, Other Planned 
Analyses
The previous major secondary endpoint of corticosteroid-free remission in subjects 
induced into clinical response with ustekinumab and receiving corticosteroids at Week 0 
of maintenance was moved to the subsection of Other Secondary Endpoints:
… (first 13 other secondary endpoints/10 other planned analyses)

Clinical remission and not receiving concomitant corticosteroids at Week 44 among 
the subjects receiving concomitant corticosteroids at maintenance baseline.
11.2.2, Table 7
The order of the third and fourth major secondary endpoints in the power calculations 
shown in Table 7 was revised.  The power to detect a treatment effect for the (new) third 
major secondary endpoint (corticosteroid-free remission at Week 44) also changed 
because of the revision of the analysis population for the endpoint to include all subjects 
randomized into the maintenance study, regardless of corticosteroid use at the M-0 visit:
Table 7:Power for detecting a treatment effect for each of the major secondary 
endpoints with 327 subjects in the primary population (109 in each 
treatment group)
Major secondary endpoints
Proportion of subjects 
achieving the endpoint
Powera 
(%)
Placebo
Ustekinumab
Maintenance of clinical response through 
Week 44
25
50
97
Endoscopic healing at Week 44
25
45
88
Clinical remission and not receiving 
concomitant corticosteroids at Week 44
15
30
76
Maintenance of clinical remission through 
Week 44 among the subjects who had 
achieved clinical remission at maintenance 
baseline (both global and US definitions) b
25
50
65
a: Based on testing the SC ustekinumab 90 mg q8w group versus placebo at α=0.05 (2-sided).
b: It is estimated that about 37% of subjects in the primary population (40 subjects per treatment 
group) will be in clinical remission at Week 0 of maintenance.
Synopsis (Statistical 
Methods)
Maintenance:  Except for the fourth major secondary endpoint of maintenance of clinical 
remission, analyses of major secondary endpoints will be conducted using a 2-sided 
CMH chi-square test stratified by clinical remission status at maintenance baseline (as 
determined by the IWRS) and induction treatment. For the fourth major secondary 
endpoint, a 2-sided CMH chi-square test stratified by induction treatment will be used. 
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Clinical Protocol CNTO1275UCO3001 Amendment 2
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11.3.2.3, Major 
Secondary Endpoint 
Analyses
Except for the fourth major secondary endpoint of maintenance of clinical remission, 
analyses of major secondary endpoints will be conducted using a 2-sided CMH chi-
square test stratified by clinical remission status at maintenance baseline (as determined 
by the IWRS) and induction treatment. For the fourth major secondary endpoint, a 2-
sided CMH chi-square test stratified by induction treatment will be used. Note that, for 
the United States, for the fourth major secondary endpoint of maintenance of clinical 
remission through Week 44 among the subjects who had achieved clinical remission at 
maintenance baseline, the US-specific definition of clinical remission should also be used 
to determine whether or not a subject had achieved clinical remission at maintenance 
baseline.
Rationale:  Text was added to clarify procedures to determine clinical flare and loss of response.
Table 2, Time and 
Events Schedule: 
Maintenance, 
footnote b
b. Subjects in clinical flare who have not previously met the criteria for loss of clinical 
response (ie, are in clinical flare for the first time or have flared previously and not met 
the criteria for loss of response) should complete all visit assessments indicated for the 
M-44 visit (including an endoscopy, which need only be a sigmoidoscopy) during their 
scheduled visit or at any unscheduled visit. Subjects with subsequent clinical flares after 
loss of clinical response should complete all assessments indicated for the visit at which 
the clinical flare occurred.
Table 2, Time and 
Events Schedule: 
Maintenance, footnote l
l.
A subject who meets the criteria for clinical flare but has not previously met the 
criteria of loss of clinical response (ie, is in clinical flare for the first time or flared 
previously and not met the criteria for loss of response) should undergo an additional 
endoscopy (which need only be a sigmoidoscopy) to determine loss of response based on 
the Mayo score. An endoscopy is not required if the subject has a subsequent clinical 
flare after loss of response criteria were met for the previous clinical flare.
3.1.2.1, Management of 
Clinical Flare and Loss 
of Response
In paragraph 2, sigmoidoscopy was added as an acceptable type of endoscopy required to 
establish loss of response: 
Subjects in clinical flare who have not previously met the criteria for loss of clinical 
response in the maintenance study (ie, are in clinical flare for the first time or have flared 
previously and not met the criteria for loss of response) should undergo endoscopy, 
which need only be a sigmoidoscopy, and be evaluated for loss of clinical response…
New text was added as paragraph 6:
Subjects will be strongly encouraged to undergo endoscopy at the time of first clinical 
flare to establish if loss of clinical response criteria were met. A subject who declines to 
undergo an endoscopy on initial clinical flare will be assessed for partial Mayo response 
16 weeks after the initial flare.
9.1.4.1, Management of 
Clinical Flare and Loss 
of Response
A sentence was added at the end of paragraph 2: 
Subjects who meet the criteria for clinical flare and who have not previously met the 
criteria for loss of clinical response in the maintenance study (ie, are in clinical flare for 
the first time or have flared previously and not met the criteria for loss of response) 
should undergo an endoscopy to assess the Mayo endoscopy subscore, as well as the 
safety and efficacy evaluations specified for the M-44 visit (Table 2) during their 
scheduled visit or at any unscheduled visit. The endoscopy at the time of clinical flare 
need only be a sigmoidoscopy. The Mayo score should be calculated from the partial 
Mayo obtained at the assessment for clinical flare and the subsequent Mayo endoscopy 
subscore as assigned by the local endoscopist. 
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Clinical Protocol CNTO1275UCO3001 Amendment 2
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New text was added as the second-to-last paragraph:
Subjects will be strongly encouraged to undergo endoscopy at the time of first clinical 
flare to establish if loss of clinical response criteria were met. A subject who declines to 
undergo an endoscopy on initial clinical flare will be assessed for partial Mayo response 
16 weeks after the initial flare. 
Rationale:  Beclomethasone dipropionate was added to Inclusion Criterion 6e because this extended-release 
formulation is approved for the treatment of UC in some regions where this study is being conducted. (Renumbered 
as 6.e.1.)
4.1, Inclusion Criteria, 
6e
e. If receiving budesonide or beclomethasone dipropionate, the dose must have been 
stable for at least 2 weeks.
Rationale:  Specific reference to budesonide as a corticosteroid was deleted from selected Inclusion Criteria and in 
text because use of the term “corticosteroids” includes prednisone-like corticosteroids as well as corticosteroids that 
have been developed for targeted delivery to the colon (ie, budesonide and beclomethasone dipropionate) and are 
approved for the treatment of UC in some regions where this study is being conducted.
4.1, Inclusion Criteria, 
6f
f.
If oral 5-ASA compounds or oral corticosteroids have been recently discontinued, 
they must have been stopped for at least 2 weeks. (Renumbered as 6.f.1.)
4.1, Inclusion Criteria, 
7e
e. Rectal corticosteroids (ie, corticosteroids administered to the rectum or sigmoid colon 
via foam or enema or suppository) for at least 2 weeks. (Renumbered as 7.e.1.)
8.1.1, Induction Study

Oral corticosteroids.
8.1.1.1.1, Restricted 
Medications/Therapies

Rectal corticosteroids (ie, corticosteroids administered to the rectum or sigmoid colon 
via foam, enema, or suppository).
8.1.2.3, Corticosteroids
Oral corticosteroids for UC should not be initiated or have the dose increased during 
the maintenance study, unless corticosteroids are used as rescue medication for loss of 
response (Section 3.1.2.1). 
For subjects who are receiving oral corticosteroids on entry into the maintenance study,
the investigator should begin tapering the daily dose of corticosteroids beginning at 
Week 0 of the maintenance study.
9.1.4, Maintenance 
Study
All subjects enrolled in the maintenance study will be responders to study agent 
administered in the induction study (ie, have received study agent at Week 0 in the 
induction study and been in clinical response at Week 8, or at Week 16 in subjects who 
were not responders at Week 8). Subjects who initiated or increased their dose of UC 
medications (ie, oral 5-ASAs, oral corticosteroids, or the immunomodulators AZA, 
6-MP, or MTX) or initiated a restricted or prohibited medication during the 
induction study are not eligible to enter maintenance.
Rationale:   The word “full” was added to Inclusion Criteria 8 and 9 to clarify the extent of the colonoscopy that 
satisfies these criteria. Corresponding changes were made in Table 1 and in Section 9.1.2.
4.1, Inclusion Criteria, 
8
8. A subject 45 years of age must either have had a full colonoscopy to assess for the 
presence of adenomatous polyps within 5 years before the first administration of study 
agent or a full colonoscopy to assess for the presence of adenomatous polyps at the 
screening visit. The adenomatous polyps must be removed before the first administration 
of study agent. (Renumbered as 8.1.)
4.1, Inclusion Criteria, 
9
9. A subject who has had extensive colitis for 8 years, or disease limited to the left side 
of the colon for 10 years, must either have had a full colonoscopy to assess for the 
presence of dysplasia within 1 year before the first administration of study agent or a full 
colonoscopy to assess for the presence of malignancy at the screening visit. (Renumbered 
as 9.1.)
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Ustekinumab (CNTO1275)
Clinical Protocol CNTO1275UCO3001 Amendment 2
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Approved, Date: 20 April 2016
Table 1, Time and 
Events Schedule:
Induction, footnote p
p. The screening endoscopy must be performed within 2 weeks before the I-0 visit. The 
interval from the endoscopy procedure to the availability of the Mayo endoscopy 
subscore as assessed by the central reader is approximately 4 days; therefore, the 
screening endoscopy must be performed at least 4 days before the baseline (I-0) visit. The 
Mayo endoscopy subscore assessed by the central reader will be used to determine 
eligibility (ie, Mayo endoscopy subscore ≥2) and to calculate the baseline Mayo score. A 
full colonoscopy will replace a sigmoidoscopy if screening for polyps or dysplasia is 
required. At least 48 hours must elapse between a colonoscopy with polypectomy and the 
I-0 visit.
9.1.2, Screening Phase
The screening endoscopy must be performed within 2 weeks (and at least 4 days) 
before the induction Week 0/baseline (I-0) visit. Subjects who are identified as being at 
increased risk for colon cancer (Inclusion Criterion 9) or for adenomatous polyps 
(Inclusion Criterion 8) will undergo a full colonoscopy instead of a sigmoidoscopy to 
allow screening for dysplasia or to assess for the presence of adenomatous polyps, 
respectively. Any screening colonoscopy for malignancy should include surveillance 
biopsies consistent with local practice. At least 48 hours must elapse between a 
colonoscopy with polypectomy and the I-0 visit.
Rationale:  International System of Units (SI) equivalents were added to the specified results for screening 
laboratory tests in Inclusion Criterion 15 for clarity. 
4.1, Inclusion Criteria, 
15
15.
Has screening laboratory test results within the following parameters:
a.
Hemoglobin 8.0 g/dL (SI:  ≥80.0 g/L)
b.
White blood cell count (WBC) 3 × 103 cells/L (SI:  3.0 × 109 cells/L)
c.
Neutrophils 1.5 × 103 cells /L (SI:  1.5 × 109 cells/L)
d.
Platelets 100 × 103 cells /L (SI:  100 × 109 cells/L)
e.
Serum creatinine ≤1.5 mg/dL (SI:  133 mol/L)
f.
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
concentrations must be within 2 times the upper limit of the normal range 
(ULN) for the laboratory conducting the test.
Rationale:  An additional method of apheresis that has a similar mechanism of action was added to Exclusion 
Criterion 12e. (Renumbered as 12.e.1.)
4.2, Exclusion Criteria, 
12e
e. Apheresis (eg, Adacolumn or Cellsorba apheresis) within 2 weeks before the first 
administration of study agent. 
Rationale:  Exclusion Criterion 17 was updated to reflect the availability of highly effective antiviral therapy with 
HCV clearance (as measured by HCV RNA) leading to patients who remain seropositive but are considered to be 
clinically cured of their hepatitis C. (Renumbered as 17.1.)
4.2, Exclusion Criteria, 
17
17. Are seropositive for antibodies to hepatitis C virus (HCV) without a history of 
successful treatment, defined as being negative for HCV RNA at least 24 weeks after 
completing antiviral treatment. 
Rationale:  Exclusion Criterion 29 was updated to reference the most current (5th) edition of the Diagnostic and 
Statistical Manual of Mental Disorders. (Renumbered as 29.1.)
4.2, Exclusion Criteria, 
29
29. Has a history of drug or alcohol abuse according to the Diagnostic and Statistical 
Manual of Mental Disorders, 5th edition (DSM-V), within 1 year before screening. 
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Ustekinumab (CNTO1275)
Clinical Protocol CNTO1275UCO3001 Amendment 2
15
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Rationale:  The recommendation for tapering budesonide has been revised and tapering for beclomethasone 
dipropionate has been incorporated. These revisions reflect the current approved doses and the absence of general 
tapering guidelines for these specific corticosteroids.
8.1.2.3, Corticosteroids
Recommended tapering schedule for oral prednisone-equivalent corticosteroids: 

Subjects receiving >20 mg/day prednisone or equivalent:  taper daily dose by 
5 mg/week until 0 mg/day. 

Subjects receiving ≤20 mg/day prednisone or equivalent:  taper daily dose by 
2.5 mg/week until 0 mg/day.
Tapering of budesonide or beclomethasone dipropionate should follow local clinical 
practice.
Rationale:  Text was added to clarify unblinding related to the futility analysis and the third database lock during 
induction. 
5, Treatment Allocation 
and Blinding
In the Blinding subsection, the following text was added to paragraph 6:
In the induction study, at the first DBL for the futility analysis, the induction treatment 
assignment information will be unblinded for the first 30% of randomized subjects in the 
study and released for analysis to an external statistical support group (the sponsor will 
remain blinded). The induction treatment assignment for the remaining subjects and the 
maintenance treatment assignment information for all subjects will remain blinded at that 
time. Further details about unblinding for the futility analysis will be provided in the 
Interim Analysis Plan (IAP). At the second DBL when all randomized subjects in the 
induction study have either completed the I-8 visit or have terminated study participation 
before Week 8, the induction treatment assignment information will be unblinded for all 
subjects and released to selected sponsor personnel for analysis. The maintenance 
treatment assignment information for all subjects will remain blinded at that time. At the 
third DBL when all randomized subjects in the induction study have entered the 
maintenance study, or have completed their final safety visit (20 weeks after the last 
administration of study agent) for those not participating in the maintenance study, or 
have terminated their study participation, data will be released to selected sponsor 
personnel for analysis. The maintenance treatment assignment information for all 
subjects will continue to remain blinded at that time. Identification of sponsor personnel 
who will have access to the unblinded subject-level data at the time of each DBL will be 
documented before unblinding.
Rationale:  Guidance was added about what to do if a subject’s screening procedures cannot be completed within 
the specified 8-week window. 
9.1.2, Screening Phase
Completion of screening and randomization procedures within the specified 8-week 
window is required. If a subject is approaching the completion of that period, the medical 
monitor can be contacted to discuss eligibility. 
If any delay leads to the expiration of time-specific assessments (eg, TB, chest 
radiograph, stool analysis), the subject will be considered a screen failure because he/she 
will not meet eligibility criteria, and the expired assessments (along with the non-time-
specific laboratory tests) will have to be repeated on rescreening.
Rationale:  Text was revised to explicitly state the visit that represents the first opportunity for dose adjustment in 
the LTE. 
9.1.5.1, Dose 
Adjustment During the 
LTE
During the LTE, if a subject’s UC disease activity worsens (in the investigator’s 
judgment), the subject may be eligible for a dose adjustment, as described in 
Section 3.1.3. These subjects will be allowed 1 dose adjustment during the LTE. The 
IWRS will ensure that a subject is eligible for a dose adjustment and, if he or she is 
eligible, that SC ustekinumab is not administered more frequently than q8w. The first 
opportunity for dose adjustment in the LTE is at the Week 56 visit.
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Clinical Protocol CNTO1275UCO3001 Amendment 2
16
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Rationale:  To clarify which endoscopy score will be used to determine subject eligibility at baseline and for the 
primary and major secondary endpoints involving the endoscopy subscore. 
9.2.1, Evaluations
The Mayo score (Attachment 5) was developed from the criteria of Truelove and Witts34
for mild, moderate, and severe UC and from the criteria of Baron et al3 for grading 
endoscopic appearance. The Mayo score is calculated as the sum of 4 subscores (stool 
frequency, rectal bleeding, PGA, and endoscopy findings) and ranges from 0 to 12 points. 
A score of 3 to 5 points indicates mildly active disease, a score of 6 to 10 points indicates 
moderately active disease, and a score of 11 to 12 points indicates severe disease. The 
endoscopic findings will be assessed by the investigator (ie, local endoscopist) during the 
endoscopy procedure and by the central reader reviewing a video of the endoscopy. 
Subject eligibility at baseline will be based on the final reported endoscopic subscore as 
determined by the following process:

If the local endoscopist and the central reader agree on the endoscopic subscore, the 
agreed score will be the final reported endoscopic subscore.  

If there is a discrepancy between the local endoscopist and the central reader 
subscores, the video endoscopy will be submitted to a second central reader 
(designated for adjudication). The median score of the 3 completed reads (ie, local 
read, central read 1, and central read 2 designated for adjudication) will be the final 
reported endoscopic subscore.
Specific details will be provided in the imaging charter. A subject’s clinical response 
status at Week 8 (or Week 16) of the induction study, or loss of response status in the 
maintenance study, to determine subsequent treatment, will be based on the endoscopy 
subscore assigned by the local endoscopist.
9.2.2, Endpoints
The second paragraph was revised to cross-reference the new text in Section 9.2.1 
described above:
For the primary and major secondary endpoints involving the endoscopy subscore of the 
Mayo score (eg, clinical remission, clinical response, endoscopic healing), the final 
reported endoscopic subscore will be used, as described in Section 9.2.1. 
Rationale:  The Statistical Methods section was revised to specify that a fixed-sequence testing procedure will be 
used for the United States.
Synopsis (Statistical 
Methods: Primary 
Efficacy Analysis)
Maintenance:  The primary analysis is based on the primary population (ie, subjects who 
are in clinical response to IV ustekinumab induction). The primary endpoint is clinical 
remission at Week 44. The definition of clinical remission is different for countries 
outside of the United States and the United States. For both definitions of clinical 
remission, the comparisons between each ustekinumab treatment group and the placebo 
group will be conducted using a 2-sided CMH chi-square test stratified by clinical 
remission status at maintenance baseline (as determined by the interactive web response 
system [IWRS]) and induction treatment. For countries outside the United States, a fixed-
sequence testing procedure (ustekinumab 90 mg SC q8w will first be tested; if positive, 
then ustekinumab 90 mg SC q12w will be tested) will be used to control the overall Type 
I error rate at the 0.05 level for the primary endpoint. For the United States, a fixed-
sequence testing procedure will be employed to strongly control the overall Type 1 error 
rate at the 0.05 level across the primary and all 4 major secondary endpoints and across 
the 2 ustekinumab doses, starting with the high maintenance dose group of the primary 
endpoint.
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Clinical Protocol CNTO1275UCO3001 Amendment 2
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Approved, Date: 20 April 2016
11.2.2, Maintenance 
Study
The second paragraph was revised: 
A fixed-sequence testing procedure, starting with the high dose group (q8w), will be used 
to control the overall Type I error rate at the 0.05 level (2-sided). As such, sample 
size/power calculations were based on the chi-square test to detect a significant 
difference between subjects receiving SC ustekinumab 90 mg q8w and those receiving 
placebo.
11.3.2.2, Primary 
Analysis
Text was added to the subsection for countries outside the United States:
A fixed-sequence testing procedure will be used to control the overall Type I error 
rate at the 0.05 level for the primary endpoint. Specifically, the high maintenance 
dose group (ustekinumab 90 mg SC q8w) will first be compared with the placebo 
maintenance dose group at the 2-sided 0.05 level of significance. Only if this test is 
positive will the low maintenance dose group (ustekinumab 90 mg SC q12w) be 
compared with the placebo maintenance dose group at the 2-sided 0.05 level of 
significance.
The study will be considered positive if the test involving the high maintenance dose 
group (ustekinumab 90 mg SC q8w) is positive, regardless of the result of the test for 
the low maintenance dose group (ustekinumab 90 mg SC q12w).
Text was added to the subsection for the United States and the paragraph about Type I 
error control was deleted:
A fixed-sequence testing procedure will be employed for the United States to strongly 
control the overall Type 1 error rate at the 0.05 level across the primary and all 4 
major secondary endpoints and across the 2 ustekinumab doses, starting with the high 
maintenance dose group (ustekinumab 90 mg SC q8w) of the primary endpoint. The 
exact testing procedure will be detailed in the SAP before the Week 44 DBL in the 
maintenance study. The study will be considered positive if the test involving the high 
maintenance dose group is positive.
11.3.4.2, Maintenance 
Study
The last phrase of the first paragraph was deleted:
The maintenance study will be considered positive if the test involving the high 
maintenance dose group (ustekinumab 90 mg SC q8w) shows a statistically significant 
difference versus placebo for the maintenance primary endpoint, clinical remission at 
Week 44 (global definition for the countries outside the United States and US-specific 
definition for the United States).
Rationale:  In Attachment 1, “approved biosimilars” were added as TNF antagonist therapies to which definitions 
of inadequate initial response, loss of response, or intolerance can be applied to identify a subject as a biologic 
failure. Similar changes were made where applicable in the body of the protocol.
Attachment 1
Title changed:
Definition of Inadequate Initial Response, Loss of Response, or Intolerance to TNF 
Antagonist Therapies (Infliximab, Adalimumab, Golimumab, or Approved 
Biosimilars for Infliximab or Adalimumab) or Vedolizumab
Item I was revised as follows; similar changes were made in Items II and III:
I.
Inadequate initial response to at least 8 weeks of therapy with infliximab, 
adalimumab, or golimumab (or approved biosimilars for infliximab or adalimumab), 
or vedolizumab (primary nonresponse)
Eligible subjects must satisfy criteria A, B, and C.
A. Have received induction doses of:
•
REMICADE (infliximab; 3 intravenous [IV] doses ≥5 mg/kg) at Weeks 0, 2, 
and 6 (or approved biosimilar for infliximab)
OR
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•
Humira (adalimumab; subcutaneous [SC] doses of 160 mg at Week 0 and 
≥80 mg at Week 2 followed by a dose ≥40 mg every 2 weeks) or approved 
biosimilar for adalimumab
…
B. Did not initially respond to these induction doses of infliximab, adalimumab, 
golimumab (or approved biosimilars for infliximab or adalimumab), or 
vedolizumab, as evidenced by the presence of at least 1 of the following signs or 
symptoms related to persistence of ulcerative colitis (UC), as assessed by a 
treating physician:
…
These signs and symptoms of UC must have occurred ≥2 weeks after receiving 
the last induction dose of infliximab, adalimumab, golimumab (or approved 
biosimilars for infliximab or adalimumab), or vedolizumab and are offered only as 
a benchmark of the minimally acceptable criteria required to designate a subject as 
having had an inadequate initial response to infliximab, adalimumab, golimumab 
(or approved biosimilars for infliximab or adalimumab), or vedolizumab.
…
C. Have documentation available to the investigator that meets the following 2 
requirements:
•
Provides the dates and doses of the failed infliximab, adalimumab, golimumab 
(or approved biosimilars for infliximab or adalimumab), or vedolizumab induction 
therapy.
•
Documents that the subject had persistence of disease activity following 
infliximab, adalimumab, golimumab (or approved biosimilars for infliximab or 
adalimumab), or vedolizumab induction therapy.
4.1, Inclusion Criteria, 
7b
7.
The following medications/therapies must have been discontinued before first 
administration of study agent:
b.
TNF-antagonist therapy (eg, infliximab, etanercept, certolizumab, adalimumab, 
golimumab [or approved biosimilars for these therapies]) for at least 8 weeks. 
(Renumbered as 7.b.1.)
Rationale:  In Attachment 2, the corticosteroid text has been updated to include approved extended-release 
corticosteroids such as budesonide and beclomethasone dipropionate for the treatment of UC, and to clarify the 
definition of corticosteroid dependence.
Attachment 2, 
Definition of 
Inadequate Response to 
or Intolerance of 
Corticosteroids or 
AZA/6-MP and 
Corticosteroid 
Dependence
Text under the Corticosteroids subhead was revised as follows: 
Subjects have failed to respond to corticosteroids if they have had evidence of an 
initial inadequate response, recurrent disease, or a relapse despite receiving at least 
0.75 mg/kg/day or ≥40 mg/day of prednisone (or corticosteroid equivalent, given 
orally or intravenously) for 2 weeks; or ≥9 mg/day of budesonide or ≥5 mg/day of 
beclomethasone dipropionate given orally for at least 4 weeks.
Subjects are intolerant of corticosteroids if:
•
They have developed clinically significant adverse events (eg, osteonecrosis or 
osteoporosis, psychosis, uncontrolled diabetes) unresponsive to dose reduction that, in 
the judgment of the investigator, precluded the use of corticosteroids to treat 
ulcerative colitis (UC). 
OR
•
They have a medical condition that precludes the use of corticosteroids as a 
treatment for UC.
Subjects are corticosteroid dependent if they have failed to successfully taper their 
corticosteroid (ie, had a flare of disease) within 3 months of starting therapy, or if a 
relapse occurs within 3 months after stopping corticosteroids or if they are unable to 
discontinue these agents without flare within 3 months after starting them.
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Rationale:  Attachment 6, Anticipated Events, was added and text in Section 12.1.1, Adverse Event Definitions, and 
Section 12.3.1 was revised to comply with current protocol template requirements. 
12.1.1, Adverse Event 
Definitions (Adverse 
Events Associated with 
the Study Population)
Adverse Events Associated with the Study Population
Anticipated events are events that are considered common for the study population 
defined in this protocol and, when determined to be serious, should be reported by the 
investigator as described in Section 12.3.2. Anticipated events will be recorded and 
reported as described in Attachment 6.
12.3.1, All Adverse 
Events
The following sentence was added as the second paragraph:
Anticipated events will be recorded and reported as described in Attachment 6.
Attachment 6
Added to protocol; includes a revised list of events deleted from Section 12.1.1.
Rationale:  The estimated patient-years of exposure for ustekinumab was updated.
1.1, Background
Paragraph 3: 
Considerable data available from other completed or ongoing clinical studies of 
ustekinumab in additional indications (including Crohn’s disease, multiple sclerosis, 
primary biliary cirrhosis, sarcoidosis, and rheumatoid arthritis), together with extensive 
postmarketing data based on an estimated 551,966 person-years of exposure through 
31 December 2015, also support the safety profile of ustekinumab.
1.2, Overall Rationale 
for the Study
Paragraph 6, last sentence:
Finally, ustekinumab provides a novel mechanism of action in the treatment of UC, with 
a documented long-term safety profile in excess of 5 years of clinical data, which is 
complemented by postmarketing data representing 551,966 person-years of exposure.
Rationale:   Minor errors were noted and corrected.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
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Amendment 1 (14 July 2015)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment:  To address health authority feedback and provide additional 
clarifications.
Applicable Section(s)
Description of Change(s)
Rationale: At the request of a health authority, a sample collection for antibodies to ustekinumab has been moved 
during induction and another sample collection has been added during maintenance.
Table 1, Time and 
Events Schedule:
Induction Study
The sample collection for antibodies to ustekinumab was moved from the Week 2 visit to 
the Week 4 visit in induction.
Table 2, Time and 
Events Schedule:
Maintenance Study
A sample collection for antibodies to ustekinumab was added at the Week 4 visit in 
maintenance.
Rationale: Study agent administrations at Week 20 and Week 28 have been deleted from the Time and Events
Schedule for Maintenance because both administrations, for placebo only, are not required to maintain the study 
blind for either maintenance dose regimen.
Table 2, Time and 
Events Schedule:
Maintenance Study
In the Study agent administration row of the schedule, notations were deleted at Week 20 
and Week 28. 
Synopsis; 3.1.2, 
Maintenance Study; 5, 
Treatment Allocation 
and Blinding; 9.1.4, 
Maintenance Study
Because the Week 20 and 28 administrations were deleted, text indicating that study agent 
would be administered every 4 weeks in maintenance was revised throughout the protocol 
as follows: 
All subjects will receive their assigned dose of SC study agent at maintenance 
Week 0. Thereafter, to maintain the blind, all subjects will receive study agent at all 
scheduled study agent administration visits specified in the Time and Events Schedule 
for maintenance.
Rationale: The first dose of study agent in the long-term extension (LTE) will be at Week 48, not Week 44;
therefore, the Week 44 column has been deleted from the Time and Events Schedule for the LTE. Language was 
added to an existing footnote to clarify the timing of the first LTE dose and note that study agent will not be 
administered at Week 52, because only placebo would be given at that visit and therefore is not required to maintain 
the blind.
Table 3, Time and 
Events Schedule:
Long-Term Extension
The Week 44 column was deleted, along with footnote c, which was only applicable if 
study agent was administered at Week 44.
Footnote c (previously footnote d) was revised as follows:
c. The first study agent administration in the LTE will occur at Week 48; no study agent 
will be administered at Week 52. After the study is unblinded to the investigative 
sites, subjects receiving placebo will be terminated from study participation and 
subjects receiving ustekinumab will continue to receive ustekinumab, but will have 
study visits scheduled to coincide with their dose regimen (ie, either every 8 or every 
12 weeks).
Table 2, Time and 
Events Schedule:
Maintenance Study
Footnote h was deleted because it referenced study agent administration at Week 44 of the 
LTE.
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Approved, Date: 20 April 2016
Applicable Section(s)
Description of Change(s)
3.1.3, Long-Term 
Extension, 2nd 
paragraph; 
9.1.5, Long-Term 
Extension,
1st paragraph
Text in the body of the protocol was edited to indicate that the first dose of study agent in 
the LTE will occur at Week 48, not Week 44. 
Rationale: A notation was added in the Time and Events Schedule for the LTE to clarify the timing of the last 
potential dose of study agent during the LTE.
Table 3, Time and 
Events Schedule: 
Long-Term Extension
A study agent administration was added at Week 200 (ie, final efficacy visit) on the Time 
and Events Schedule for the LTE for the last dose of study agent.
Rationale: Text was added to clarify the first visit at which a subject is eligible for dose adjustment in the LTE.
3.1.3, Long-Term 
Extension, 4th
paragraph;
9.1.5.1, Dose 
Adjustment During the 
LTE
Text was added to indicate that Week 56 is the first visit at which a subject is eligible for 
dose adjustment in the LTE. 
The first visit at which a subject can be considered for a dose adjustment is at 
Week 56. Subjects will be allowed 1 dose adjustment during the LTE.
During the LTE, if a subject’s UC disease activity worsens (in the investigator’s 
judgment), the subject may be eligible for a dose adjustment, beginning at Week 56, 
as described in Section 3.1.3.
Rationale:  The Common Terminology Criteria for Adverse Events (CTCAE) defines a grade 1 AE for “white 
blood cell decreased” (ie, below the lower limit of normal) as <3 × 109/L (or 3.0 × 103/µL); therefore, for inclusion 
in the study, the permissible lower limit for a subject’s white blood cell count has been increased to at least 3 ×
103/µL.
4.1, Inclusion Criteria, 
15b
15. Has screening laboratory test results within the following parameters:
b. White blood cell count (WBC) ≥3 × 103/µL
Rationale:  To clarify that eligible subjects should have a serum creatinine level that is not higher than 1.5 mg/dL.
4.1, Inclusion Criteria, 
15e
15. Has screening laboratory test results within the following parameters:
e. Serum creatinine ≤1.5 mg/dL
Rationale:  Additional information about the Mayo score has been incorporated, including a Mayo Score 
attachment. Reference to the modified Mayo score was removed; it will be described in the SAP.
9.2.1, Evaluations
The Mayo score (Attachment 5) was developed from the criteria of Truelove and Witts34
for mild, moderate, and severe UC and from the criteria of Baron et al3 for grading 
endoscopic appearance. The Mayo score is calculated as the sum of 4 subscores (stool 
frequency, rectal bleeding, PGA, and endoscopy findings) and ranges from 0 to 12 points. 
A score of 3 to 5 points indicates mildly active disease, a score of 6 to 10 points indicates 
moderately active disease, and a score of 11 to 12 points indicates severe disease. The 
endoscopic findings will be assessed by the investigator (ie, local endoscopist) during the 
endoscopy procedure and by the central reader reviewing a video of the endoscopy. 
Subject eligibility at baseline will be based on the endoscopy subscores assigned by the 
central reader. Specific details will be provided in the imaging charter. A subject’s clinical 
response status at Week 8 (or Week 16) of the induction study, or loss of response status 
in the maintenance study, to determine subsequent treatment, will be based on the 
endoscopy subscore assigned by the local endoscopist. 
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Approved, Date: 20 April 2016
Applicable Section(s)
Description of Change(s)
Rationale:  Text was added to clarify that the global definition of clinical remission will also be used to stratify 
subjects randomized into the maintenance study.
9.2.2, Endpoints
A sentence was added to the global definition of clinical remission:
•
The following global definition of clinical remission will be used for countries 
outside the United States:  a Mayo score ≤2 points, with no individual subscore >1. 
This definition will also be used to stratify subjects by clinical remission status at 
maintenance baseline for the maintenance study.
Rationale:  A discontinuation criterion has been revised to include an absolute minimum value for blood pressure 
so that the subjects meeting symptomatic hypotension applying either of the 2 criteria (ie, based on a change in 
systolic blood pressure or a minimum blood pressure) are not permitted to receive additional study drug.
9.7, Safety 
Evaluations: Allergic 
Reactions;
10.2, Discontinuation 
of Study Agent
Subjects who experience reactions after an injection or infusion that result in 
bronchospasm with wheezing and/or dyspnea that requires ventilatory support OR that 
result in symptomatic hypotension with a decrease in systolic blood pressure >40 mm Hg 
or blood pressure <90/60 mm Hg will not be permitted to receive additional study agent.

A serious adverse reaction related to an injection or an infusion, including an 
injection site or infusion reaction, resulting in bronchospasm with wheezing and/or 
dyspnea that requires ventilatory support OR that results in symptomatic 
hypotension with a decrease in systolic blood pressure >40 mm Hg or blood pressure 
<90/60 mm Hg.
Rationale: As recommended by a Health Authority, the Cochran-Mantel-Haenszel test (rather than the logistic 
regression model) will be used for the primary and major secondary efficacy analyses for both the induction and 
maintenance studies.
11.3.1.2, Statistical 
Methods: Induction: 
Primary Analysis
The third and sixth paragraphs have been revised as follows: 
The comparison between each ustekinumab treatment group and the placebo group 
will be conducted using a 2-sided Cochran-Mantel-Haenszel (CMH) chi-square test 
stratified by biologic failure status (yes or no) and region (Eastern Europe, Asia, or 
rest of world).
The Bonferroni method will be used to control the overall Type I error rate at the 0.05 
level (2 sided) for comparisons of the 2 ustekinumab induction treatment groups with 
placebo, with each comparison being tested at the 0.025 level (2-sided). The 
comparison between each ustekinumab treatment group and the placebo group will be 
based on a 2-sided CMH chi-square test stratified by biologic failure status and region 
at the 0.025 level of significance.
Synopsis, Primary 
Efficacy Analysis: 
Induction
The corresponding section of the Synopsis has been revised as follows:  
Induction:  The primary analysis is based on all randomized subjects. The primary 
endpoint is clinical remission at Week 8. The definition of clinical remission (as well 
as the testing procedure) will be different for countries outside of the United States 
and for the United States. For the global definition of clinical remission, a step-up 
Hochberg testing procedure will be employed to control the Type 1 error. For the 
US-specific definition, the Bonferroni method will be used to control the overall 
Type I error rate at the 0.05 level (2-sided) for comparisons of the 2 ustekinumab 
induction treatment groups with placebo, with each comparison being tested at the 
0.025 level (2-sided). For both definitions of clinical remission, the comparisons 
between each ustekinumab treatment group and the placebo group will be conducted 
using a 2-sided Cochran-Mantel-Haenszel (CMH) chi-square test stratified by biologic 
failure status and region.
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Applicable Section(s)
Description of Change(s)
11.3.1.3, Statistical 
Methods: Induction: 
Major Secondary 
Endpoint Analyses
The first paragraph has been revised as follows: 
The major secondary endpoint analyses in the induction study will be based on all 
randomized subjects. The major secondary endpoints of endoscopic healing (ie, 
improvement in the endoscopic appearance of the mucosa) at Week 8 and clinical 
response at Week 8 will be compared between each ustekinumab treatment group and 
the placebo group using a 2-sided CMH chi-square test stratified by biologic failure 
status and region. For the major secondary endpoint of change from induction baseline 
in the IBDQ score at Week 8, the treatment groups will be compared using ANCOVA 
on the van der Waerden normal scores with induction baseline IBDQ score, biologic 
failure status, region, and treatment group as covariates.
Synopsis, Major 
Secondary Efficacy 
Analyses: Induction
The corresponding section of the Synopsis has been revised as follows:
Induction:  For the major secondary endpoints of endoscopic healing (ie, improvement 
in the endoscopic appearance of the mucosa) at Week 8 and clinical response at 
Week 8, the treatment groups will be compared using a 2-sided CMH chi-square test 
stratified by biologic failure status and region. For the major secondary endpoint of 
change from induction baseline in the IBDQ score at Week 8, the treatment groups 
will be compared using analysis of covariance (ANCOVA) on the van der Waerden 
normal scores with induction baseline IBDQ score, biologic failure status, region, and 
treatment group as covariates.
11.3.2.2, Statistical 
Methods: 
Maintenance: 
Primary Analysis
The third and fifth paragraphs have been revised as follows: 
The comparisons between each ustekinumab treatment group and the placebo group 
will be conducted using a 2-sided CMH chi-square test stratified by clinical remission 
status at maintenance baseline (yes/no as determined by the IWRS) and induction 
treatment (placebo IV [I-0] → ustekinumab ~6 mg/kg IV [I-8], ustekinumab 130 mg 
IV [I-0], or ustekinumab ~6 mg/kg IV [I-0]).
The comparison between each ustekinumab treatment group and the placebo group 
will be conducted using a 2-sided CMH chi-square test stratified by clinical remission 
status (as determined by the IWRS) at maintenance baseline and induction treatment.
Synopsis, Primary 
Efficacy Analysis: 
Maintenance
The corresponding section of the Synopsis has been revised as follows:
Maintenance:  The primary analysis is based on the primary population (ie, subjects 
who are in clinical response to IV ustekinumab induction). The primary endpoint is 
clinical remission at Week 44. The definition of clinical remission is different for 
countries outside of the United States and for the United States. For both definitions of 
clinical remission, the comparisons between each ustekinumab treatment group and 
the placebo group will be conducted using a 2-sided CMH chi-square test stratified by 
clinical remission status at maintenance baseline (as determined by the interactive web 
response system [IWRS]) and induction treatment. A fixed-sequence testing procedure 
(ustekinumab 90 mg SC q8w will first be tested; if positive, then ustekinumab 90 mg 
SC q12w will be tested) will be used to control the overall Type I error rate at the 0.05 
level for the primary endpoint.
11.3.2.3, Statistical 
Methods: 
Maintenance: Major 
Secondary Endpoint 
Analyses
The first 3 paragraphs have been revised into 2 paragraphs, as follows: 
The major secondary endpoint analyses will be based on the primary population. 
Except for the third major secondary endpoint of maintenance of clinical remission, 
analyses of major secondary endpoints will be conducted using a 2-sided CMH chi-
square test stratified by clinical remission status at maintenance baseline (as 
determined by the IWRS) and induction treatment. For the third major secondary 
endpoint, a 2-sided CMH chi-square test stratified by induction treatment will be used. 
Note that, for the United States, for the third major secondary endpoint of maintenance 
of clinical remission through Week 44 among the subjects who had achieved clinical 
remission at maintenance baseline, the US-specific definition of clinical remission 
should also be used to determine whether or not a subject had achieved clinical 
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Applicable Section(s)
Description of Change(s)
remission at maintenance baseline.
Synopsis, Major 
Secondary Efficacy 
Analyses: 
Maintenance
The corresponding section of the Synopsis has been revised as follows:
Maintenance:  Except for the third major secondary endpoint of maintenance of clinical 
remission, analyses of major secondary endpoints will be conducted using a 2-sided CMH 
chi-square test stratified by clinical remission status at maintenance baseline (as 
determined by the IWRS) and induction treatment. For the third major secondary 
endpoint, a 2-sided CMH chi-square test stratified by induction treatment will be used.
Rationale: Details were clarified about the futility analysis and the roles of the DMC and the sponsor.
3.1, Overview of 
Study Design; 
An independent Data Monitoring Committee (DMC) will assess the safety of subjects 
participating in the induction and maintenance studies, participate in the futility interim 
analysis (Section 11.11.1), and make recommendations to the sponsor about continuation 
of the studies. Refer to Section 11.12 for details.
3.1.1, Induction Study; 
An interim analysis to assess for futility is planned when the first 30% of subjects either 
complete the induction Week 8 (I-8) visit or terminate study participation before Week 8. 
This analysis will be based on clinical remission at Week 8. The whole study may be 
stopped for futility when the conditional power (ie, the probability of success at the end of 
the study, given the data at the interim analysis) on both ustekinumab doses is less than a 
prespecified cutoff. Refer to Section 11.11 for details.
5, Treatment 
Allocation and 
Blinding;
In the induction study, at the first DBL for the futility analysis, the induction treatment 
assignment information will be unblinded for the first 30% of randomized subjects in the 
study and released for analysis to an external statistical support group (the sponsor will 
remain blinded).
11.11.1 Interim 
Analysis: Induction 
Study;
A futility analysis based on the primary endpoint of clinical remission (global definition) 
at Week 8 will be conducted when 30% of randomized subjects have either completed the 
I-8 visit or have terminated study participation before Week 8. The whole study may be 
stopped for futility when the conditional power (ie, the probability of success at the end of 
the study, given the data at the interim analysis) on both ustekinumab doses is less than a 
prespecified cutoff. The DMC will review the interim analysis results and form a 
recommendation on whether or not to stop the trial for futility. The sponsor decision 
committee will then review the DMC’s recommendation and make a final decision. 
11.12, Data 
Monitoring Committee
A DMC will be established to monitor data on an ongoing basis to ensure the continuing 
safety of the subjects enrolled in this protocol. The committee will meet periodically to 
review safety data. After the review, the DMC will make recommendations regarding the 
continuation of the study. The same DMC will also review the interim analysis results 
from the induction study and form a recommendation to the sponsor on whether or not to
stop the trial for futility. Details will be provided in a separate DMC charter.
Rationale: The definition of failure to respond to corticosteroids was clarified in Attachment 2.
Attachment 2
Subjects have failed to respond to corticosteroids if they have had evidence of an 
initial inadequate response, recurrent disease, or a relapse despite receiving at least 
0.75 mg/kg/day or ≥40 mg/day of prednisone (or corticosteroid equivalent, given orally or 
intravenously) for 2 weeks.
Rationale: Minor errors were noted
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
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SYNOPSIS
A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Protocol to 
Evaluate the Safety and Efficacy of Ustekinumab Induction and Maintenance Therapy in Subjects 
with Moderately to Severely Active Ulcerative Colitis
Protocol Number:
CNTO1275UCO3001
EudraCT Number:
2014-005606-38
Ustekinumab (STELARA®) is a fully human immunoglobulin G1 kappa (IgG1k) monoclonal antibody to 
human interleukin (IL)-12/23p40 that binds with high affinity to human IL-12 and IL-23. Ustekinumab 
prevents IL-12 and IL-23 bioactivity by preventing their interaction with their cell surface IL-12Rβ1 
receptor protein. Through this mechanism of action, ustekinumab effectively neutralizes IL-12 (Th1)- and 
IL-23 (Th17)-mediated cellular responses. Abnormal regulation of IL-12 and IL-23 has been associated 
with multiple immune-mediated diseases, including inflammatory bowel disease (IBD). Therefore, 
binding and inhibiting the IL-12/23p40 subunit may provide effective therapy in IBD, including Crohn's 
disease and ulcerative colitis (UC).
Ustekinumab has received marketing approval globally, including countries in North America, Europe, 
South America, and the Asia-Pacific region, for the treatment of adult patients with chronic moderate to 
severe plaque psoriasis or active psoriatic arthritis. Ustekinumab is currently being evaluated in a Phase 3 
development program for Crohn’s disease.
Data from completed Phase 2 studies of ustekinumab in Crohn’s disease, along with the shared biology 
and the similar response to current treatments between Crohn’s disease and UC, provide a substantial 
scientific and clinical rationale to justify a direct-to-Phase-3 approach to the study of ustekinumab in UC. 
Relative to approved therapies for UC (ie, tumor necrosis factor antagonists and the anti-α4β7 integrin 
antagonist, vedolizumab), ustekinumab offers the potential for a more convenient treatment regimen, with 
subcutaneous (SC) administration every 8 to 12 weeks during maintenance, as well as a novel mechanism 
of action in the treatment of UC, and a documented long-term safety profile.
The Phase 3 development program for ustekinumab in the treatment of UC will be conducted under a 
single protocol but will be designed and analyzed as 2 separate studies, an induction study and a 
maintenance study.
OBJECTIVES AND HYPOTHESES
INDUCTION STUDY 
Primary Objectives

To evaluate the efficacy of intravenous (IV) ustekinumab in inducing clinical remission in subjects 
with moderately to severely active UC.

To evaluate the safety of IV ustekinumab in subjects with moderately to severely active UC.
Secondary Objectives

To evaluate the efficacy of IV ustekinumab in inducing endoscopic healing (ie, improvement in the 
endoscopic appearance of the mucosa) in subjects with moderately to severely active UC.

To evaluate the efficacy of IV ustekinumab in inducing clinical response in subjects with moderately 
to severely active UC.

To evaluate the impact of IV ustekinumab on disease-specific health-related quality of life.
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
To evaluate the efficacy of ustekinumab treatment on mucosal healing (ie, endoscopic healing and 
histologic healing).

To evaluate the efficacy of induction therapy with IV ustekinumab by biologic failure status. 

To evaluate the pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD) of 
ustekinumab induction therapy in subjects with moderately to severely active UC, including changes 
in C-reactive protein (CRP), fecal calprotectin, fecal lactoferrin, and other PD biomarkers.
MAINTENANCE STUDY
Primary Objectives

To evaluate clinical remission for SC maintenance regimens of ustekinumab in subjects with 
moderately to severely active UC induced into clinical response with ustekinumab.

To evaluate the safety of SC maintenance regimens of ustekinumab in subjects with moderately to 
severely active UC induced into clinical response with ustekinumab.
Secondary Objectives

To evaluate the efficacy of ustekinumab in maintaining clinical response in subjects induced into 
clinical response with ustekinumab.

To evaluate endoscopic healing (ie, improvement in the endoscopic appearance of the mucosa) in 
subjects induced into clinical response with ustekinumab.

To evaluate the efficacy of ustekinumab in achieving corticosteroid-free clinical remission in 
subjects induced into clinical response with ustekinumab.

To evaluate the efficacy of ustekinumab in maintaining clinical remission in subjects induced into 
clinical remission with ustekinumab. 

To evaluate the efficacy of ustekinumab treatment on mucosal healing (ie, endoscopic healing and 
histologic healing).

To evaluate the impact of SC ustekinumab on disease-specific health-related quality of life. 

To evaluate the efficacy of maintenance therapy with SC ustekinumab by biologic failure status. 

To evaluate the PK, immunogenicity, and PD of ustekinumab maintenance therapy, including 
changes in CRP, fecal calprotectin, fecal lactoferrin, and other PD biomarkers in subjects induced 
into clinical response with ustekinumab. 
Exploratory Objectives

To evaluate response using the Mayo score without the physician's global assessment (PGA) 
subscore in both induction and maintenance. 

To evaluate the performance of the Bristol Stool Form Scale score in the induction study.
Hypotheses
Induction Study: Ustekinumab is superior to placebo in inducing clinical remission at Week 8 in 
subjects with moderately to severely active UC.
Maintenance Study: Ustekinumab maintenance therapy is superior to placebo in achieving clinical 
remission at Week 44 of maintenance in subjects with moderately to severely active UC who were 
induced into clinical response with ustekinumab.
NCT02407236


Ustekinumab (CNTO1275)
Clinical Protocol CNTO1275UCO3001 Amendment 2
27
Approved, Date: 20 April 2016
OVERVIEW OF STUDY DESIGN
The Phase 3 development program for ustekinumab in the treatment of UC will be conducted under a 
single protocol but will be designed and analyzed as 2 separate studies, an induction study and a 
maintenance study. Both will be Phase 3, randomized, double-blind, placebo-controlled, parallel-group, 
multicenter studies of ustekinumab in subjects with moderately to severely active UC. The induction 
study will target subjects with moderately to severely active UC who demonstrate an inadequate response 
or failure to tolerate conventional or biologic therapy. The maintenance study will be a randomized 
withdrawal study targeting subjects with moderately to severely active UC who demonstrate a clinical 
response to induction treatment with IV ustekinumab. 
Overall, the program will evaluate ustekinumab treatment in subjects with moderately to severely active 
UC through at least 1 year of induction and maintenance therapy. After completion of the maintenance 
study through Week 44, a long-term extension (LTE) will follow eligible subjects for an additional 
3 years. 
Throughout the induction and maintenance studies, efficacy, PK, biomarkers, and safety will be assessed 
at timepoints indicated in the appropriate Time and Events Schedules. 
Blood samples for pharmacogenomic analyses will be collected from subjects who consent separately to 
this component of the study (where local regulations permit). Subject participation in pharmacogenomic 
research is optional.
An interim analysis to assess for futility is planned when the first 30% of subjects randomized in the 
induction study either complete the induction Week 8 visit or terminate study participation before 
Week 8.
An independent Data Monitoring Committee will be commissioned for this study.
The end of the CNTO1275UCO3001 study is defined as the date on which the last subject completes the 
last visit in the LTE.
SUBJECT POPULATION
The target population is men or women 18 years of age or older with moderately to severely active UC, as 
defined by a Mayo score of 6 to 12, inclusive, at Week 0 of the induction study, including an endoscopy
subscore ≥2 as assigned by the central reader. Subjects must not be at imminent risk of colectomy. The 
broad subject population to be evaluated will include subjects who have had an inadequate response to or 
are intolerant of either conventional or biologic therapy. 
DOSAGE AND ADMINISTRATION
Induction: A target of 951 subjects will be randomized in a 1:1:1 ratio to 1 of 3 treatment groups and will 
receive their assigned IV dose of study agent at Week 0: 

Placebo IV

Ustekinumab 130 mg IV

Weight-range-based ustekinumab doses approximating ustekinumab 6 mg/kg IV (ie, ustekinumab 
~6 mg/kg IV):

Ustekinumab 260 mg (weight ≤55 kg)

Ustekinumab 390 mg (weight >55 kg but ≤85 kg)

Ustekinumab 520 mg (weight >85 kg)
NCT02407236


Ustekinumab (CNTO1275)
Clinical Protocol CNTO1275UCO3001 Amendment 2
28
Approved, Date: 20 April 2016
At Week 8, all subjects will be evaluated for the primary endpoint of clinical remission, and for clinical 
response. Further study agent administration will be determined by clinical response status (using the 
Mayo endoscopy subscore assigned by the local endoscopist) at Week 8, as follows:

Subjects who are in clinical response at Week 8 are eligible to enter the maintenance study.

Subjects who are not in clinical response at Week 8 will receive ustekinumab as follows:

Subjects who were randomized to placebo at Week 0 will receive 1 dose of ustekinumab 
~6 mg/kg IV plus placebo SC (to maintain the blind) at Week 8. 

Subjects who were randomized to ustekinumab at Week 0 will receive 1 dose of ustekinumab 
90 mg SC plus placebo IV (to maintain the blind) at Week 8. 
At Week 16, the subjects who were not in clinical response at Week 8 will be re-evaluated for clinical 
response (clinical response status will be based on the Mayo endoscopy subscore assigned by the local 
endoscopist): 

Subjects who achieve clinical response at Week 16 are eligible to enter the maintenance study. 

Subjects who do not achieve clinical response at Week 16 will not enter the maintenance study 
and will have a safety follow-up visit approximately 20 weeks after their last (ie, Week 8) 
administration of study agent.
Maintenance:  A target of 327 subjects who are in clinical response to IV ustekinumab induction will be 
randomized in a 1:1:1 ratio to 1 of 3 treatment groups and will receive their assigned SC dose of study 
agent at maintenance Week 0: 

Placebo SC

Ustekinumab 90 mg SC every 12 weeks (q12w)

Ustekinumab 90 mg SC every 8 weeks (q8w)
Subjects who were in clinical response to IV ustekinumab during induction will comprise the primary 
population in the maintenance study: 

Subjects who were randomized to receive ustekinumab at Week 0 of the induction study and were in 
clinical response at induction Week 8.

Subjects who were randomized to receive placebo at Week 0 of the induction study and were not in 
clinical response at induction Week 8, but were in clinical response at induction Week 16 after 
receiving a dose of IV ustekinumab at induction Week 8.
Additional subjects entering the maintenance study will include the following; these subjects will not be 
part of the primary population:

Subjects who are in clinical response to placebo IV induction will receive placebo SC. 

Subjects who were delayed responders to ustekinumab induction (ie, were not in clinical response at 
induction Week 8 but were in clinical response at induction Week 16) will receive ustekinumab 
90 mg SC q8w.
All subjects will receive their assigned dose of SC study agent at maintenance Week 0. Thereafter, to 
maintain the blind, all subjects will receive study agent at all scheduled study agent administration visits 
specified in the Time and Events Schedule for maintenance. Subjects will be assessed for clinical flare at 
every visit.
NCT02407236


Ustekinumab (CNTO1275)
Clinical Protocol CNTO1275UCO3001 Amendment 2
29
Approved, Date: 20 April 2016
EFFICACY EVALUATIONS/ENDPOINTS
Efficacy evaluations will include the following:

Mayo score and partial Mayo score

Ulcerative Colitis Endoscopic Index of Severity (UCEIS)

C-reactive protein

Fecal lactoferrin and fecal calprotectin

Bristol Stool Form Scale

Inflammatory Bowel Disease Questionnaire (IBDQ)

36-item Short Form Health Survey (SF-36)

EuroQoL-5D Health Questionnaire (EQ-5D)
Induction Endpoints
The primary endpoint of the induction study is clinical remission at Week 8. 
The following are the major secondary endpoints in the induction study, presented in the order in which 
they will be tested:  endoscopic healing at Week 8; clinical response at Week 8; the change from 
induction baseline in the total score of the IBDQ at Week 8.
Maintenance Endpoints
The primary endpoint of the maintenance study is clinical remission at Week 44.
The following are the major secondary endpoints in the maintenance study, presented in the order in 
which they will be tested:  maintenance of clinical response through Week 44; endoscopic healing at 
Week 44; clinical remission and not receiving concomitant corticosteroids at Week 44; and maintenance 
of clinical remission through Week 44 among the subjects who had achieved clinical remission at 
maintenance baseline.
PHARMACOKINETIC AND IMMUNOGENICITY EVALUATIONS
Blood samples will be used to evaluate the PK and immunogenicity of ustekinumab (antibodies to 
ustekinumab) and will be collected from each subject at the timepoints indicated in the Time and Events 
Schedules. 
BIOMARKER EVALUATIONS
Biomarker assessments will be performed to identify protein, RNA (mRNA or microRNA) expression 
patterns, and microbial activities that are relevant to ustekinumab treatment and/or UC, to conduct 
histologic and immunohistochemical assessment of disease and healing, and to evaluate if biomarkers can 
be used to predict clinical response. Biomarker assessments will include the evaluation of relevant 
markers in serum and feces for all subjects as specified in the Time and Events Schedules. 
PHARMACOGENOMIC (DNA) EVALUATIONS
Whole blood samples of approximately 10 mL will be collected (where local regulations permit) for 
genetic and epigenetic analyses as specified in the Time and Events Schedules. Only subjects who sign 
the consent form to participate in the genetic assessment will have whole blood DNA samples collected.
Subject participation in the pharmacogenomic research is optional.
NCT02407236


Ustekinumab (CNTO1275)
Clinical Protocol CNTO1275UCO3001 Amendment 2
30
Approved, Date: 20 April 2016
SAFETY EVALUATIONS
Safety evaluations will include adverse events; clinical laboratory tests (chemistry and hematology); vital 
signs and physical examinations; a screening electrocardiogram; allergic reactions, infusion reactions and 
injection site reactions; and early detection of active tuberculosis.
STATISTICAL METHODS
Clinical remission is the primary endpoint in both the induction and maintenance studies, and is also used 
to define some of the major secondary endpoints in the maintenance study. Two separate definitions for 
clinical remission will be used to accommodate the global and US-preferred definitions of clinical 
remission. 

The following global definition of clinical remission will be used for countries outside the United 
States:  a Mayo score ≤2 points, with no individual subscore >1.

The following US-specific definition of clinical remission will be used for the United States:  an 
absolute stool number ≤3, a rectal bleeding subscore of 0, and a Mayo endoscopy subscore of 0 or 1. 
Each definition of clinical remission will be applied to all subjects in the analysis population.
Sample Size
Induction: The sample size in the induction study is based on statistical power considerations (for both the 
global and US-specific definitions of clinical remission) and the objective of providing the primary 
population for the maintenance study (ie, subjects in clinical response to IV ustekinumab in induction). 
To control the overall Type I error at the 0.05 significance level, a step-up Hochberg testing procedure 
will be employed for countries outside of the United States (globally) and the Bonferroni method will be 
used for the United States. Assuming a 7% clinical remission (global definition) rate in the placebo group 
and 19% in each ustekinumab group, 135 subjects per treatment group (405 subjects in total) will provide 
an overall power of 90% using a step-up Hochberg testing procedure at the α=0.05 (2-sided) level. 
Assuming a 12% clinical remission (US-specific definition) rate in the placebo group and 25% in each 
ustekinumab group, 220 subjects per treatment group (660 subjects in total) will provide statistical power 
of 90% for comparison of each ustekinumab induction treatment group versus placebo at a significance 
level of 0.025 (2-sided). To provide a sufficient number of subjects for the primary population in the 
maintenance study, however, it is estimated that a target of 951 subjects (317 subjects per treatment 
group) should be enrolled in the induction study.
Maintenance:  Assuming a 20% clinical remission rate (for both the global and US definitions) in the 
placebo group and 40% in the SC ustekinumab 90 mg q8w group, 109 subjects in each randomized 
treatment group (327 subjects in total) will provide statistical power of 90% at a significance level of 0.05 
(2-sided) based on the fixed-sequence testing procedure, starting with the high dose group (q8w). 
Primary Efficacy Analysis
Induction: The primary analysis is based on all randomized subjects. The primary endpoint is clinical 
remission at Week 8. The definition of clinical remission (as well as the testing procedure) will be 
different for countries outside the United States and for the United States. For the global definition of 
clinical remission, a step-up Hochberg testing procedure will be employed to control the Type 1 error. For 
the US-specific definition, the Bonferroni method will be used to control the overall Type I error rate at 
the 0.05 level (2-sided) for comparisons of the 2 ustekinumab induction treatment groups with placebo, 
with each comparison being tested at the 0.025 level (2-sided). For both definitions of clinical remission, 
the comparisons between each ustekinumab treatment group and the placebo group will be conducted 
using a 2-sided Cochran-Mantel-Haenszel (CMH) chi-square test stratified by biologic failure status and 
region.
NCT02407236


Ustekinumab (CNTO1275)
Clinical Protocol CNTO1275UCO3001 Amendment 2
31
Approved, Date: 20 April 2016
Maintenance:  The primary analysis is based on the primary population (ie, subjects who are in clinical 
response to IV ustekinumab induction). The primary endpoint is clinical remission at Week 44. The 
definition of clinical remission is different for countries outside of the United States and for the United 
States. For both definitions of clinical remission, the comparisons between each ustekinumab treatment 
group and the placebo group will be conducted using a 2-sided CMH chi-square test stratified by clinical 
remission status at maintenance baseline (as determined by the interactive web response system [IWRS]) 
and induction treatment. For countries outside the United States, a fixed-sequence testing procedure 
(ustekinumab 90 mg SC q8w will first be tested; if positive, then ustekinumab 90 mg SC q12w will be 
tested) will be used to control the overall Type I error rate at the 0.05 level for the primary endpoint. For 
the United States, a fixed-sequence testing procedure will be employed to strongly control the overall 
Type 1 error rate at the 0.05 level across the primary and all 4 major secondary endpoints and across the 2 
ustekinumab doses, starting with the high maintenance dose group of the primary endpoint.
Major Secondary Efficacy Analyses
Induction:  For the major secondary endpoints of endoscopic healing (ie, improvement in the endoscopic 
appearance of the mucosa) at Week 8 and clinical response at Week 8, the treatment groups will be 
compared using a 2-sided CMH chi-square test stratified by biologic failure status and region. For the 
major secondary endpoint of change from induction baseline in the IBDQ score at Week 8, the treatment 
groups will be compared using analysis of covariance (ANCOVA) on the van der Waerden normal scores 
with induction baseline IBDQ score, biologic failure status, region, and treatment group as covariates. 
Maintenance:  Except for the fourth major secondary endpoint of maintenance of clinical remission, 
analyses of major secondary endpoints will be conducted using a 2-sided CMH chi-square test stratified 
by clinical remission status at maintenance baseline (as determined by the IWRS) and induction 
treatment. For the fourth major secondary endpoint, a 2-sided CMH chi-square test stratified by induction 
treatment will be used.
Other Planned Analyses
The consistency of efficacy for clinical remission at Week 8 (induction study) and at Week 44 
(maintenance study), for both the global and US-specific definitions, will be examined in subgroups for 
each study defined by baseline demographics, baseline clinical disease characteristics, baseline 
concomitant UC medications, UC medication history, and stratification variables. Other planned analyses 
include analysis of the secondary endpoints for each study, such as alternative definitions of remission,
mucosal healing, the partial Mayo score, IBDQ score, CRP, fecal calprotectin and lactoferrin. 
Pharmacokinetic Analyses
Serum ustekinumab concentrations will be summarized for each treatment group over time using 
descriptive statistics. A population PK analysis using a nonlinear mixed-effects model will be used to 
characterize the PK of ustekinumab. The influence of important covariates on the population PK 
parameter estimates may be evaluated. Details will be provided in a population PK analysis plan, and 
results of the population PK analysis will be presented in a separate technical report.
Immunogenicity Analyses
The incidence and titers of antibodies to ustekinumab will be summarized for all subjects who receive a 
dose of ustekinumab and have appropriate samples for detection of antibodies to ustekinumab (ie, 
subjects with at least 1 sample obtained after their first dose of ustekinumab).
NCT02407236


Ustekinumab (CNTO1275)
Clinical Protocol CNTO1275UCO3001 Amendment 2
32
Approved, Date: 20 April 2016
Biomarker Analyses
Changes in the concentration of individual serum markers from baseline to the selected posttreatment 
time points will be summarized. RNA analyses and additional analyses such as histology assessment and 
microbiome analysis will be performed. Biomarker analyses are considered exploratory and will be 
summarized in a separate technical report.
Genetic and Epigenetic (DNA) Analyses 
Genetic and epigenetic (DNA) analyses will be conducted only in subjects who sign the consent form to 
participate in the genetics and epigenetic assessments. These analyses are considered exploratory and will 
be summarized in a separate technical report.
Health Economics and Medical Resource Utilization Analyses
The potential pharmacoeconomic benefits of ustekinumab treatment will be examined by comparing the 
difference in direct medical resource utilization and drivers of indirect costs among treatment groups. 
Health economics and medical resource utilization data will be descriptively summarized by treatment 
group. 
Safety Analyses
Safety analyses will include summaries of AEs and laboratory parameters. These summaries will be 
provided separately for the induction and maintenance studies and will be based on subjects who received 
at least 1 dose of study agent in each respective study.
NCT02407236


Ustekinumab (CNTO1275)
Clinical Protocol CNTO1275UCO3001 Amendment 2
33
Approved, Date: 20 April 2016
TIME AND EVENTS SCHEDULE: INDUCTION STUDY
Table 1:
Schedule of events: Induction study
Phase
Screening
Treatment
Safety 
Follow-up g
Study Procedures a,b,c,d                   Week
Within 8 weeks
I-0
I-2
I-4
I-8
I-16e,f
Screening/Administrative
Informed consent
X
Inclusion/exclusion criteria
X
X
Medical history and demographics
X
Prestudy therapy
X
Preplanned surgery/procedure(s)
X
QuantiFERON-TB Gold test h
X
HBV and HCV testing
X
HIV test
X
Chest radiograph i
X
Serum pregnancy test j
X
Stool for enteric pathogens k
X
Training on Mayo diary card completion
X
Study Agent Administration
Randomization
X
Administer study agent
X
X l
Safety Assessments
Physical examination
X
X
X
X
12-lead ECG
X
TB evaluation m/ other infection 
assessment
X
X
X
X
X
X
X
Vital signs n
X
X
X
X
X
X
X
Weight
X
X
X
X
X
Height
X
Urine pregnancy test j
X
X
X
X
X
X
AE review
X
X
X
X
X
X
X
Concomitant medication review
X
X
X
X
X
X
X
UC-related surgeries/hospitalizations
X
X
X
X
X
X
Injection-site evaluation (only for subjects 
who receive study agent at I-8 visit)
X
X
Efficacy Assessments
Endoscopy o
X p
X
X
Mayo score
X
X
X
Partial Mayo score
X
X
X
Bristol Stool Form Scale
X
X
X
X
X
Collect and review diary cards
X
X
X
X
X
IBDQ
X
X
X
SF-36
X
X
X
EQ-5D
X
X
X
Health Economics
Productivity VAS
X
X
X
WPAI-GH
X
X
X
Clinical Laboratory Assessments
Hematology, chemistry
X
X
X
X
X
X
CRP
X
X
X
X
X
Stool sample (fecal calprotectin, fecal 
lactoferrin)
X
X
X
X
X
Pharmacokinetics
Serum ustekinumab concentration
X q
X
X
X q
X
X
Antibodies to ustekinumab
X
X
X
X
X
Biomarkers 
Biopsy (RNA, histology)
X r
X
X
Serum biomarkers
X
X
X
X
Fecal biomarkers
X
X
X
X
Genetic and Epigenetic (DNA) 
NCT02407236


Ustekinumab (CNTO1275)
Clinical Protocol CNTO1275UCO3001 Amendment 2
34
Approved, Date: 20 April 2016
Table 1:
Schedule of events: Induction study
Evaluations
Whole blood (DNA) s
X
X
X
X
AE=adverse event; CRP=C-reactive protein; ECG=electrocardiogram; EQ-5D=EuroQoL-5D Health Questionnaire; 
HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; I=induction; IBDQ=Inflammatory Bowel 
Disease Questionnaire; IV=intravenous; PK=pharmacokinetic; PRO=patient-reported outcome; SC=subcutaneous; SF-36=36-item 
Short Form Health Survey; TB=tuberculosis; UC=ulcerative colitis; VAS=visual analog scale; WPAI-GH=Work Productivity and 
Activity Impairment Questionnaire-General Health. 
a.
Screening should occur within 8 weeks before the I-0 visit. Visit dates are based on the subject’s original randomization date; 
visit windows are as follows: 
▪I-2 and I-4 visits:  day of the scheduled visit ±4 days (ie, plus or minus 4 days).
▪I-8 and I-16 visits: day of the scheduled visit +3 days (ie, plus 3 days).
b.
Subjects who discontinue study agent (but have not terminated study participation) before or at the I-8 visit should complete the 
I-8 assessments at the time of discontinuation and a safety follow-up visit approximately 20 weeks after their last study agent 
administration. After Week 8, subjects who do not wish to continue into the maintenance study, but are willing to complete 
their participation in the induction study, should complete the I-16 assessments at the time of discontinuation and a safety 
follow-up visit approximately 20 weeks after their last study agent administration.
c.
Subjects who terminate their study participation before or at the I-8 visit should complete the I-8 assessments at the time of 
termination. Subjects who terminate their study participation after the I-8 visit but before or at I-16 visit should complete the 
I-16 assessments at the time of termination.
d.
All assessments are to be completed before study agent administration, unless otherwise specified. It is recommended that PRO 
assessments be completed first.
e.
Only subjects who were not in clinical response to study agent at Week 8 will have an I-16 visit.
f.
Subjects who are in clinical response at Week 16 will enter the maintenance study; subjects who are not in clinical response at 
Week 16 will not enter the maintenance study and will have a safety follow-up visit approximately 20 weeks after their last 
dose of study agent.
g.
Subjects who do not enter the maintenance study (or who have not terminated study participation) should have a safety 
follow-up visit approximately 20 weeks after their last dose of study agent. 
h.
All subjects will undergo QuantiFERON-TB Gold testing. In countries where the QuantiFERON-TB Gold test is not 
registered/approved, TB skin testing will also be required (recommended but not required for study centers in Ukraine if 
tuberculin is not available).
i.
Chest radiograph (posterior-anterior view) must be obtained within 3 months before the I-0 visit. 
j.
Must be performed before any study agent administration for female subjects of childbearing potential. 
k.
Stool studies for enteric pathogens may be performed at either the central or local laboratory and must include a stool culture 
and Clostridium difficile toxin assay. These must be performed during screening or have been performed during the current 
episode of disease exacerbation (as long as the stool studies were performed within 4 months before the first administration of 
study agent). Additional testing (eg, ova and parasites or Escherichia coli O157:H7 assessments) may be performed at the 
investigator’s clinical discretion. 
l.
Subjects who are not in clinical response at Week 8 as assessed by Mayo score will receive ustekinumab (and placebo to 
maintain the blind; see Figure 2). 
m. If TB is suspected at any time, a chest radiograph and QuantiFERON-TB Gold test should be performed. In countries where the 
QuantiFERON-TB Gold test is not registered/approved, TB skin testing should also be performed (recommended but not 
required for study centers in Ukraine if tuberculin is not available). 
n.
Temperature, pulse/heart rate, respiratory rate, and blood pressure. At a study agent administration visit, vital signs will be 
obtained before, approximately every 30 minutes during, and twice (at approximately 30-minute intervals) after completion of 
the IV infusion(s), or before and approximately 30 minutes after the SC injection.
o.
Endoscopy findings will be assessed by the investigator (ie, local endoscopist) during the procedure and a video of the 
endoscopy must be submitted to the central reader. 
p.
The screening endoscopy must be performed within 2 weeks before the I-0 visit. The interval from the endoscopy procedure to 
the availability of the Mayo endoscopy subscore as assessed by the central reader is approximately 4 days; therefore, the 
screening endoscopy must be performed at least 4 days before the baseline (I-0) visit. The Mayo endoscopy subscore assessed 
by the central reader will be used to determine eligibility (ie, Mayo endoscopy subscore ≥2) and to calculate the baseline Mayo 
score. A full colonoscopy will replace a sigmoidoscopy if screening for polyps or dysplasia is required. At least 48 hours must 
elapse between a colonoscopy with polypectomy and the I-0 visit. 
q.
At study agent administration visits (ie, at I-0 for all subjects and I-8 for nonresponders at Week 8), blood samples for PK 
analysis should be collected before the start of and approximately 60 minutes after completion of the infusion.
r.
The screening biopsy samples for histology and RNA analyses will be collected during the screening endoscopy performed 
within 2 weeks before the first study agent administration. Additional colonic mucosal biopsies will be performed at the I-8 
visit; subjects who are nonresponders at the I-8 visit will undergo an additional colonic mucosal biopsy at the I-16 visit.
s.
Whole blood for genetic and epigenetic analyses will be collected only from subjects who sign a separate informed consent 
form to participate in the DNA substudy.
NCT02407236


Ustekinumab (CNTO1275)
Clinical Protocol CNTO1275UCO3001 Amendment 2
35
Approved, Date: 20 April 2016
TIME AND EVENTS SCHEDULE: MAINTENANCE STUDY
Table 2:
Schedule of events: Maintenance study
Study Procedures a,b
Week
M-0
M-4
M-8
M-12
M-16
M-20
M-24
M-28
M-32
M-36
M-40
M-44
Early 
Term c
Safety 
F/U d
Administrative
Inclusion/exclusion criteria e
X
Study Agent Administration
Randomization f
X
Study agent administration g
X
X
X
X
X
X
X
X
Safety Assessments
Physical examination
X
X
X
Weight
X h
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs i
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine pregnancy test j
X
X
X
X
X
X
X
X
X
X
X
X
X
TB evaluation k/other infection assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study agent injection-site evaluation
X
X
X
X
X
X
X
X
X
X
X
X
X
AE review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
UC-related hospitalizations and surgeries
X h
X
X
X
X
X
X
X
X
X
X
X
X
X
Efficacy Assessments
Endoscopy l
X h
X
X
Mayo score 
X h
X
X
Partial Mayo score 
X
X
X
X
X
X
X
X
X
X
IBDQ
X h
X
X
X
SF-36
X h
X
X
X
EQ-5D
X h
X
X
X
Health Economics
Productivity VAS
X h
X
X
X
WPAI-GH
X h
X
X
X
Clinical Laboratory Assessments
Hematology and chemistry
X h
X
X
X
X
X
X
X
X
X
X
X
X
CRP
X h
X
X
X
X
Stool sample (fecal lactoferrin and 
calprotectin)
X h
X
X
X
X
Pharmacokinetics/Immunogenicity
Serum ustekinumab concentration m
X h
X
X
X
X
X
X
X
X
X
X
X
X
X
Antibodies to ustekinumab
X h
X
X
X
X
X
X
X
Biomarkers
Biopsy (RNA, histology)
X
Serum biomarkers
X h
X
X
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Table 2:
Schedule of events: Maintenance study
Study Procedures a,b
Week
M-0
M-4
M-8
M-12
M-16
M-20
M-24
M-28
M-32
M-36
M-40
M-44
Early 
Term c
Safety 
F/U d
Fecal biomarkers
X h
X
X
Genetic and Epigenetic (DNA) Evaluations
Whole blood (DNA) n
X h
X
X
AE=adverse event; CRP=C-reactive protein; Early Term=early study termination visit; EQ-5D=EuroQoL-5D Health Questionnaire; F/U=follow-up; I=induction; IBDQ=Inflammatory Bowel 
Disease Questionnaire; LTE=long-term extension; M=maintenance; PRO=patient-reported outcome; SC=subcutaneous; SF-36=36-item Short Form Health Survey; TB=tuberculosis; 
VAS=visual analog scale; WPAI-GH=Work Productivity and Activity Impairment Questionnaire-General Health; UC=ulcerative colitis. 
a.
Except for the M-0 visit, the visit window for each visit is 10 days. The M-0 visit (ie, Week 0 visit for the maintenance study) should occur within 4 days after the I-8 visit (or the I-16 
visit for subjects who were not in clinical response at Week 8 but were in clinical response at Week 16). 
b.
Subjects in clinical flare who have not previously met the criteria for loss of clinical response (ie, are in clinical flare for the first time or have flared previously and not met the criteria for 
loss of response) should complete all visit assessments indicated for the M-44 visit (including an endoscopy, which need only be a sigmoidoscopy) during their scheduled visit or at any 
unscheduled visit. Subjects with subsequent clinical flares after loss of clinical response should complete all assessments indicated for the visit at which the clinical flare occurred.
c.
Subjects who discontinue study treatment or terminate study participation should undergo procedures described for an Early Term visit. 
d.
Subjects who discontinue study agent administration (but have not terminated study participation) or who do not enter the LTE will have a final follow-up safety visit approximately 20 
weeks after the last administration of study agent.
e.
All subjects enrolled in the maintenance study will be responders to study agent administered in the induction study. Subjects must be able to complete the M-0 visit within 4 days after the 
I-8 or I-16 visit. At the investigator’s discretion, the window may be extended to 8 days to allow appropriate treatment of and/or recovery from nonserious infections (eg, acute upper 
respiratory tract infection, simple urinary tract infection). Subjects who initiated or increased the dose of a UC-specific medication (or any restricted/prohibited medication) during the 
induction study are prohibited from entering the maintenance study. 
f.
Subjects who were in clinical response to IV ustekinumab induction dosing at the I-8 or I-16 visit.
g.
All assessments are to be completed before study agent administration, unless otherwise specified. It is recommended that PRO assessments be completed first.
h.
No new data will be collected for this procedure at this visit; data from the study procedure performed at the I-8 visit (for subjects in clinical response at Week 8) or I-16 visit (for subjects 
who were not in clinical response at Week 8 but were in clinical response at Week 16) will be used for the M-0 visit.
i.
Temperature, pulse/heart rate, respiratory rate, and blood pressure. At a study agent administration visit, vital sign measurements should be obtained before and approximately 30 minutes 
after the SC injection.
j.
Must be performed before any study agent administration for female subjects of childbearing potential.
k.
If TB is suspected at any time during the study, a chest radiograph and QuantiFERON-TB Gold test should be performed. In countries where the QuantiFERON-TB Gold test is not 
registered/approved, TB skin testing should also be performed (recommended but not required for study centers in Ukraine if tuberculin is not available).
l.
A subject who meets the criteria for clinical flare but has not previously met the criteria of loss of clinical response (ie, is in clinical flare for the first time or flared previously and not met 
the criteria for loss of response) should undergo an additional endoscopy (which need only be a sigmoidoscopy) to determine loss of response based on the Mayo score. An endoscopy is 
not required if the subject has a subsequent clinical flare after loss of response criteria were met for the previous clinical flare. 
m. Samples should be collected before any study agent administration.
n.
Whole blood for genetic and epigenetic analyses will be collected only from subjects who sign a separate informed consent form to participate in the DNA substudy.
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TIME AND EVENTS SCHEDULE: LONG-TERM EXTENSION
Table 3:
Schedule of events: Long-term extension study
Study Procedures a,b
Every 
4 weeks c
Every 
3 months d,e
Every 
6 months f,g
Final Efficacy 
Visit h
Final Safety 
Visit i
Study Agent Administration
Administer study agent
X
X j
Safety Assessments
Physical examination
X
X
Weight
X
X
X
Vital signs k
X
X
X
Urine pregnancy test l
X
X
X
TB evaluation m/other infection assessment
X
X
X
Study agent injection-site evaluation
X
X
AE review
X
X
X
Concomitant medication review
X
X
X
UC-related hospitalizations and surgeries
X
X
X
Efficacy Assessments
Endoscopy
X
Mayo score
X
Partial Mayo score
X
IBDQ
X
X
SF-36
X
X
EQ-5D
X
Health Economics
WPAI-GH
X
X
Productivity VAS
X
X
Clinical Laboratory Assessments
Hematology and chemistry
X
X
CRP
X
X
Stool sample (fecal lactoferrin and calprotectin)
X
X
Pharmacokinetics/Immunogenicity
Serum ustekinumab concentration n
X
X
X
Antibodies to ustekinumab
X
X
X
AE=adverse event; CRP=C-reactive protein; EQ-5D=EuroQoL-5D Health Questionnaire; IBDQ=Inflammatory Bowel Disease 
Questionnaire; M=maintenance; PRO=patient-reported outcome; SC=subcutaneous; SF-36=36-item Short Form Health Survey; 
TB=tuberculosis; VAS=visual analog scale; WPAI-GH=Work Productivity and Activity Impairment Questionnaire-General 
Health; UC=ulcerative colitis. 
a.
Visit window is ±10 days for each visit.
b.
All assessments are to be completed before study agent administration unless otherwise specified. It is recommended that 
PRO assessments be completed first.
c.
The first study agent administration in the LTE will occur at Week 48; no study agent will be administered at Week 52. After 
the study is unblinded to the investigative sites, subjects receiving placebo will be terminated from study participation and 
subjects receiving ustekinumab will continue to receive ustekinumab, but will have study visits scheduled to coincide with 
their dose regimen (ie, either every 8 or every 12 weeks).
d.
Visits every 3 months include scheduled visits at Weeks 56, 68, 80, 92, 104, 116, 128, 140, 152, 164, 176, and 188. 
e.
The evaluations specified for visits every 4 weeks should also be conducted at the visits every 3 months. 
f.
Visits every 6 months include scheduled visits at Weeks 68, 92, 116, 140, 164, and 188. 
g.
The evaluations specified for visits every 3 months should also be conducted at the visits every 6 months.
h.
At Week 200, at the time of study agent discontinuation, or at the time of study participation termination.
i.
At Week 220 or approximately 20 weeks after a subject’s last administration of study agent (for subjects who have not 
terminated study participation).
j.
Only at Week 200.
k.
Temperature, pulse/heart rate, respiratory rate, and blood pressure. At a study agent administration visit, vital signs should be 
obtained before and approximately 30 minutes after the SC injection.
l.
Must be performed before each study agent administration in female subjects of childbearing potential.
m.
If TB is suspected at any time, a chest radiograph and QuantiFERON-TB Gold test should be performed. In countries where 
the QuantiFERON-TB Gold test is not registered/approved, TB skin testing should also be performed (recommended but not 
required for study centers in Ukraine if tuberculin is not available). 
n.
At a study agent administration visit, blood samples should be collected before study agent injection.
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ABBREVIATIONS
5-ASA
5-aminosalicylate
6-MP
6-mercaptopurine
6-TG
6-thioguanine
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANOVA
analysis of variance 
anti-HBc 
HBV core antibody
anti-HBs 
HBV surface antibody 
AST
aspartate aminotransferase
AZA
azathioprine
BCG
Bacille Calmette-Guerin
CMH
Cochran-Mantel-Haenszel
CRF
case report form (paper or electronic as appropriate for this study)
CRP
C-reactive protein
DBL
database lock
DMC
Data Monitoring Committee
ECG
electrocardiogram
eDC
electronic data capture
EQ-5D
EuroQoL-5D Health Questionnaire
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (United States)
FVP
final vialed product
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
I-0, I-8, etc
induction Week 0, induction Week 8 (visit), etc 
IB
Investigator's Brochure
IBD
inflammatory bowel disease
IBDQ
Inflammatory Bowel Disease Questionnaire
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IFN
interferon
IL
interleukin
IRB
Institutional Review Board
IV
intravenous
IWRS
interactive web response system
JAK
Janus kinase
LTE
long-term extension
M-0, M-8, etc.
maintenance Week 0, maintenance Week 8 (visit), etc.
mAb
monoclonal antibody
MCS
mental component summary
MedDRA
Medical Dictionary for Regulatory Activities
MMF
mycophenolate mofetil
MTX
methotrexate
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
PCS
physical component summary
PD
pharmacodynamic(s)
PFS
prefilled syringe
PGA
physician’s global assessment
PK
pharmacokinetic(s)
PQC
Product Quality Complaint
PRO
patient-reported outcome(s)
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q8w
every 8 weeks
q12w
every 12 weeks
SAE
serious adverse event
SAP
Statistical Analysis Plan
SC
subcutaneous
SF-36
36-item Short Form Health Survey
SUSAR
suspected unexpected serious adverse reaction
TB
tuberculosis
TNFα
tumor necrosis factor (alpha)
TPN
total parenteral nutrition
UC
ulcerative colitis
UCEIS
Ulcerative Colitis Endoscopic Index of Severity 
VAS
visual analog scale
WPAI-GH
Work Productivity and Activity Impairment Questionnaire–General Health
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1.
INTRODUCTION
Ustekinumab (STELARA®) is a fully human immunoglobulin G1 kappa (IgG1k) monoclonal 
antibody (mAb) to human interleukin (IL)-12/23p40 that binds with high affinity to human IL-12 
and IL-23. Ustekinumab prevents IL-12 and IL-23 bioactivity by preventing their interaction 
with their cell surface IL-12Rβ1 receptor protein. Through this mechanism of action, 
ustekinumab effectively neutralizes IL-12 (Th1)- and IL-23 (Th17)-mediated cellular responses. 
Abnormal regulation of IL-12 and IL-23 has been associated with multiple immune-mediated 
diseases, including inflammatory bowel disease (IBD). Therefore, binding and inhibiting the 
IL-12/23p40 subunit may provide effective therapy in IBD, including Crohn's disease and 
ulcerative colitis (UC). 
For comprehensive nonclinical and clinical information regarding the efficacy and safety of 
ustekinumab, refer to the latest version of the Investigator's Brochure (IB).
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
1.1.
Background
Ustekinumab has received marketing approval globally, including countries in North America, 
Europe, South America, and the Asia-Pacific region, for the treatment of adult patients with 
chronic moderate to severe plaque psoriasis or active psoriatic arthritis. 
The safety of ustekinumab reflects exposure in 7 controlled Phase 2 and Phase 3 studies in 
4,135 adult subjects with psoriasis and/or psoriatic arthritis, including 3,256 exposed for at least 
6 months, 1,482 exposed for at least 4 years, and 838 for at least 5 years. These data represent a 
significant database establishing a favorable benefit/risk for ustekinumab, with a safety profile 
that is well-established and has been stable for 5 years of maintenance treatment with 
ustekinumab doses of up to 90 mg given every 8 weeks (q8w).
Considerable data available from other completed or ongoing clinical studies of ustekinumab in 
additional indications (including Crohn’s disease, multiple sclerosis, primary biliary cirrhosis, 
sarcoidosis, and rheumatoid arthritis), together with extensive postmarketing data based on an 
estimated 551,966 person-years of exposure through 31 December 2015, also support the safety
profile of ustekinumab. 
Ustekinumab has not been previously evaluated in UC. However, the efficacy and safety of 
ustekinumab in Crohn’s disease has been evaluated in 2 completed Phase 2 clinical studies
(C0379T07 and C0743T26) and 2 completed Phase 3 induction studies (CNTO1275CRD3001 
and CNTO1275CRD3002). A Phase 3 maintenance study (CNTO1275CRD3003) is ongoing. 
Additional details on the clinical and postmarketing experience with ustekinumab are provided in 
the IB. 
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1.1.1.
Ustekinumab in Crohn’s Disease
Evidence for the role of IL-12/23p40 in Crohn’s disease was supported by the results of 2
Phase 2 studies in Crohn’s disease. C0379T07 was a Phase 2a study of ustekinumab induction 
therapy administered intravenously (IV) or subcutaneously (SC) in subjects who had failed 
conventional Crohn’s disease therapy25; this study demonstrated promising efficacy, with a 
greater treatment effect observed in subjects who received IV induction. C0743T26 (CERTIFI)
was a positive Phase 2b study of ustekinumab in subjects with Crohn’s disease who had failed to 
respond to or were intolerant of anti-tumor necrosis factor alpha (TNF-α) agents.29
In the induction phase of C0743T26, subjects received IV doses of 1 mg/kg, 3 mg/kg, or 6 mg/kg 
ustekinumab or placebo at Week 0. In the maintenance phase, subjects who had been randomized 
to ustekinumab induction therapy at Week 0 were rerandomized (based on their clinical response 
status at Week 6) to receive SC maintenance doses of 90 mg ustekinumab or placebo at Weeks 8 
and 16 in the induction phase. Efficacy results are summarized below:

Greater proportions of subjects in the 1 mg/kg, 3 mg/kg, and 6 mg/kg ustekinumab groups 
achieved clinical response at Week 6 (36.6%, 34.1%, and 39.7%, respectively) compared 
with subjects in the placebo group (23.5%), and the comparison between the ustekinumab 
6 mg/kg group and the placebo group was statistically significant (p=0.005). 

The proportions of subjects who achieved clinical remission at Week 6 in the ustekinumab 
1 mg/kg, 3 mg/kg, and 6 mg/kg groups were 16.0%, 15.9%, and 12.2%, respectively, 
compared with 10.6% in the placebo group. Although this endpoint was not significant at 
Week 6, remission rates continued to increase over time, particularly in subjects in the 
6 mg/kg group. This finding led to the use of the clinical remission at Week 8 endpoint in 
the Phase 3 Crohn’s disease induction studies. 

Among subjects rerandomized as responders to ustekinumab induction, the proportion of 
subjects who achieved clinical remission at Week 22 in the maintenance phase was 
significantly greater in the ustekinumab 90 mg SC group (41.7%) compared with the 
placebo SC group (27.4%, p=0.029).

The proportion of subjects who achieved clinical response at Week 22 in the maintenance 
phase was also significantly greater in the ustekinumab 90 mg SC group (69.4%) than in the 
placebo SC group (42.5%, p=0.001). 

Among the limited number of subjects who achieved clinical remission at Week 6, 
78.6% remained in clinical remission at Week 22 in the maintenance study in the 
ustekinumab 90 mg SC group compared with 53.3% in the placebo SC group (p=0.056). 
In the Phase 2 studies, both IV and SC ustekinumab were generally well tolerated and the results 
indicated a safety profile that was consistent with the safety profile of ustekinumab in the 
approved psoriasis indication. 
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The Phase 3 development program in subjects with Crohn’s disease includes 2 induction studies
(CNTO1275CRD3001 
and 
CNTO1275CRD3002) 
and 
1 
maintenance 
study
(CNTO1275CRD3003). To protect the integrity of the maintenance study, the results of the 
completed induction studies were to remain blinded to all but a select group of individuals within 
Janssen R&D until the database lock for the primary endpoint of the maintenance study.
Refer to the IB for the most current data on the Phase 2 and 3 studies in Crohn’s disease. 
1.2.
Overall Rationale for the Study
Inflammatory bowel diseases, including UC, are chronic relapsing disorders characterized by 
destructive inflammation and epithelial injury in the gastrointestinal tract.4,10 The incidence of 
UC in the United States is estimated to be between 9 and 12 per 100,000 with a prevalence of 
205 to 240 per 100,000.32 The etiology of UC is unknown; however, abnormal immune 
responses to contents in the gut, including intestinal microbes, are thought to drive disease in 
genetically predisposed individuals.14 Disregulated innate and adaptive immune pathways 
contribute to aberrant intestinal inflammation in IBD, and cytokines, including IL-12, interferon 
gamma (IFNγ), and IL-23 have been implicated in the pathogenesis of UC.14,23
The involvement of the IL-12/23 pathway in the pathogenesis of IBD is well established. Early 
studies showed that treatment with anti-IFNγ mAb5,11 or anti-IL-12p40 mAb prevented disease in 
experimental colitis models, suggesting an important role for Th-1 cells in promoting intestinal 
inflammation.24 Subsequently, an important role for IL-23 in intestinal inflammation was 
elucidated in colitis.1,19,35,38 In humans, genome-wide association studies have implicated several 
genetic loci in the IL-12/23 pathway that are associated with increased susceptibility to UC, 
including IL-23R, IL-12B, Janus kinase (JAK) 2, and STAT3 genes.2,6 Patients with active UC 
were shown to have significantly more IL-23, IL-22, IL-22R1 and p-STAT3-positive cells than 
patients with inactive UC and normal controls.39 Th1- and Th17-related genes are upregulated 
comparably in the mucosa of both UC and Crohn’s disease patients, suggesting that once 
established, the inflammatory mechanisms at the mucosal level between the two diseases are 
largely the same15; similar conclusions were reached in a genome-wide association study of IBD 
patients conducted by Jostins and colleagues.20
Ustekinumab, which neutralizes both IL-12 and IL-23 by binding to the common p40 subunit of 
these cytokines, has already demonstrated efficacy in a Phase 2b study in subjects with moderate 
to severe Crohn’s disease29 and is currently being studied in a global Phase 3 program for the 
treatment of Crohn’s disease. Of note, biologic therapies currently approved for the treatment of 
UC are either TNF-α or integrin inhibitors and, when tested, these therapies have also 
demonstrated efficacy in Crohn’s disease.8,16,28,30
Biologic therapies for the treatment of patients with moderately to severely active UC include 
anti-TNF agents such as infliximab (REMICADE), adalimumab (Humira), golimumab 
(SIMPONI), and the recently approved α4β7 integrin antagonist vedolizumab (Entyvio). These 
agents are currently approved for the treatment of patients with UC who are no longer 
responding to corticosteroids or immunomodulators;
however, only vedolizumab has 
demonstrated efficacy in patients who have had an inadequate response to (ie, primary 
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nonresponse or secondary loss of response) or are intolerant of anti-TNFs. These agents are 
administered either IV (infliximab and vedolizumab) or SC (golimumab and adalimumab). 
Anti-TNFs have safety risks associated with immunosuppression and not all patients adequately 
respond to therapy, while the long-term safety of vedolizumab has yet to be established. 
Therefore, there is a need for novel therapies with alternative mechanisms of action and 
potentially more favorable safety profiles. 
Ustekinumab is a novel therapy with a favorable long-term safety profile that has the potential to 
offer an SC treatment option for maintenance, following a single IV induction dose, that could be 
safe and efficacious for patients with moderately to severely active UC who have had an 
inadequate response to or are intolerant of either conventional or biologic therapy, thereby 
addressing a clear unmet medical need in this patient population.
These data, along with the shared biology of, and similar response to current treatments between,
Crohn’s disease and UC provide a substantial scientific and clinical rationale to justify a direct-
to-Phase-3 approach to the study of ustekinumab in UC. Relative to approved therapies for UC 
(ie, anti-TNFs and vedolizumab), ustekinumab offers the potential for a more convenient 
treatment regimen, with SC administration every 8 to 12 weeks during maintenance. Finally, 
ustekinumab provides a novel mechanism of action in the treatment of UC, with a documented 
long-term safety profile in excess of 5 years of clinical data, which is complemented by 
postmarketing data representing 551,966 person-years of exposure.
The Phase 3 development program for ustekinumab in the treatment of UC will be conducted 
under a single protocol but will be designed and analyzed as 2 separate studies, an induction 
study and a maintenance study. Both will be Phase 3, randomized, double-blind, placebo-
controlled, parallel-group, multicenter studies of ustekinumab in subjects with moderately to 
severely active UC. A long-term extension study (LTE) will follow subjects for an additional 
3 years. 
2.
OBJECTIVES AND HYPOTHESES
2.1.
Objectives
2.1.1.
Induction Study
2.1.1.1.
Primary Objectives

To evaluate the efficacy of IV ustekinumab in inducing clinical remission in subjects with 
moderately to severely active UC.

To evaluate the safety of IV ustekinumab in subjects with moderately to severely active UC.
2.1.1.2.
Secondary Objectives

To evaluate the efficacy of IV ustekinumab in inducing endoscopic healing (ie, 
improvement in the endoscopic appearance of the mucosa) in subjects with moderately to 
severely active UC.
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
To evaluate the efficacy of IV ustekinumab in inducing clinical response in subjects with 
moderately to severely active UC.

To evaluate the impact of IV ustekinumab on disease-specific health-related quality of life.

To evaluate the efficacy of ustekinumab treatment on mucosal healing (ie, endoscopic 
healing and histologic healing).

To evaluate the efficacy of induction therapy with IV ustekinumab by biologic failure status. 

To evaluate the pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD) of 
ustekinumab induction therapy in subjects with moderately to severely active UC, including 
changes in C-reactive protein (CRP), fecal calprotectin, fecal lactoferrin, and other PD
biomarkers.
2.1.2.
Maintenance Study
2.1.2.1.
Primary Objectives

To evaluate clinical remission for SC maintenance regimens of ustekinumab in subjects with 
moderately to severely active UC induced into clinical response with ustekinumab.

To evaluate the safety of SC maintenance regimens of ustekinumab in subjects with 
moderately to severely active UC induced into clinical response with ustekinumab.
2.1.2.2.
Secondary Objectives

To evaluate the efficacy of ustekinumab in maintaining clinical response in subjects induced 
into clinical response with ustekinumab.

To evaluate endoscopic healing (ie, improvement in the endoscopic appearance of the 
mucosa) in subjects induced into clinical response with ustekinumab.

To evaluate the efficacy of ustekinumab in achieving corticosteroid-free clinical remission 
in subjects induced into clinical response with ustekinumab.

To evaluate the efficacy of ustekinumab in maintaining clinical remission in subjects 
induced into clinical remission with ustekinumab. 

To evaluate the efficacy of ustekinumab treatment on mucosal healing (ie, endoscopic 
healing and histologic healing).

To evaluate the impact of SC ustekinumab on disease-specific health-related quality of life. 

To evaluate the efficacy of maintenance therapy with SC ustekinumab by biologic failure 
status. 

To evaluate the PK, immunogenicity, and PD of ustekinumab maintenance therapy, 
including changes in CRP, fecal calprotectin, fecal lactoferrin, and other PD biomarkers in 
subjects induced into clinical response with ustekinumab. 
2.1.3.
Exploratory Objectives

To evaluate response using the Mayo score without the physician's global assessment (PGA)
subscore in both induction and maintenance. 

To evaluate the performance of the Bristol Stool Form Scale score in the induction study. 
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2.2.
Hypotheses
2.2.1.
Induction Study
Ustekinumab is superior to placebo in inducing clinical remission at Week 8 in subjects with 
moderately to severely active UC.
2.2.2.
Maintenance Study
Ustekinumab maintenance therapy is superior to placebo in achieving clinical remission at 
Week 44 of maintenance in subjects with moderately to severely active UC who were induced 
into clinical response with ustekinumab.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
The Phase 3 development program for ustekinumab in the treatment of UC will be conducted 
under a single protocol but will be designed and analyzed as 2 separate studies, an induction 
study and a maintenance study. Both studies will be Phase 3, randomized, double-blind, placebo-
controlled, parallel-group, multicenter studies of ustekinumab in subjects with moderately to 
severely active UC. The induction study will target subjects with moderately to severely active 
UC who have demonstrated an inadequate response or failure to tolerate conventional or biologic 
therapy. The maintenance study will be a randomized withdrawal study targeting subjects with 
moderately to severely active UC who have demonstrated a clinical response to induction 
treatment with IV ustekinumab. Overall, the program will evaluate ustekinumab treatment in 
subjects with moderately to severely active UC through at least 1 year of induction and 
maintenance therapy; after completion of the maintenance study through Week 44, an LTE will 
follow eligible subjects for an additional 3 years. 
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Figure 1:
Overall schema for CNTO1275UCO3001 protocol
The target population is men or women 18 years of age or older with moderately to severely 
active UC, as defined by a Mayo score of 6 to 12, inclusive, at Week 0 of the induction study, 
including an endoscopy subscore ≥2 as assessed by the central reader. Subjects must not be at 
imminent risk of colectomy. 
A broad subject population will be evaluated and will include both subjects who have failed 
biologic therapy and those who have not: 

Subjects may be biologic failures, ie, have received treatment with 1 or more TNF 
antagonists or vedolizumab at a dose approved for the treatment of UC, and either did not 
respond initially, responded initially but then lost response, or were intolerant to the 
medication. A minimum of 40% and a maximum of 50% of the total subject population in 
the induction study will be biologic failures. 

Subjects may be biologic-naive or may have been exposed to biologic therapy but not
demonstrated an inadequate response or intolerance to treatment with a biologic agent (ie, a 
TNF antagonist or vedolizumab). These subjects must have demonstrated an inadequate 
response to, or have failed to tolerate, at least 1 of the following conventional UC therapies:  
oral or 
IV 
corticosteroids or 
the immunomodulators azathioprine (AZA)
or 
6-mercaptopurine (6-MP). Subjects who have demonstrated corticosteroid dependence (ie, 
an inability to successfully taper corticosteroids without a return of the symptoms of UC) are 
also eligible for entry into the study. 
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Throughout the induction and maintenance studies, efficacy, PK, biomarkers, and safety will be 
assessed at timepoints indicated in the appropriate Time and Events Schedules. 
Endpoints are defined in Section 9.2.2.4.
Blood samples for pharmacogenomic analyses will be collected from subjects who consent 
separately to this component of the protocol (where local regulations permit). Subject 
participation in pharmacogenomic research is optional.
An independent Data Monitoring Committee (DMC) will assess the safety of subjects 
participating in the induction and maintenance studies, participate in the futility interim analysis 
(Section 11.11.1), and make recommendations to the sponsor about continuation of the studies. 
Refer to Section 11.12 for details.
3.1.1.
Induction Study
In the placebo-controlled induction study, a target of 951 subjects will be randomized in a 1:1:1
ratio to 1 of 3 treatment groups: 

Placebo IV

Ustekinumab 130 mg IV

Weight-range-based ustekinumab doses approximating ustekinumab 6 mg/kg IV (ie, 
ustekinumab ~6 mg/kg IV):

Ustekinumab 260 mg (weight ≤55 kg)

Ustekinumab 390 mg (weight >55 kg but ≤85 kg)

Ustekinumab 520 mg (weight >85 kg)
The schema for the induction study is shown in Figure 2.
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Figure 2:
Schema for the CNTO1275UCO3001 induction study
Eligible subjects will be allocated to a treatment group using permuted block randomization with 
biologic failure status (yes or no) and region (Eastern Europe, Asia, or rest of world) as 
stratification variables. 
Randomized subjects will receive their assigned IV dose of ustekinumab or placebo at Week 0. 
At Week 8, all subjects will be evaluated for the primary endpoint of clinical remission. All 
subjects will also be assessed for clinical response at Week 8. Further study agent administration 
will be determined by clinical response status (using the Mayo endoscopy subscore assigned by 
the local endoscopist) at Week 8, as follows:

Subjects who are in clinical response at Week 8 are eligible to enter the maintenance study 
(Section 3.1.2).

Subjects who are not in clinical response at Week 8 will receive ustekinumab as follows 
(Figure 3): 

Subjects who were randomized to placebo at Week 0 will receive 1 dose of 
ustekinumab ~6 mg/kg IV plus placebo SC (to maintain the blind) at Week 8. 

Subjects who were randomized to ustekinumab at Week 0 will receive 1 dose of 
ustekinumab 90 mg SC plus placebo IV (to maintain the blind) at Week 8. 
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At Week 16, the subjects who were not in clinical response at Week 8 will be re-evaluated for 
clinical response (clinical response status will be based on the Mayo endoscopy subscore
assigned by the local endoscopist): 

Subjects who achieve clinical response at Week 16 are eligible to enter the maintenance 
study (Section 3.1.2). 

Subjects who do not achieve clinical response at Week 16 will not enter the 
maintenance study and will have a safety follow-up visit approximately 20 weeks after 
their last (ie, Week 8) administration of study agent.
Figure 3:
Treatment of subjects who are not in clinical response to induction in CNTO1275UCO3001
All UC-specific medical therapies (ie, oral corticosteroids, oral 5-aminosalicylate (5-ASA) 
compounds, or the immunomodulators 6-MP, AZA, or methotrexate [MTX]) must be maintained 
at a stable dose through to the end of the induction study and can only be discontinued or 
reduced in dose if investigator judgment requires it because of toxicity or medical necessity
(Section 8.1.1). The initiation or increase in dose of UC-specific therapies (or any 
restricted/prohibited medication or therapy) during the induction study will prohibit a subject 
from entering the maintenance study (Section 8.1.1.1).
The primary endpoint of the induction study is clinical remission at Week 8; the major secondary 
endpoints are endoscopic healing at Week 8, clinical response at Week 8, and the change from 
induction baseline in the Inflammatory Bowel Disease Questionnaire (IBDQ) at Week 8. 
Efficacy, PK parameters, biomarkers, and safety will be assessed according to the Time and 
Events Schedule (Table 1).
An interim analysis to assess for futility is planned when the first 30% of subjects either 
complete the induction Week 8 (I-8) visit or terminate study participation before Week 8. This 
analysis will be based on clinical remission at Week 8. The whole study may be stopped for 
futility when the conditional power (ie, the probability of success at the end of the study, given 
the data at the interim analysis) on both ustekinumab doses is less than a prespecified cutoff.
Refer to Section 11.11 for details. 
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Three database locks (DBLs) are planned for the induction study. The first is for the futility 
analysis and will occur when the first 30% of randomized subjects in the induction study have 
either completed the I-8 visit or have terminated study participation before Week 8. The second 
DBL will occur when all randomized subjects in the induction study have either completed the
I-8 visit or have terminated study participation before Week 8. The third DBL will occur when 
all randomized subjects in the induction study have either entered the maintenance study, or have 
completed their final safety visit (20 weeks after the last administration of study agent) for those 
not participating in the maintenance study, or have terminated their study participation.
3.1.2.
Maintenance Study
In the randomized-withdrawal maintenance study, all subjects enrolled will be responders to 
study agent administered in the induction study. The schema for the maintenance study is shown 
in Figure 4. 
Figure 4:
Schema for the CNTO1275UCO3001 maintenance study
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Subjects who were in clinical response to IV ustekinumab during induction will comprise the 
primary population in the maintenance study; this population will include the following:

Subjects who were randomized to receive ustekinumab at Week 0 of the induction study and 
were in clinical response at induction Week 8. 

Subjects who were randomized to receive placebo at Week 0 of the induction study and 
were not in clinical response at induction Week 8, but were in clinical response at induction 
Week 16 after receiving an induction dose of IV ustekinumab (~6 mg/kg) at induction 
Week 8.
A target of 327 subjects who are in clinical response to IV ustekinumab induction will be 
randomized in a 1:1:1 ratio to 1 of 3 treatment groups at the maintenance Week 0/baseline (M-0) 
visit of the maintenance study: 

Placebo SC

Ustekinumab 90 mg SC every 12 weeks (q12w)

Ustekinumab 90 mg SC q8w
Eligible subjects will be allocated to a treatment group using a permuted block randomization 
with clinical remission status at maintenance baseline (yes/no), oral corticosteroid use at 
maintenance baseline (yes/no), and induction treatment (placebo IV [I-0]→ ustekinumab 
~6 mg/kg IV [I-8], ustekinumab 130 mg IV [I-0], or ustekinumab ~6 mg/kg IV [I-0]) as 
stratification variables. 
Additional subjects entering the maintenance study will include the following; these subjects will 
not be part of the primary population:

Subjects who are in clinical response to placebo IV induction will receive placebo SC. 

Subjects who were delayed responders to ustekinumab induction (ie, were not in clinical 
response to ustekinumab at induction Week 8 but were in clinical response at induction 
Week 16) will receive ustekinumab 90 mg SC q8w.
All subjects will receive their assigned dose of SC study agent at the M-0 visit. Thereafter, to 
maintain the blind, all subjects will receive study agent at all scheduled study agent 
administration visits specified in Table 2. Subjects will be assessed for clinical flare at every visit 
and, if loss of response is confirmed (based on the Mayo score that includes the endoscopy 
subscore assigned by the local endoscopist), may be eligible for rescue medication, as described 
in Section 3.1.2.1.
Concomitant medical therapy for UC must have been stable from the I-0 visit through the M-0 
visit unless, in the judgment of the investigator, the therapy had to be discontinued or reduced in 
dose because of toxicity or medical necessity (Section 8.1.1). Subjects who initiated or increased 
the dose of a UC-specific medication (or any restricted/prohibited medication) during the 
induction study are prohibited from entering the maintenance study (Section 8.1.1.1).
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With the exception of corticosteroids, which should be tapered, UC-specific medical therapies 
(ie, oral 5-ASA compounds, or the immunomodulators 6-MP, AZA, or MTX) must be 
maintained at stable doses through Week 44 unless investigator judgment requires that the 
therapy be discontinued or the dose reduced because of toxicity or medical necessity, or unless 
there is a documented loss of response that makes the subject eligible for rescue medication. 
Corticosteroids will be tapered beginning at the M-0 visit for all subjects who enter the 
maintenance study. Refer to Section 8.1.2 for details.
The primary endpoint of the maintenance study is clinical remission at Week 44 among subjects 
who were responders to IV ustekinumab induction. The major secondary endpoints of the 
maintenance study are maintenance of clinical response through Week 44; endoscopic healing at 
Week 44; clinical remission and not receiving concomitant corticosteroids at Week 44; and 
maintenance of clinical remission through Week 44 among the subjects who had achieved 
clinical remission at maintenance baseline.
Efficacy, PK parameters, biomarkers, and safety will be assessed according to the Time and 
Events Schedule (Table 2). Blood samples for pharmacogenomics analyses will be collected 
from subjects who consent separately to this component of the study (where local regulations 
permit).
The primary DBL will occur when all subjects in the maintenance study have either completed 
the M-44 visit or have terminated study participation before Week 44. The final DBL will occur 
when all subjects have either completed the Week 220 visit or have terminated study 
participation before Week 220. One or more additional DBLs may occur between Week 44 and 
Week 220 for publication purposes or for regulatory requirements.
No interim analysis is planned during the maintenance study.
3.1.2.1.
Management of Clinical Flare and Loss of Response
During the maintenance study, subjects who meet the following criteria will be considered to be 
in clinical flare:  an increase from maintenance baseline in the partial Mayo score (ie, the Mayo 
score without the endoscopy subscore) of at least 2 points and an absolute partial Mayo score 
≥4; OR an absolute partial Mayo score ≥7 points (Section 9.1.4.1). 
Subjects in clinical flare who have not previously met the criteria for loss of clinical response in 
the maintenance study (ie, are in clinical flare for the first time or have flared previously and not 
met the criteria for loss of response) should undergo endoscopy, which need only be a 
sigmoidoscopy, and be evaluated for loss of clinical response (based on the Mayo score that 
includes the endoscopy subscore assigned by the local endoscopist). These subjects should 
maintain stable doses of their UC medications after meeting clinical flare criteria and while 
waiting for their endoscopy score to establish loss of clinical response. 
Subjects who have lost response will be eligible to receive rescue medication (ie, corticosteroids, 
6-MP, AZA, MTX, and/or 5-ASAs; Section 8.1.2.1) while continuing to receive study agent 
administration as scheduled. 
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Subjects who have lost response will be assessed 16 weeks after the visit at which the loss of 
clinical response criteria was met. During this interval, clinical flare criteria will not be applied. 
Subjects who have not achieved a partial Mayo response (ie, a decrease from induction baseline 
of ≥2 in the partial Mayo score) at 16 weeks after loss of response will be discontinued from 
study agent administration, and should return for a final safety visit approximately 20 weeks 
after their last study agent administration. Subjects who are assessed as being in partial Mayo 
response will continue in the study. 
After the 16 weeks following loss of clinical response, subjects who remain in the study will 
continue to be assessed for clinical flare using the criteria based on the partial Mayo score.  
Subjects who subsequently meet the criteria for clinical flare again will not be required to 
undergo an endoscopy. These subjects will be eligible to receive rescue medication at the time of 
clinical flare and be assessed for partial Mayo response 16 weeks after the visit at which clinical 
flare was met and managed as described above. 
Subjects will be strongly encouraged to undergo endoscopy at the time of first clinical flare to 
establish if loss of clinical response criteria were met. A subject who declines to undergo an 
endoscopy on initial clinical flare will be assessed for partial Mayo response 16 weeks after the 
initial flare.
A subject who meets the criteria of clinical flare on more than 2 occasions during the 
maintenance study will be discontinued from study agent administration.
3.1.3.
Long-Term Extension
Subjects who complete the safety and efficacy evaluations at Week 44 and who may benefit 
from continued treatment, in the opinion of the investigator, will have the opportunity to 
participate in the LTE. The LTE begins after the assessments listed for the M-44 visit (ie, the 
last assessments in the maintenance study) have been completed and will continue through 
Week 220 or until the sponsor decides not to pursue an indication in UC, whichever occurs first.
Subjects will continue to receive the same treatment regimen during the LTE that they were 
receiving at the end of the maintenance study (either placebo or ustekinumab 90 mg SC q8w or
q12w), with the first dose in the LTE being administered at Week 48.
During the LTE, all subjects will be assessed for worsening of disease activity based on the 
clinical judgment of the investigator. Subjects in the primary analysis population whose UC 
disease activity worsens will be eligible for a dose adjustment as follows:

Placebo SC → ustekinumab 90 mg SC q8w

Ustekinumab 90 mg SC q12w → ustekinumab 90 mg SC q8w

Ustekinumab 90 mg SC q8w → continue on ustekinumab 90 mg SC q8w
The first visit at which a subject can be considered for a dose adjustment is at Week 56. Subjects 
will be allowed 1 dose adjustment during the LTE.
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The interactive web response system (IWRS) will ensure that SC ustekinumab is not
administered more frequently than q8w. For example, subjects randomized to the ustekinumab 
90 mg SC q12w group who meet dose adjustment criteria will receive ustekinumab 90 mg SC at 
the current visit only if the last dose of ustekinumab was administered at least 8 weeks before 
this visit. If the last administration of ustekinumab 90 mg SC was less than 8 weeks before, the 
next administration of ustekinumab 90 mg SC will be initiated at the next scheduled visit that 
occurs at least 8 weeks after the previous administration of ustekinumab.
Subjects who are not in the primary analysis population (ie, induction placebo responders, 
delayed ustekinumab responders) will not be eligible for a dose adjustment during the LTE.
Any subject who has not shown improvement in his or her UC disease activity by 16 weeks after 
worsening of their UC disease activity (as assessed by the investigator) will be discontinued from 
further study agent administration.
During the LTE, all concomitant medications, including UC-specific medications (with the 
exception of the prohibited medications listed in Section 8.1.1.1.2), may be administered at the 
discretion of the investigator. 
Efficacy evaluations during the LTE will generally be based on the partial Mayo score, markers 
of inflammation, and corticosteroid use. The full Mayo score (including an endoscopy) will be 
assessed at the final efficacy visit. Selected patient-reported outcomes (PRO) and health 
economics data will also be collected. Safety evaluations will include an assessment of adverse 
events (AEs) and routine laboratory analyses. All study evaluations to be performed during the 
LTE are listed in the Time and Events Schedule (Table 3).
The study blind will be maintained during the LTE until the last subject in the maintenance study 
has completed the M-44 visit evaluations and the Week 44 analyses have been completed. 
Therefore, subjects will continue to receive study agent at all monthly visits until that time. After 
the study is unblinded to the investigative sites, subjects receiving placebo will be terminated 
from study participation, and subjects receiving ustekinumab will continue to receive 
ustekinumab, but will have their study visits scheduled to coincide with their dose regimen 
(either q8w or q12w, as appropriate for their dose regimen).
3.2.
Study Design Rationale
3.2.1.
Study Population
Ustekinumab is a novel therapy with a favorable long-term safety profile in psoriasis that has the 
potential to offer an SC treatment option for maintenance, following a single IV induction dose, 
which could be safe and efficacious for patients with moderately to severely active UC who have 
had an inadequate response to or are intolerant of either conventional or biologic therapy. There 
is a clear unmet medical need in this broad patient population (Section 1.2), which will be the 
target population for the induction study. 
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3.2.1.1.
Induction
Subjects with moderately to severely active UC (defined as a Mayo score of 6 to 12 inclusive, 
including a Mayo endoscopy score ≥2) who have had an inadequate response or have failed to 
tolerate conventional or biologic therapy will be eligible for the induction study. At Week 8, all 
subjects will be evaluated for clinical response; those in clinical response (either to ustekinumab 
or placebo) will be eligible to enter the maintenance study as described in Section 3.1.2. 
Subjects who were randomized to placebo and are not in clinical response at Week 8 will receive 
a single IV infusion of ustekinumab at the highest dose studied (ie, ~6 mg/kg) in a blinded 
manner. This will ensure that those subjects who did not achieve clinical response with placebo 
have the option to receive and potentially respond to active drug.
Subjects who were randomized to ustekinumab and are not in clinical response at Week 8 will 
receive a single SC injection of 90 mg ustekinumab in a blinded manner. This will allow the 
study to identify if a delayed response can be achieved for some subjects.
All subjects who were not in clinical response at Week 8 and who received additional induction 
treatment at Week 8 will be evaluated for clinical response at Week 16. Those who do not 
achieve clinical response at Week 16 will not be eligible to enter the maintenance study, to limit 
exposure to a therapy from which they are not deriving benefit. Subjects who are in clinical 
response at Week 16 will be eligible to enter the maintenance study as described in Section 3.1.2.
Among the subjects in clinical response at Week 16 will be those who are delayed responders to 
ustekinumab (ie, did not respond to IV ustekinumab administered at induction Week 0 but 
responded after an additional SC administration of ustekinumab at Week 8). Enrollment of these 
subjects in the maintenance study will allow an evaluation of the benefit-risk of continued 
therapy with ustekinumab following a delayed induction response to ustekinumab. However, 
these subjects will not be included in the primary population for maintenance.
An additional group of subjects in clinical response at Week 16 will be those who were initially 
randomized to IV placebo at induction Week 0 and were not in clinical response at Week 8, but 
responded at Week 16 after a single IV administration of ustekinumab at induction Week 8. Like 
the subjects initially randomized to a single IV administration of ustekinumab at induction 
Week 0, these subjects will be considered part of the primary population for maintenance (ie,
subjects in clinical response 8 weeks after a single IV administration of ustekinumab) to assess 
the evaluation of the benefit-risk of continued therapy with ustekinumab following an initial 
response.
To limit the exposure of subjects with UC should ustekinumab treatment prove to be ineffective, 
a futility analysis based on the primary endpoint of clinical remission at Week 8 will be 
conducted when the first 30% of randomized subjects in the induction study reach Week 8 
(Section 11.11.1). 
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3.2.1.2.
Maintenance
Subjects with moderately to severely active UC who were in clinical response to IV ustekinumab 
during induction will comprise the primary population in the maintenance study (Section 3.1.2) 
and will be randomized to receive ustekinumab (90 mg q8w or 90 mg q12w) or placebo to 
evaluate the efficacy and safety of ustekinumab maintenance therapy. 
Additional subjects, including placebo induction responders and delayed responders (ie, those 
who were not in clinical response to ustekinumab IV at induction Week 8 but were in clinical 
response at induction Week 16) will be enrolled in the maintenance study to maintain the blind
but will not be randomized. 
All subjects will be evaluated for clinical flare and potential loss of clinical response throughout 
the 44 weeks of the maintenance study. Subjects who lose response will continue to receive 
study agent and be eligible to receive rescue medications to manage the increase in their UC 
disease activity (Section 8.1.2.1). 
To limit exposure to a potentially ineffective therapy, subjects will be evaluated for response 
16 weeks after loss of clinical response (Section 3.1.2.1). If a prespecified measure of response is 
not achieved (ie, partial Mayo response), the administration of further study agent will be 
discontinued.
3.2.2.
Endpoints
3.2.2.1.
Induction
The primary endpoint of the induction study is clinical remission at Week 8. Clinical remission is 
generally considered to reflect the absence of ongoing symptoms. The choice of Week 8 is based 
on Phase 2b data with ustekinumab induction in Crohn’s disease.29
3.2.2.2.
Maintenance
The primary endpoint of the maintenance study is clinical remission at Week 44 among IV 
ustekinumab induction responders. At this timepoint, subjects will have had at least 52 weeks of 
exposure to ustekinumab and will have received either 4 or 6 maintenance doses (depending on 
their dose frequency of either q12w or q8w, respectively), which is deemed sufficient to assess 
the efficacy and safety of the maintenance regimens. This will be followed by an LTE of up to 3 
additional years to assess longer-term safety and efficacy. 
3.2.3.
Efficacy Assessments
The efficacy evaluations selected for the induction and maintenance studies (eg, Mayo score, 
partial Mayo score; Section 9.2.1) are accepted disease activity measures in UC studies. 
3.2.4.
Pharmacokinetic Assessments
Pharmacokinetic assessments will be used to further understand the disposition of ustekinumab 
in subjects with UC. 
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3.2.5.
DNA and Biomarker Collection
It is recognized that genetic variation can be an important contributory factor to interindividual 
differences in drug response and can also serve as a marker for disease susceptibility and 
prognosis. Pharmacogenomic research may help to explain interindividual variability in clinical 
outcomes and may help to identify population subgroups that respond differently to a drug. The 
goal of the pharmacogenomic component is to collect DNA to allow the identification of genetic 
factors that may influence the PK, PD, or efficacy of ustekinumab and to identify genetic factors 
associated with UC.
Biomarker samples will be collected to evaluate the mechanism of action of ustekinumab, help 
explain interindividual variability in clinical outcomes, or help to identify population subgroups 
that respond differently to a drug. The goal of the biomarker analyses is to evaluate the PD of 
ustekinumab and aid in evaluating the drug-clinical response outcome relationship. 
DNA and biomarker samples may be used to help address emerging issues and to enable the 
development of more effective and ultimately individualized therapies. 
3.2.6.
Patient-Reported Outcomes on Health-Related Quality of Life
Patient-reported outcomes evaluations (eg, IBDQ, 36-item Short Form Health Survey [SF-36], 
EuroQoL-5D Health Questionnaire [EQ-5D]); Section 9.2.1) will be used to assess general as 
well as disease-specific health-related quality of life.
3.2.7.
Health Economics and Medical Resource Utilization
Medical resource utilization evaluations such as UC-related hospitalizations and UC-related 
surgeries will be collected for evaluation of the health economics of ustekinumab treatment. 
Additionally, the impact of ustekinumab treatment on work productivity will be assessed using 
the Work Productivity and Activity Impairment Questionnaire-General Health (WPAI-GH) and 
work productivity visual analog scale (VAS). 
3.2.8.
Control, Randomization, and Blinding in the Induction and 
Maintenance Studies
In the induction study and for the primary population of the maintenance study, a placebo control 
will be used to establish the frequency and magnitude of changes in clinical endpoints that may 
occur in the absence of active treatment. The choice of a placebo comparator accommodates the 
enrollment of patients with the highest unmet need, namely patients who have failed or are 
intolerant of the anti-TNFs, which are the current gold standard for biologic therapy in 
moderately to severely active UC. Furthermore, the overall objective of the maintenance study is 
to assess the benefit-risk of continuing treatment with ustekinumab following induction response 
and is therefore designed as a randomized withdrawal study targeting subjects who are in clinical 
response to ustekinumab, who are randomized to continue treatment with ustekinumab compared 
with subjects who are withdrawn from therapy and receive placebo. 
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Randomization will be used to minimize bias in the assignment of subjects to treatment groups, 
to increase the likelihood that known and unknown subject attributes (eg, demographic and 
baseline characteristics) are evenly balanced across treatment groups, and to enhance the validity 
of statistical comparisons across treatment groups. Blinded treatment will be used to reduce 
potential bias during data collection and evaluation of clinical endpoints.
3.2.9.
Dose Rationale
Ustekinumab has not been studied in UC. However, considering the similarities in the genetics 
and biology of UC and Crohn’s disease, it is reasonable to assume that ustekinumab will also be 
effective in UC. The doses selected for this Phase 3 protocol for ustekinumab in subjects with 
UC parallel those being studied in the Phase 3 program for ustekinumab in subjects with Crohn’s 
disease. 
3.2.9.1.
Induction
Intravenous administration was chosen for the induction studies in the ustekinumab Crohn’s 
disease program because the evaluation of biomarker changes in response to ustekinumab 
treatment in the Phase 2a ustekinumab study (C0379T07) suggested a very rapid onset of action 
after IV administration that was not observed after SC administration. 
The specific IV doses selected for the Phase 3 induction studies in the ustekinumab Crohn’s 
disease program were based on the results of the Phase 2b ustekinumab study (C0743T26). 
Greater proportions of subjects in the ustekinumab 1 mg/kg, 3 mg/kg, and 6 mg/kg treatment 
groups were in clinical response at Week 6 (36.6%, 34.1%, and 39.7%, respectively) and at 
Week 8 (32.1%, 31.8%, and 43.5%, respectively) compared with placebo (23.5% and 17.4% at 
Weeks 6 and 8, respectively). However, in the 1 mg/kg group, serum ustekinumab 
concentrations through Week 8 appeared lower in nonresponders compared with responders at 
Week 6; this difference between responders and nonresponders was not apparent in the 3 mg/kg 
or the 6 mg/kg treatment groups. Furthermore, subjects in the 1 mg/kg treatment group appeared 
to lose response earlier than those in the 3 mg/kg or 6 mg/kg treatment groups, suggesting that 
some subjects in the 1 mg/kg group may not have had sufficient drug exposure to achieve or 
maintain clinical response through 8 weeks. 
Accordingly, it was determined that a single 6 mg/kg IV dose (which was well tolerated and was 
the most effective induction dose in C0743T26), along with a lower dose (which would be higher 
than 1 mg/kg), would be evaluated in the Phase 3 Crohn’s disease studies. In addition, an 
approach was adopted that allowed the use of complete vials, resulting in simpler drug 
administration. Based on these considerations, a ustekinumab 130 mg IV fixed dose 
(approximately 2 mg/kg on a milligram per kilogram basis) was chosen for the low-dose arm, 
while weight-range-based doses approximating 6 mg/kg IV (<55 kg: 260 mg ustekinumab; 
55-90 kg: 390 mg ustekinumab; >90 kg: 520 mg ustekinumab) were chosen as the high-dose arm 
in the Phase 3 Crohn’s disease studies and will be used in this induction study of ustekinumab 
in UC.
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3.2.9.2.
Maintenance
The two SC ustekinumab regimens planned for the UC maintenance study are the same as those 
being used in the Phase 3 maintenance study in the ustekinumab Crohn’s disease program, which 
were chosen based on data from the Phase 2b study in Crohn’s. The ustekinumab 90 mg SC q8w 
regimen was selected because it was considered safe and effective in achieving remission at 
Week 22 among subjects randomized as responders to ustekinumab induction. To explore a 
lower dose regimen, the ustekinumab 90 mg SC every 12 weeks (q12w) regimen was included 
because it was the next lower dose regimen that had been studied extensively in psoriasis and 
was thought likely to succeed in maintaining clinical efficacy over time in patients with Crohn’s 
disease. These maintenance doses provided systemic exposures that were likely to meet the 
safety and efficacy objectives for the development of ustekinumab in Crohn’s disease. 
Similarly, the dose adjustment planned for the LTE is based on the strategy for dose adjustment
in the Phase 3 Crohn’s disease maintenance study. Subjects randomized to receive ustekinumab 
90 mg SC q12w who subsequently lose clinical response in that study can be dose adjusted to the 
more frequent q8w dose regimen (shown to be effective in the Phase 2b study).
4.
SUBJECT POPULATION
A target of 951 subjects will be randomized in the induction study so that approximately 
327 subjects will be randomized in the maintenance study.
Screening for eligible subjects will be performed within 8 weeks before study agent
administration in the induction study. Inclusion and exclusion criteria are described in the 
following subsections. For questions about inclusion or exclusion criteria, the investigator should 
consult with the appropriate sponsor representative before enrolling a subject in the study.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the induction 
study: 
1.
Be a man or woman 18 years of age or older.
2.
Has a clinical diagnosis of UC at least 3 months before screening.
3.
Has moderately to severely active UC, defined as a baseline (Week 0) Mayo score of 6 to 
12, inclusive, using the Mayo endoscopy subscore assigned during the central reading of the 
video endoscopy.
4.
Has a screening endoscopy with 2 endoscopy subscore of the Mayo score as determined by 
a central reading of the video endoscopy.
5.
Have failed biologic therapy, ie, have received treatment with 1 or more TNF antagonists or 
vedolizumab at a dose approved for the treatment of UC, and have a documented history of 
failure to respond to or tolerate such treatment; Attachment 1); 
OR
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Be naïve to biologic therapy (ie, TNF antagonists or vedolizumab) or not have demonstrated 
a history of failure to respond to, or tolerate, a biologic therapy (Attachment 1) and have a 
prior or current UC medication history that includes at least 1 of the following:
a.
Inadequate response to or failure to tolerate current treatment with oral corticosteroids
or immunomodulators (6-MP or AZA) (Attachment 2).
OR
b.
History of failure to respond to, or tolerate, at least 1 of the following therapies:  oral or 
IV corticosteroids or immunomodulators (6-MP or AZA) (Attachment 2).
OR
c.
History of corticosteroid dependence (ie, an inability to successfully taper 
corticosteroids without a return of the symptoms of UC; Attachment 2).
6.
Before the first administration of study agent, the following conditions must be met:
a.
If receiving conventional immunomodulators (ie, AZA, 6-MP, or MTX), must have 
been taking them for ≥12 weeks, and on a stable dose for at least 4 weeks. 
b.
If AZA, 6-MP, or MTX has been recently discontinued, it must have been stopped for at 
least 4 weeks.
c.
If receiving oral 5-ASA compounds, the dose must have been stable for at least 
2 weeks.
d.
If receiving oral corticosteroids other than budesonide or beclomethasone, the dose 
must be ≤20 mg/day prednisone or its equivalent and must have been stable for at least 
2 weeks.
e.
Criterion modified per Amendment 2. 
e.1
If receiving budesonide or beclomethasone dipropionate, the dose must have been 
stable for at least 2 weeks.
f.
Criterion modified per Amendment 2. 
f.1
If oral 5-ASA compounds or oral corticosteroids have been recently discontinued, 
they must have been stopped for at least 2 weeks.
7.
The following medications/therapies must have been discontinued before first administration 
of study agent:
a.
Vedolizumab for at least 4 months.
b.
Criterion modified per Amendment 2.
b.1
TNF-antagonist therapy (eg, infliximab, etanercept, certolizumab, adalimumab, 
golimumab [or approved biosimilars for these therapies]) for at least 8 weeks.
c.
Cyclosporine, tacrolimus, or sirolimus, for at least 4 weeks.
d.
6-thioguanine (6-TG) must have been discontinued for at least 4 weeks.
e.
Criterion modified per Amendment 2.
e.1
Rectal corticosteroids (ie, corticosteroids administered to the rectum or sigmoid 
colon via foam or enema or suppository) for at least 2 weeks.
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f.
Rectal 5-ASA compounds (ie, 5-ASAs administered to the rectum or sigmoid colon via 
foam or enema or suppository) for at least 2 weeks.
g.
Parenteral corticosteroids for at least 2 weeks.
h.
Total parenteral nutrition (TPN) for at least 2 weeks.
i.
Antibiotics for the treatment of UC (eg, ciprofloxacin, metronidazole, or rifaximin) for 
at least 2 weeks.
8.
Criterion modified per Amendment 2.
8.1 A subject 45 years of age must either have had a full colonoscopy to assess for the 
presence of adenomatous polyps within 5 years before the first administration of study 
agent or a full colonoscopy to assess for the presence of adenomatous polyps at the 
screening visit. The adenomatous polyps must be removed before the first 
administration of study agent.
9.
Criterion modified per Amendment 2.
9.1 A subject who has had extensive colitis for 8 years, or disease limited to the left side 
of the colon for 10 years, must either have had a full colonoscopy to assess for the 
presence of dysplasia within 1 year before the first administration of study agent or a 
full colonoscopy to assess for the presence of malignancy at the screening visit.
10. Is considered eligible according to the following tuberculosis (TB) screening criteria:
a.
Has no history of latent or active TB before screening. An exception is made for 
subjects who have a history of latent TB and are currently receiving treatment for latent 
TB, will initiate treatment for latent TB before the first administration of study agent, or 
have documentation of having completed appropriate treatment for latent TB within 
3 years before the first administration of study agent. It is the responsibility of the 
investigator to verify the adequacy of previous anti-tuberculous treatment and provide 
appropriate documentation. 
b.
Has no signs or symptoms suggestive of active TB upon medical history and/or physical 
examination.
c.
Has had no recent close contact with a person with active TB or, if there has been such 
contact, will be referred to a physician specializing in TB to undergo additional 
evaluation and, if warranted, receive appropriate treatment for latent TB before the first 
administration of study agent.
d.
Within 2 months before the first administration of study agent, has a negative 
QuantiFERON-TB Gold test result (Attachment 3), or has a newly identified positive 
QuantiFERON-TB Gold test result in which active TB has been ruled out and for which 
appropriate treatment for latent TB has been initiated before the first administration of 
study agent. Within 2 months before the first administration of study agent, a negative 
tuberculin skin test (Attachment 4), or a newly identified positive tuberculin skin test in 
which active TB has been ruled out and for which appropriate treatment for latent TB 
has been initiated before the first administration of study agent, is additionally required 
if the QuantiFERON-TB Gold test is not approved/registered in that country or the 
tuberculin skin test is mandated by local health authorities. A tuberculin skin test is 
recommended but not required for study centers in Ukraine if tuberculin is not 
available.
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A subject whose first QuantiFERON-TB Gold test result is indeterminate should have 
the test repeated (Section 9.1.2). In the event that the second QuantiFERON-TB Gold 
test result is also indeterminate, the subject may be enrolled without treatment for latent 
TB, if active TB is ruled out, his/her chest radiograph shows no abnormality suggestive 
of TB (active or old, inactive TB), and the subject has no additional risk factors for TB 
as determined by the investigator. This determination must be promptly reported to the 
sponsor’s medical monitor and recorded in the subject's source documents and initialed 
by the investigator.
The QuantiFERON-TB Gold test and tuberculin skin test are not required at screening 
for subjects with a history of latent TB and ongoing treatment for latent TB or 
documentation of having completed adequate treatment as described above; subjects 
with documentation of having completed adequate treatment as described above are not 
required to initiate additional treatment for latent TB.
e.
Has a chest radiograph (posterior-anterior view), taken within 3 months before the first 
administration of study agent and read by a qualified radiologist, with no evidence of 
current, active TB or old, inactive TB.
11. Before randomization, a woman must be either: 
a.
Not of childbearing potential: premenarchal; postmenopausal (>45 years of age with 
amenorrhea for at least 12 months or any age with amenorrhea for at least 6 months and 
a serum follicle-stimulating hormone level >40 IU/L); permanently sterilized (eg, 
bilateral tubal occlusion [which includes tubal ligation procedures consistent with local 
regulations], hysterectomy, bilateral salpingectomy, bilateral oophorectomy); or 
otherwise be incapable of pregnancy.
OR
b.
Of childbearing potential:  if heterosexually active, must be practicing a highly effective 
method of birth control consistent with local regulations regarding the use of birth 
control methods for subjects participating in clinical studies: eg, established use of oral, 
injected or implanted hormonal methods of contraception; placement of an intrauterine 
device (IUD) or intrauterine system (IUS); barrier methods: condom with spermicidal 
foam/gel/film/cream/suppository or occlusive cap (diaphragm or cervical/vault caps) 
with spermicidal foam/gel/film/cream/suppository; male partner sterilization (the 
vasectomized partner should be the sole partner for that subject); true abstinence (when 
this is in line with the preferred and usual lifestyle of the subject). 
Note: If the subject’s childbearing potential changes after the start of the study (eg, a 
woman who is not heterosexually active becomes active, a premenarchal woman 
experiences menarche), that subject must begin practicing a highly effective method of 
birth control as described above.
12. A woman of childbearing potential must have a negative serum (β-human chorionic 
gonadotropin) pregnancy test result at screening and a negative urine pregnancy test result at 
Week 0.
13. A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during the study and for 20 weeks after the last study agent administration.
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14. A man who is sexually active with a woman of childbearing potential and who has not had a 
vasectomy must agree to use a barrier method of birth control, eg, either condom with 
spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository; all men must also 
agree not to donate sperm during the study and for 20 weeks after receiving the last 
administration of study agent. 
15. Has screening laboratory test results within the following parameters:
a.
Hemoglobin 8.0 g/dL (SI:  ≥80.0 g/L)
b.
White blood cell count (WBC) 3 × 103 cells/L (SI:  3.0 × 109 cells/L)
c.
Neutrophils 1.5 × 103 cells/L (SI:  1.5 × 109 cells/L)
d.
Platelets 100 × 103 cells/L (SI:  100 × 109 cells/L)
e.
Serum creatinine ≤1.5 mg/dL (SI:  133 mol/L)
f.
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations 
must be within 2 times the upper limit of the normal range (ULN) for the laboratory 
conducting the test.
16. Be willing and able to adhere to the prohibitions and restrictions specified in this protocol. 
17. Each subject must sign an informed consent form (ICF) indicating that he or she understands 
the purpose of and procedures required for the study and is willing to participate in the 
study. In regions where the legal age of consent is older than 18 years, informed consent 
must be obtained from and signed by both the subject and his or her legally acceptable 
representative.
18. Each subject must sign a separate ICF if he or she agrees to provide optional DNA samples 
for research where local regulations permit. (In regions where the legal age of consent is 
older than 18 years, informed consent must be obtained from and signed by both the subject 
and his or her legally acceptable representative.) Refusal to give consent for the optional 
DNA samples does not exclude a subject from participation in the study.
4.2.
Exclusion Criteria
A potential subject who meets any of the following criteria will be excluded from participating in 
the induction study:  
1.
Has severe extensive colitis as evidenced by:
a.
Current hospitalization for the treatment of UC.
OR
b.
Investigator judgment that the subject is likely to require a colectomy within 12 weeks 
of baseline.
OR
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c.
Symptom complex at screening or baseline visits that includes at least 4 of the 
following:
1)
Diarrhea with 6 bowel movements/day with macroscopic blood in stool
2)
Focal severe or rebound abdominal tenderness
3)
Persistent fever (37.5°C)
4)
Tachycardia (>90 beats/minute)
5)
Anemia (hemoglobin <8.5 g/dL) 
2.
Has UC limited to the rectum only or to <20 cm of the colon.
3.
Presence of a stoma.
4.
Presence or history of a fistula.
5.
Require, or required within the 2 months before screening, surgery for active gastrointestinal 
bleeding, peritonitis, intestinal obstruction, or intra-abdominal or pancreatic abscess 
requiring surgical drainage, or other conditions possibly confounding the evaluation of 
benefit from study agent treatment.
6.
Presence of symptomatic colonic or small bowel obstruction, confirmed by objective 
radiographic or endoscopic evidence of a stricture with resulting obstruction (dilation of the 
colon or small bowel proximal to the stricture on barium radiograph or an inability to 
traverse the stricture at endoscopy).
7.
History of extensive colonic resection (eg, less than 30 cm of colon remaining) that would 
prevent adequate evaluation of the effect of study agent on clinical disease activity.
8.
History of colonic mucosal dysplasia. Subjects will not be excluded from the study because 
of a pathology finding of “indefinite dysplasia with reactive atypia.”
9.
Presence on screening endoscopy of adenomatous colonic polyps, if not removed before 
study entry, or history of adenomatous colonic polyps that were not removed.
10. Diagnosis of indeterminate colitis, microscopic colitis, ischemic colitis, or Crohn’s disease 
or clinical findings suggestive of Crohn’s disease.
11. Has a stool culture or other examination positive for an enteric pathogen, including 
Clostridium difficile toxin, in the previous 4 months, unless a repeat examination is negative 
and there are no signs of ongoing infection with that pathogen.
Concomitant or previous medical therapies received:
12. Has received the following concomitant or previous medical therapies:
a.
A biologic therapy targeted at IL-12 and/or IL-23 (eg, ustekinumab, briakinumab, 
guselkumab).
b.
Natalizumab within 12 months of first study agent administration.
c.
Agents that deplete B or T cells (eg, rituximab, alemtuzumab) within 12 months of first 
study agent administration, or continue to manifest depletion of B or T cells more than 
12 months after completion of therapy with lymphocyte-depleting agents.
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d.
Any investigational drug within 4 weeks before first administration of study agent or 
within 5 half-lives of the investigational agent, whichever is longer.
e.
Criterion modified per Amendment 2.
e.1
Apheresis (eg, Adacolumn or Cellsorba apheresis) within 2 weeks before the first 
administration of study agent.
Infections or predisposition to infections:
13. Has a history of latent or active granulomatous infection, including histoplasmosis or 
coccidioidomycosis, before screening. Refer to Inclusion Criterion 10 for information 
regarding eligibility with a history of latent TB.
14. Has a history of, or ongoing, chronic or recurrent infectious disease, including but not 
limited to, chronic renal infection, chronic chest infection (eg, bronchiectasis), sinusitis, 
recurrent urinary tract infection (eg, recurrent pyelonephritis, recurrent cystitis), an open, 
draining, or infected skin wound, or an ulcer. 
15. Has a chest radiograph within 3 months before the first administration of study agent that 
shows an abnormality suggestive of a malignancy or current active infection, including TB.
16. Have a history of being human immunodeficiency virus (HIV) antibody-positive, or tests 
positive for HIV at screening.
17. Criterion modified per Amendment 2.
17.1
Are seropositive for antibodies to hepatitis C virus (HCV) without a history 
of successful treatment, defined as being negative for HCV RNA at least 
24 weeks after completing antiviral treatment.
18. Subjects must undergo screening for hepatitis B virus (HBV). At a minimum, this includes 
testing for HBV surface antigen (HBsAg), HBV surface antibody (anti-HBs), and HBV core 
antibody (anti-HBc) total:
a.
Subjects who test negative for all HBV screening tests (ie, HBsAg-, anti-HBc-, and 
anti-HBs-) are eligible for this study.
b.
Subjects who test positive for surface antigen (HBsAg+) are not eligible for this study, 
regardless of the results of other hepatitis B tests.
c.
Subjects who test negative for surface antigen (HBsAg-) and test positive for core 
antibody (anti-HBc+) and surface antibody (anti-HBs+) are eligible for this study.
d.
Subjects who test positive only for surface antibody (anti-HBs+) are eligible for this 
study.
e.
Subjects who test positive only for core antibody (anti-HBc+) must undergo further 
testing for hepatitis B deoxyribonucleic acid (HBV DNA test). If the HBV DNA test is 
positive, the subject is not eligible for this study. If the HBV DNA test is negative, the 
subject is eligible for this study. In the event the HBV DNA test cannot be performed, 
the subject is not eligible for this study.
Note: For subjects who are not eligible for this study due to HIV, HCV, and HBV test 
results, consultation with a physician with expertise in the treatment of those infections is 
recommended.
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19. Has had a Bacille Calmette-Guerin (BCG) vaccination within 12 months or any other live 
bacterial or live viral vaccination within 12 weeks before baseline. 
20. Has or has ever had a nontuberculous mycobacterial infection or serious opportunistic 
infection (eg, cytomegalovirus colitis, Pneumocystis carinii, aspergillosis).
21. Has had a serious infection (eg, hepatitis, pneumonia, or pyelonephritis), has been 
hospitalized for an infection, or has been treated with parenteral antibiotics for an infection 
within 2 months before first administration of study agent. Less serious infections (eg, acute 
upper respiratory tract infection, simple urinary tract infection) need not be considered 
exclusionary at the discretion of the investigator. 
22. Has evidence of a herpes zoster infection ≤8 weeks before baseline. 
Malignancy or increased potential for malignancy:
23. Has any known malignancy or has a history of malignancy (with the exception of basal cell 
carcinoma; squamous cell carcinoma in situ of the skin; or cervical carcinoma in situ that 
has been treated with no evidence of recurrence; or squamous cell carcinoma of the skin that 
has been treated with no evidence of recurrence within 5 years before screening). 
24. Presence or history of lymphoproliferative disease including lymphoma, or signs and 
symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy of 
unusual size or location (eg, nodes in the posterior triangle of the neck, infraclavicular, 
epitrochlear, or periaortic areas), or clinically significant hepatomegaly or splenomegaly, or 
monoclonal gammopathy of undetermined significance. 
Coexisting medical conditions or past medical history:
25. Has known allergies, hypersensitivity, or intolerance to ustekinumab or its excipients (refer 
to the ustekinumab IB). 
26. Has severe, progressive, or uncontrolled renal, hepatic, hematologic, endocrine, pulmonary, 
cardiac, neurologic, psychiatric, or cerebral disease, or signs or symptoms thereof. 
27. Has a transplanted organ (with the exception of a corneal transplant performed >12 weeks 
before screening).
28. Has previously undergone allergy immunotherapy for prevention of anaphylactic reactions. 
29. Criterion modified per Amendment 2.
29.1
Has a history of drug or alcohol abuse according to the Diagnostic and 
Statistical Manual of Mental Disorders, 5th edition (DSM-V), within 1 year 
before screening.
30. Has poor tolerability of venipuncture or lacks adequate venous access for required blood 
sample collections during the study period. 
31. Is a woman who is pregnant, or breast-feeding, or planning to become pregnant, or is a man 
who plans to father a child while enrolled in this study or within 20 weeks after the last dose 
of study agent.
32. Has any condition for which, in the opinion of the investigator, participation would not be in 
the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, 
or confound the protocol-specified assessments.
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General:
33. Is currently participating or intends to participate in any other study using an investigational 
agent or procedure during participation in this study. 
34. Employees of the investigator or study site with direct involvement in the proposed study or 
other studies under the direction of that investigator or study site, as well as family members 
of the employees or the investigator.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a subject's status changes (including laboratory results or receipt of additional medical records) 
after screening but before the first dose of study agent is given, such that the subject no longer 
meets all eligibility criteria, that subject should be excluded from participation in the study. 
Section 17.4, Source Documentation, describes the required documentation to support meeting 
enrollment criteria.
4.3.
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation:
1.
Must agree not to receive a live virus or live bacterial vaccination, including a BCG 
vaccination, during the study and for 12 months after receiving study agent for BCG 
vaccination or 20 weeks after receiving the last administration of study agent for other live 
vaccines. 
2.
A woman of childbearing potential who is heterosexually active must remain on a highly 
effective method of birth control (as described in Inclusion Criterion 11b) during the study 
and for 20 weeks after receiving the last administration of study agent. 
3.
A woman must agree not to donate eggs (ie, ova, oocytes) for the purposes of assisted 
reproduction during the study and for 20 weeks after receiving the last administration of 
study agent. 
4.
A man who is sexually active with a woman of childbearing potential and who is not 
surgically sterile must agree to use a barrier method of birth control (as described in 
Inclusion Criterion 14) during the study and for 20 weeks after receiving the last 
administration of study agent. 
5.
All male subjects must also agree not to donate sperm during the study and for 20 weeks 
after receiving the last administration of study agent.
6.
Subjects who require treatment for latent TB must complete the appropriate course of TB 
therapy. 
A complete list of prohibited therapies is provided in Section 8.
5.
TREATMENT ALLOCATION AND BLINDING
Central randomization for treatment allocation will be implemented in the induction and 
maintenance studies. A computer-generated randomization schedule will be prepared for each 
study under the supervision of the sponsor. 
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In the induction study, subjects will be randomized at Week 0 to 1 of 3 treatment groups 
(placebo IV, ustekinumab 130 mg IV, or ustekinumab ~6 mg/kg IV) using permuted block 
randomization with biologic failure status (yes/no) and region (Eastern Europe, Asia, or rest of 
world) as stratification variables. At Week 8, subjects who are not in clinical response will be 
assigned to treatment and matching placebo, as described in Section 3.1.1. To maintain the blind, 
both IV and SC administrations will be given to these subjects.
In the maintenance study, subjects in the primary population will be randomized to 1 of 3 
treatment groups (placebo SC, ustekinumab 90 mg SC q8w, or ustekinumab 90 mg SC q12w) 
using a permuted block randomization with clinical remission status at maintenance baseline 
(yes/no), oral corticosteroid use at maintenance baseline (yes/no), and induction treatment 
(placebo IV → ustekinumab ~6 mg/kg IV, ustekinumab 130 mg IV, or ustekinumab ~6 mg/kg
IV) as stratification variables. Other subject populations will not be randomized, but will be 
assigned to treatment as described in Section 3.1.2. All subjects will receive their assigned dose 
of SC study agent at the M-0 visit. Thereafter, to maintain the blind, all subjects will receive 
study agent at all scheduled study agent administration visits specified in Table 2.
At each call to the IWRS for a treatment assignment, the IWRS will assign a treatment code that 
will dictate the treatment assignment and matching study agent kit for each subject. The 
requestor must use his or her own personal identification number when contacting the IWRS.
Blinding
To maintain the study blind, the study agent container will have a label containing the study 
name, medication number, and reference number. A tear-off label is designed to be torn off, 
separated from the study agent container, and attached to the subject's source documents. The 
label will not identify the study agent in the container. The medication number will be entered in 
the case report form (CRF) when the drug is dispensed. The study agents will be identical in 
appearance and packaging.
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual subject.
Data that may potentially unblind the treatment assignment (ie,
study agent
serum 
concentrations, antibodies to study agent) will be handled with special care to ensure that the 
integrity of the blind is maintained and the potential for bias is minimized. This can include 
making special provisions, such as segregating the data in question from view by the 
investigators, clinical team, or others as appropriate until the study unblinding.
The postbaseline results of CRP, fecal lactoferrin, and fecal calprotectin tests performed by the 
central laboratory will be blinded to the investigative sites. If an investigative site requests these 
data, it will be provided to them after the Week 44 analyses for the maintenance study have been 
completed.
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Treatment assignment blinding will be maintained for investigative sites, site monitors, and 
subjects participating in this protocol until the Week 44 analyses for the maintenance study have 
been completed. 
In the induction study, at the first DBL for the futility analysis, the induction treatment 
assignment information will be unblinded for the first 30% of randomized subjects in the study
and released for analysis to an external statistical support group (the sponsor will remain 
blinded). The induction treatment assignment for the remaining subjects and the maintenance
treatment assignment information for all subjects will remain blinded at that time. Further details 
about unblinding for the futility analysis will be provided in the Interim Analysis Plan (IAP). At 
the second DBL when all randomized subjects in the induction study have either completed the 
I-8 visit or have terminated study participation before Week 8, the induction treatment 
assignment information will be unblinded for all subjects and released to selected sponsor 
personnel for analysis. The maintenance treatment assignment information for all subjects will 
remain blinded at that time. At the third DBL when all randomized subjects in the induction 
study have entered the maintenance study, or have completed their final safety visit (20 weeks 
after the last administration of study agent) for those not participating in the maintenance study, 
or have terminated their study participation, data will be released to selected sponsor personnel 
for analysis. The maintenance treatment assignment information for all subjects will continue to 
remain blinded at that time. Identification of sponsor personnel who will have access to the 
unblinded subject-level data at the time of each DBL will be documented before unblinding.
The sponsor will be blinded to maintenance treatment assignment until after the Week 44 
database lock has occurred. 
Under normal circumstances, the blind should not be broken until the Week 44 analyses of the 
maintenance study have been completed and the databases for the induction and maintenance 
studies are finalized. Otherwise, the blind should be broken only if specific emergency 
treatment/course of action would be dictated by knowing the treatment status of the subject. In 
such cases, the investigator may in an emergency determine the identity of the treatment by 
contacting the IWRS. It is recommended that the investigator contact the sponsor or its designee,
if possible, to discuss the particular situation before breaking the blind. Telephone contact with 
the sponsor or its designee will be available 24 hours per day, 7 days per week. In the event that 
the blind is broken, the sponsor must be informed as soon as possible. The date and reason for 
the unblinding must be documented in the appropriate section of the CRF and in the source 
document. The documentation received from the IWRS indicating the code break must be 
retained with the subject's source documents in a secure manner.
Additionally, a given subject’s treatment assignment may be unblinded to the sponsor, the 
Independent Ethics Committee/Institutional Review Board (IEC/IRB), and site personnel to 
fulfill regulatory reporting requirements for serious unexpected associated adverse reactions 
(SUAs). If a subject is unblinded by the site, the information must be entered in the appropriate 
section of the CRF and in the subject's source documents. 
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Subjects who have had their treatment assignment unblinded by the investigator will not be 
eligible to receive further study agent, but should complete evaluations specified in the 
appropriate Time and Events Schedule for subjects who discontinue study agent (Section 10.2). 
A separate code-break procedure will be available for use by J&J Global Medical Safety group 
to allow for unblinding of individual subjects to comply with specific requests from regulatory or 
health authorities.
6.
DOSAGE AND ADMINISTRATION
6.1.
Induction Study
Subjects in the induction study will receive a single IV administration of study agent (placebo or 
ustekinumab) at Week 0. Intravenous study agent will be administered to each subject over a 
period of not less than 1 hour. The infusion should be completed within 4 hours of preparation of 
the study agent. Detailed instructions about study agent administration are provided in the 
investigational product manual. 
As described in Section 3.1.1, subjects who are not in clinical response at Week 8 will receive an 
additional dose of study agent at Week 8. This additional administration will include both IV and 
SC study agent to maintain the blind; SC study agent is described in Section 14.1.
6.2.
Maintenance Study
Subjects in the maintenance study will receive SC study agent (placebo or ustekinumab) at 
Week 0 and q8w or q12w thereafter, according to their assigned treatment (eg, randomization).
7.
TREATMENT COMPLIANCE
In the induction study, study agent will be administered as an IV infusion or SC injection
(Week 8 only) by qualified staff. The details of each administration will be recorded in the CRF, 
including date, start and stop times of the IV infusion and volume infused, or date and time of SC 
injection.
In the maintenance study, study agent will be administered as an SC injection by qualified staff.
The details of each administration will be recorded in the CRF, including date and time of 
injection.
8.
PRESTUDY AND CONCOMITANT THERAPY
For all randomized subjects in the induction study, prestudy therapies administered up to 30 days 
before the first dose of study agent must be recorded in the CRF. 
Concomitant therapies must be recorded throughout the study, beginning with the start of the 
first administration of study agent to the last study visit.
All therapies (eg, prescription or over-the-counter medications, including vaccines, vitamins, 
herbal supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, 
special diets, exercise regimens) different from the study agent must be recorded in the CRF. 
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Recorded information will include a description of the type of therapy, treatment period, dosage, 
route of administration, and its indication. Modification of an effective preexisting therapy 
should not be made for the explicit purpose of entering a subject into the study.
8.1.1.
Induction Study
The following medical therapies for UC may not be initiated or have the dose increased
during the induction study: 

Oral 5-ASA compounds (eg, sulfasalazine, mesalamine, olsalazine, balsalazide).

Oral corticosteroids.

6-MP, AZA, or MTX.
Subjects who are receiving any of these therapies for UC at the time of the first administration of 
study agent must keep their prescribed dosage stable throughout the induction study and the 
therapy can only be discontinued or reduced in dose if investigator judgment requires it because 
of toxicity or other medical necessity; even if the toxicity resolves, the therapy should not be 
restarted.
Subjects who initiate or increase the dose of these UC medications will not be eligible for 
entry into the maintenance study. 
Laxatives may be used only in preparation for endoscopy or other procedures.
8.1.1.1.
Restricted or Prohibited Medications/Therapies
Medications/therapies that may confound the assessment of efficacy or safety are not permitted 
during the induction study. Subjects who initiate these medications after randomization in the 
induction study will be precluded from entering the maintenance study.
8.1.1.1.1.
Restricted Medications/Therapies
Subjects who initiate the following treatments will complete all protocol-specified visits.

Rectal corticosteroids (ie, corticosteroids administered to the rectum or sigmoid colon via 
foam, enema, or suppository).

Rectal 5-ASA compounds (ie, 5-ASA compounds administered to the rectum or sigmoid 
colon via foam, enema, or suppository).

Parenteral corticosteroids.

TPN.

Antibiotics used to treat UC (including, but not limited to, ciprofloxacin, metronidazole, or 
rifaximin).

Apheresis.
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8.1.1.1.2.
Prohibited Medications/Therapies
Subjects who initiate the following treatments will be discontinued from further study agent 
administration and should have a final safety follow-up visit approximately 20 weeks after their 
last study agent administration.

Immunomodulatory agents other than 6-MP, AZA, or MTX (including, but not limited to, 
6-TG, cyclosporine, mycophenolate mofetil [MMF], tacrolimus, sirolimus, tofacitinib, and 
other JAK inhibitors). 

Immunomodulatory biologic agents (including, but not limited to, TNF antagonists, 
natalizumab, abatacept, vedolizumab). 

A biologic therapy targeted at IL-12 and/or IL-23 (eg, commercial ustekinumab, 
briakinumab, guselkumab).

Investigational drugs. 
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
8.1.2.
Maintenance Study 
Concomitant medical therapy for UC must have been stable from Week 0 of the induction study 
through Week 0 of the maintenance study unless, in the judgment of the investigator, the therapy 
had to be discontinued or reduced in dose because of toxicity or medical necessity; even if the 
toxicity resolves, the therapy should not have been restarted.
Laxatives may be used only in preparation for endoscopy or other procedures.
8.1.2.1.
Rescue Medication on Loss of Response
Any initiation of, or increase in the dose of, a medical therapy for UC (ie, corticosteroids, 6-MP, 
AZA, MTX, and/or 5-ASAs) that is required to treat a loss of response is considered a rescue 
medication. Prohibited medications (Section 8.1.1.1.2) cannot be used as rescue medication. 
8.1.2.2.
Oral 5-ASA Compounds and Immunomodulators
The following UC-specific medical therapies should not be initiated or have the dose 
increased during the maintenance study, unless these therapies are used as rescue medication for 
loss of response (Section 3.1.2.1):  

Oral 5-ASA compounds (eg, sulfasalazine, mesalamine, olsalazine, balsalazide)

6-MP, AZA, or MTX
Subjects who were receiving any of these medical therapies for UC at the time of entry into the 
maintenance study and do not lose response must keep their prescribed dosage stable through 
completion of the Week 44 assessments in the maintenance study unless investigator judgment 
requires discontinuation or dose reduction because of toxicity or other medical necessity; even if 
the toxicity resolves, the therapy should not be restarted. 
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8.1.2.3.
Corticosteroids
Oral corticosteroids for UC should not be initiated or have the dose increased during the 
maintenance study, unless corticosteroids are used as rescue medication for loss of response 
(Section 3.1.2.1).
For subjects who are receiving oral corticosteroids on entry into the maintenance study, the 
investigator should begin tapering the daily dose of corticosteroids beginning at Week 0 of the
maintenance study.
An increase in corticosteroid dose above the dose received at maintenance baseline for subjects 
who underwent or are undergoing corticosteroid tapering and lost clinical response will be 
considered a rescue medication. Tapering of corticosteroids used as rescue medications must 
begin 2 weeks after the change in corticosteroid therapy.
Recommended tapering schedule for oral prednisone-equivalent corticosteroids:

Subjects receiving >20 mg/day prednisone or equivalent: taper daily dose by 5 mg/week 
until 0 mg/day. 

Subjects receiving ≤20 mg/day prednisone or equivalent: taper daily dose by 2.5 mg/week 
until 0 mg/day.
Tapering of budesonide or beclomethasone dipropionate should follow local clinical practice.
Subjects may transiently (ie, for 4 weeks) use increased doses of corticosteroids for reasons 
other than loss of response (eg, stress doses of corticosteroids for surgery, asthma flare, 
adrenocortical insufficiency).
8.1.2.4.
Restricted or Prohibited Medications/Therapies
Restricted medications or therapies that are not permitted during the induction study (listed in 
Section 8.1.1.1) are also not permitted during the first 44 weeks of the maintenance study, unless 
the following therapies are used as rescue medication on loss of response (Section 3.1.2.1):  
parenteral or rectal corticosteroids and/or rectal 5-ASAs.
Subjects who initiate prohibited medications or therapies (Section 8.1.1.1.2) during the 
maintenance study or the LTE are required to discontinue study agent during the maintenance 
study or the LTE. Prohibited therapies cannot be used as rescue medications.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
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9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
Informed consent must be obtained before any study-related procedures are performed in the 
induction study. In regions where the legal age of consent is older than 18 years, informed 
consent must be obtained from and signed by both the subject and his or her legally acceptable 
representative.
The Time and Events Schedules summarize the frequency and timing of efficacy, PK, 
immunogenicity, biomarker, DNA, PRO, medical resource utilization, health economics, and 
safety measurements applicable to this study.
All assessments are to be completed before study agent administration, unless otherwise 
specified. It is recommended that PRO assessments be completed first. 
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the subject's participation in the CNTO1275UCO3001 study.
In the induction study, the total blood volume to be collected from each subject is approximately 
134.5 mL, including the safety follow-up visit, but not including DNA samples (approximately 
48 mL), which are optional. 
In the maintenance study, the total blood volume to be collected from each subject is 
approximately 156.5 mL. This does not include DNA samples (approximately 24 mL), which are 
optional, or an early termination visit, the total blood volume for which would be approximately 
12.0 mL (2.5 mL chemistry, 2.0 mL hematology, 7.5 mL PK and immunogenicity samples).
In the LTE, the total blood volume to be collected from each subject is approximately 118.5 mL, 
including the final efficacy and safety visits. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
9.1.2.
Screening Phase
After written informed consent has been obtained and within 8 weeks before randomization, all 
screening evaluations (eg, laboratory test results, clinical data, and concomitant medication data) 
that establish subject eligibility will be performed by the principal investigator or designee to 
confirm that the subject satisfies all inclusion criteria and does not violate any exclusion criteria. 
Subjects who meet all of the inclusion and none of the exclusion criteria can be enrolled in the 
induction study. Every effort should be made to adhere to the Time and Events Schedules for 
each subject. The collection of AEs will start at the time informed consent is obtained. 
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Mayo diaries will be provided to each subject to record concomitant medications, stool 
production, and episodes of rectal bleeding. A Mayo diary will be completed from recall at 
screening and will be used to calculate a partial Mayo score (Section 9.2.1) to assess the 
subject’s eligibility for further screening and to train the subject on the use of the diary card. 
Subjects with a partial Mayo score ≥3 can proceed with endoscopy.
Bristol Stool Form Scale diaries will also be provided to subjects to classify the form (or
consistency) of their stools during the induction study (Section 9.2.1). 
Subjects will be instructed to complete Mayo diary cards and Bristol Stool Form Scale diaries 
7 days immediately before each visit and bring them to every visit for data collection and review 
by the investigator/study coordinator. Bristol Stool Form Scale diaries are required only during 
the induction study.
The screening endoscopy must be performed within 2 weeks (and at least 4 days) before the 
induction Week 0/baseline (I-0) visit. Subjects who are identified as being at increased risk for 
colon cancer (Inclusion Criterion 9) or for adenomatous polyps (Inclusion Criterion 8) will 
undergo a full colonoscopy instead of a sigmoidoscopy to allow screening for dysplasia or to 
assess for the presence of adenomatous polyps, respectively. Any screening colonoscopy for 
malignancy should include surveillance biopsies consistent with local practice. At least 48 hours 
must elapse between a colonoscopy with polypectomy and the I-0 visit. 
Women of childbearing potential must have a negative serum pregnancy test result at screening 
and a negative urine pregnancy test result at the I-0 visit. Sexually active subjects must consent 
to use a highly effective method of birth control, as specified in Inclusion Criterion 11, and 
continue to use contraception for the duration of the study and for 20 weeks after the last study 
agent administration. The method(s) of contraception used by each subject must be documented. 
Subjects must undergo testing for TB (Attachment 3 and Attachment 4) and their medical history 
assessment must include specific questions about a history of TB or known occupational or other 
personal exposure to individuals with active TB. The subject should be asked about past testing 
for TB, including chest radiograph results and responses to tuberculin skin or other TB testing.
Subjects with a negative QuantiFERON-TB Gold test result (and a negative tuberculin skin test 
result in countries in which the QuantiFERON-TB Gold test is not approved/registered or the 
tuberculin skin is mandated by local health authorities) are eligible to continue with 
prerandomization procedures. A tuberculin skin test is recommended but not required for study 
centers in Ukraine if tuberculin is not available. Subjects with a newly identified positive 
QuantiFERON-TB Gold (or tuberculin skin) test result must undergo an evaluation to rule out 
active TB and initiate appropriate treatment for latent TB. Appropriate treatment for latent TB is 
defined according to local country guidelines for immunocompromised patients. If no local 
country guidelines for immunocompromised patients exist, US guidelines must be followed, or 
the subject will be excluded from the study.
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A subject whose first QuantiFERON-TB Gold test result is indeterminate should have the test 
repeated. In the event that the second QuantiFERON-TB Gold test result is also indeterminate, 
the subject may be enrolled without treatment for latent TB, if active TB is ruled out, his/her 
chest radiograph shows no abnormality suggestive of TB (active or old, inactive TB), and the 
subject has no additional risk factors for TB as determined by the investigator. This 
determination must be promptly reported to the sponsor’s medical monitor and recorded in the 
subject's source documents and initialed by the investigator.
A subject with clinical laboratory test results outside the normal reference ranges may be 
enrolled only if the investigator judges the abnormalities or deviations from normal to be not 
clinically significant or to be appropriate and reasonable for the population under study. This 
determination must be recorded in the subject's source documents and initialed by the 
investigator. ·
Note: Retesting of abnormal laboratory values that may lead to exclusion will be allowed once. 
Retesting can occur at an unscheduled visit during the screening phase. 
If a subject needs to be rescreened, this should be discussed with the sponsor and/or designee. If 
a subject is a screen failure but at some point in the future is expected to meet the subject 
eligibility criteria, the subject may be rescreened on 1 occasion only after consultation with the 
sponsor. Subjects who are rescreened will be assigned a new subject number, undergo the 
informed consent process, and then start a new screening phase. 
Completion of screening and randomization procedures within the specified 8-week window is 
required. If the subject is approaching the completion of that period, the medical monitor can be 
contacted to discuss eligibility. 
If any delay leads to the expiration of time-specific assessments (eg, TB, chest radiograph, stool 
analysis), the subject will be considered a screen failure because he/she will not meet eligibility 
criteria, and the expired assessments (along with the non-time-specific laboratory tests) will have 
to be repeated on rescreening.
9.1.3.
Induction Study
Subjects will be randomized in a 1:1:1 ratio and receive their assigned IV dose of ustekinumab or 
placebo at the I-0 visit. Procedures to be performed at each visit during the induction study are 
outlined in the Time and Events Schedule (Table 1). All procedures are to be conducted before 
administration of study agent, unless otherwise specified. It is recommended that PRO 
assessments be completed first.
Visit dates are based on the subject’s original randomization date. The visit window for the I-2 
and I-4 visits is the day of the scheduled visit ±4 days (ie, plus or minus 4 days); for the I-8 and 
I-16 visits, the visit window is the day of the scheduled visit +3 days (ie, plus 3 days). 
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At Week 8, all subjects will be evaluated for the primary endpoint of clinical remission 
(Section 9.2.2.4) and for clinical response (Section 9.2.2.4). Further study agent administration 
will be determined by clinical response status (using the Mayo endoscopy subscore assigned by 
the local endoscopist) at Week 8. 
Subjects who are in clinical response at Week 8 are eligible to enter the maintenance study as 
discussed in Section 3.1.1 and shown in Figure 3. Subjects who are not in clinical response at 
Week 8 will receive an administration of ustekinumab and be re-evaluated for clinical response 
status at Week 16. Those who achieve clinical response at Week 16 (using the Mayo endoscopy 
subscore assigned by the local endoscopist) are eligible to enter the maintenance study; those 
who do not achieve clinical response at Week 16 will not be eligible to enter the maintenance 
study and will receive no further study agent administration. These subjects will have a safety 
follow-up visit approximately 20 weeks after their last study agent administration.
Subjects who discontinue study agent before or at the I-8 visit should complete the I-8
assessments at the time of discontinuation and a safety follow-up visit approximately 20 weeks 
after their last study agent administration, as specified in the Time and Events Schedule
(Table 1). After Week 8, subjects who do not wish to continue into the maintenance study, but 
are willing to complete their participation in the induction study, should complete the I-16 
assessments at the time of discontinuation, and a safety follow-up visit approximately 20 weeks 
after their last study agent administration.
Subjects who terminate study participation before or at the I-8 visit should complete the I-8
assessments at the time of study termination (as specified in the Time and Events Schedule
[Table 1]). Subjects who terminate study participation after the I-8 visit but before or at the I-16
visit should complete the I-16 assessments at the time of study termination (as specified in the 
Time and Events Schedule [Table 1]). 
Study agent should not be administered at Week 0 (or Week 8) to any subject with a clinically 
important, active infection.
9.1.4.
Maintenance Study
All subjects enrolled in the maintenance study will be responders to study agent administered in
the induction study (ie, have received study agent at Week 0 in the induction study and been in 
clinical response at Week 8, or at Week 16 in subjects who were not responders at Week 8). 
Subjects who initiated or increased their dose of UC medications (ie, oral 5-ASAs, oral 
corticosteroids, or the immunomodulators AZA, 6-MP, or MTX) or initiated a restricted or 
prohibited medication during the induction study are not eligible to enter maintenance.
Subjects who were in clinical response to IV ustekinumab induction will be randomized in a 
1:1:1 ratio to 1 of 3 treatment groups for the maintenance study, as discussed in Section 3.1.2 and 
shown in Figure 4; these subjects will comprise the primary population for analysis. Additional 
subjects entering the maintenance study will include those who were in clinical response to IV 
placebo induction and those who were delayed responders to ustekinumab induction.
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All subjects will receive study agent at the M-0 visit. Thereafter to maintain the blind, all 
subjects will receive study agent at all scheduled study agent administration visits specified in 
Table 2.
Assessments will be performed as indicated in the Time and Events Schedule (Table 2). All 
assessments are to be completed before any study agent administration, unless otherwise 
specified. It is recommended that PRO assessments be completed first.
To enroll in the maintenance study, a subject must be able to complete the M-0 visit within
4 days after the I-8 or I-16 visit. At the discretion of the investigator, the window may be 
extended to 8 days to allow for appropriate treatment of and/or recovery from nonserious 
infections (eg, acute upper respiratory tract infection, simple urinary tract infection). The 
window for other visits during the maintenance study is ±10 days.
Subjects will be evaluated for efficacy and safety through Week 44. Subjects should return for 
efficacy and/or safety evaluations at each timepoint, including evaluations at Week 44. 
Following any final visit in which a blood sample is collected, subjects may be contacted by 
study site personnel within 3 days to record any AEs that occurred within 24 hours of that blood 
sample collection and were related to it.
Subjects who discontinue study agent administration before the M-44 visit should undergo the 
procedures for an early termination visit as specified in the Time and Events Schedule (Table 2), 
as well as a safety follow-up visit approximately 20 weeks after their last study agent 
administration. Subjects who terminate their study participation should undergo the procedures 
for an early termination visit as specified in the Time and Events Schedule (Table 2).
Study agent should not be administered at any visit during the maintenance study to a subject 
with a clinically important, active infection.
9.1.4.1.
Management of Clinical Flare and Loss of Response
Subjects who meet the following criteria will be considered to have a clinical flare:

an increase from maintenance baseline in the partial Mayo score of at least 2 points with an 
absolute partial Mayo score ≥4;
OR

an absolute partial Mayo score ≥7 points.
Subjects who meet the criteria for clinical flare and who have not previously met the criteria for 
loss of clinical response in the maintenance study (ie, are in clinical flare for the first time or 
have flared previously and not met the criteria for loss of response) should undergo an 
endoscopy to assess the Mayo endoscopy subscore, as well as the safety and efficacy evaluations 
specified for the M-44 visit (Table 2) during their scheduled visit or at any unscheduled visit. 
The endoscopy at the time of clinical flare need only be a sigmoidoscopy. The Mayo score 
should be calculated from the partial Mayo obtained at the assessment for clinical flare and the 
subsequent Mayo endoscopy subscore as assigned by the local endoscopist. 
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Subjects should maintain stable doses of their UC medications after meeting clinical flare criteria 
and while waiting for their endoscopy score. However, rescue medications should not be 
withheld if, in the opinion of the investigator, failure to prescribe them would compromise 
subject safety while waiting for their endoscopy score. 
Subjects with a clinical flare are eligible for rescue medication only if they meet the criteria for 
loss of response (ie, are no longer in clinical response relative to their induction baseline Mayo 
score). 
Subjects who have a loss of response will be assessed 16 weeks after the visit at which the loss 
of clinical response criteria was met. During this interval, clinical flare criteria will not be 
applied. Subjects who have not achieved a partial Mayo response (ie, a decrease from induction 
baseline of ≥2 in the partial Mayo score) at 16 weeks after loss of response will be discontinued 
from study agent administration, and should return for a final safety visit approximately 
20 weeks after their last study agent administration. Subjects who are assessed as being in partial 
Mayo response will continue in the study.
After the 16 weeks following loss of clinical response, subjects who remain in the study will 
continue to be assessed for clinical flare using the criteria based on the partial Mayo score.  
Subjects who subsequently meet the criteria for clinical flare again will not be required to 
undergo an endoscopy. These subjects will be eligible to receive rescue medication at the time of 
clinical flare and be assessed for partial Mayo response 16 weeks after the visit at which clinical 
flare was assessed and managed as noted above. 
Subjects will be strongly encouraged to undergo endoscopy at the time of first clinical flare to 
establish if loss of clinical response criteria were met. A subject who declines to undergo an 
endoscopy on initial clinical flare will be assessed for partial Mayo response 16 weeks after the 
initial flare.
A subject who meets the criteria of clinical flare on more than 2 occasions during the 
maintenance study will be discontinued from study agent administration.
9.1.5.
Long-Term Extension
Subjects who enter the LTE will continue with study agent injections every 8 or 12 weeks 
according to their dose regimen. To maintain the blind, study agent injections will be 
administered every 4 weeks, with the first dose administered at Week 48. After the study is 
unblinded to the investigative sites, subjects receiving placebo will be terminated from study 
participation and subjects receiving ustekinumab will continue to receive ustekinumab, but will 
have their study visits scheduled to coincide with their dose regimen (q8w or q12w, as 
appropriate, through Week 200).
Procedures will be performed monthly, every 3 months, or every 6 months, as indicated in the 
Time and Events Schedule (Table 3). Study visits after Week 44 (ie, in the LTE) may occur at 
the week indicated ±10 days.
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The partial Mayo score will be assessed every 3 months during the LTE. The Mayo score 
(including an endoscopy) will be assessed at the final efficacy visit.
The final efficacy assessments will be performed at Week 200 and the final safety assessments 
will be performed at Week 220 (or approximately 20 weeks after a subject’s last administration 
of study agent). Assessments will be performed as indicated in the Time and Events Schedule
(Table 3).
Subjects who discontinue study agent administration during the LTE should undergo the 
procedures for a final efficacy visit as specified in the Time and Events Schedule (Table 3), as 
well as a safety follow-up visit approximately 20 weeks after their last study agent 
administration. Subjects who terminate their study participation during the LTE should undergo 
the procedures for a final efficacy visit as specified in the Time and Events Schedule (Table 3).
9.1.5.1.
Dose Adjustment During the LTE
During the LTE, if a subject’s UC disease activity worsens (in the investigator’s judgment), the 
subject may be eligible for a dose adjustment, as described in Section 3.1.3. These subjects will 
be allowed 1 dose adjustment during the LTE. The IWRS will ensure that a subject is eligible for 
a dose adjustment and, if he or she is eligible, that SC ustekinumab is not administered more 
frequently than q8w. The first opportunity for dose adjustment in the LTE is at the Week 56 
visit.
If, by 16 weeks after the worsening of a subject’s UC disease activity, the subject has not shown 
an improvement in his or her UC disease activity (as assessed by the investigator), the subject 
should be discontinued from further study agent administration and complete the final efficacy 
and safety assessments indicated in the Time and Events Schedule (Table 3).
9.2.
Efficacy
The Mayo score will be the primary tool for assessing disease activity response to ustekinumab. 
The degree of inflammation will be assessed by measuring serum CRP concentrations and fecal 
markers of inflammation (ie, lactoferrin and calprotectin). Subject well-being will be measured 
using the IBDQ, the SF-36, and the EQ-5D. 
9.2.1.
Evaluations
Efficacy evaluations will include the following:

Mayo score and partial Mayo score.

Ulcerative Colitis Endoscopic Index of Severity (UCEIS)

CRP

Fecal lactoferrin and fecal calprotectin

Bristol Stool Form Scale

Inflammatory Bowel Disease Questionnaire (IBDQ)
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
36-item Short Form Health Survey (SF-36)

EuroQoL-5D Health Questionnaire (EQ-5D)
The Mayo score (Attachment 5) was developed from the criteria of Truelove and Witts34 for 
mild, moderate, and severe UC and from the criteria of Baron et al3 for grading endoscopic 
appearance. The Mayo score is calculated as the sum of 4 subscores (stool frequency, rectal 
bleeding, PGA, and endoscopy findings) and ranges from 0 to 12 points. A score of 3 to 5 points 
indicates mildly active disease, a score of 6 to 10 points indicates moderately active disease, and 
a score of 11 to 12 points indicates severe disease. The endoscopic findings will be assessed by 
the investigator (ie, local endoscopist) during the endoscopy procedure and by the central reader 
reviewing a video of the endoscopy. Subject eligibility at baseline will be based on the final 
reported endoscopic subscore as determined by the following process:

If the local endoscopist and the central reader agree on the endoscopic subscore, the agreed 
score will be the final reported endoscopic subscore.  

If there is a discrepancy between the local endoscopist and the central reader subscores, the 
video endoscopy will be submitted to a second central reader (designated for adjudication). 
The median score of the 3 completed reads (ie, local read, central read 1, and central read 2 
designated for adjudication) will be the final reported endoscopic subscore.
Specific details will be provided in the imaging charter. A subject’s clinical response status at 
Week 8 (or Week 16) of the induction study, or loss of response status in the maintenance study, 
to determine subsequent treatment, will be based on the endoscopy subscore assigned by the 
local endoscopist.
Mayo scores are calculated using the following:
1.
The stool frequency and rectal bleeding data from the most recent consecutive 3-day period 
within the 1 week before the visit. The average of the 3-day period will be used to calculate 
the stool frequency and rectal bleeding subscores for the visit. Days on which the following 
conditions are met should be excluded from the calculation:
a.
The day on which medications for constipation, diarrhea, or irregularity were taken.  
(For subjects maintained on a stable dose of bulking or stool-softening agents 
throughout the study, the days on which these agents are taken should not be excluded 
from consideration in calculating the Mayo score.)
b.
The day(s) of a procedure or preparation for a procedure (eg, enemas, other laxatives, a 
clear liquid diet) that would affect bowel frequency and/or blood content of the stool.
c.
The 48 hours after the use of antimotility agents (ie, diphenoxylate hydrochloride with 
atropine sulfate, loperamide, or other opioids).
d.
The 48 hours immediately following a colonoscopy.
2.
The physician’s global assessment.
3.
The results of a sigmoidoscopy or colonoscopy.
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The partial Mayo score is the Mayo score without the endoscopy subscore and ranges from 0 to 
9 points.
If 1 or more of the 4 Mayo subscores is missing at a specific visit, but not all 4 subscores are 
missing, the last available value for each missing subscore will be carried forward to compute a 
full Mayo score and a partial Mayo score at that visit. If all 4 subscores are missing at a specific 
visit, the Mayo score and partial Mayo score will be considered missing at that visit.
The UCEIS is an index that provides an overall assessment of endoscopic severity of UC, based 
on mucosal vascular pattern, bleeding, and ulceration.33 The score ranges from 3 to 11. The 
UCEIS score will be assessed only by the central video readers for all endoscopies.
C-reactive protein has been demonstrated to be useful as a marker of inflammation in patients 
with IBD. In UC, elevated CRP has been associated with severe clinical activity, an elevated 
sedimentation rate, and active disease as detected by colonoscopy. CRP will be assayed using a 
validated, high-sensitivity CRP assay.
Fecal lactoferrin and fecal calprotectin have been demonstrated to be sensitive and specific 
markers in identifying intestinal inflammation and response to treatment in patients with 
IBD.7,9,21 Stool samples for fecal lactoferrin and calprotectin concentrations will be collected 
from all subjects at visits indicated in the Time and Events Schedules. Assays for fecal 
lactoferrin and calprotectin concentrations will be performed using a validated method. 
Additional tests may also be performed on the stool samples for additional markers related to 
intestinal inflammation and treatment response. 
The Bristol Stool Form Scale is a medical aid to classify the form (or consistency) of human 
feces into 7 categories.22 It has been used as a research tool to evaluate the effectiveness of 
treatments for various diseases of the bowel (eg, irritable bowel syndrome [IBS]).12 The daily
average of the same 3-day period used to calculate the stool frequency and rectal bleeding 
subscores of the Mayo score will be used to calculate the average Bristol Stool Form Scale score 
for the visit.
The IBDQ18 is a 32-item questionnaire for subjects with IBD that will be used to evaluate the 
disease-specific health-related quality of life across 4 dimensional scores:  bowel (loose stools, 
abdominal pain), systemic (fatigue, altered sleep pattern), social (work attendance, need to cancel 
social events), and emotional (anger, depression, irritability).
The SF-36 was developed as part of the Rand Health Insurance Experiment and consists of 8 
multi-item scales:  limitations in physical functioning due to health problems; limitations in usual 
role activities due to physical health problems; bodily pain; general mental health (psychological 
distress and well-being); limitations in usual role activities due to personal or emotional 
problems; limitations in social functioning due to physical or mental health problems; vitality 
(energy and fatigue); and general health perception. Scales are scored from 0 to 100, with higher 
scores indicating better health. Another algorithm yields 2 summary scores, the physical 
component summary (PCS) and the mental component summary (MCS), which are also scaled 
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with higher scores indicating better health, but are scored using a norm-based system where 
linear transformations are performed to transform scores to a mean of 50 and standard deviations 
of 10, based upon general US population norms.36 The concepts measured by the SF-36 are not 
specific to any age, disease, or treatment group, allowing comparison of relative burden of 
different diseases and the relative benefit of different treatments.37
The EQ-5D is a self-administered, non-disease-specific measure of health status that provides a 
simple descriptive profile and a single index value that can be used in the clinical and economic 
evaluation of health care and in population health surveys. Specifically, the EQ-5D assesses 
health outcomes from a wide variety of interventions on a common scale for purposes of 
evaluation, allocation, and monitoring.
9.2.2.
Endpoints
Unless otherwise stated, the analysis time points mentioned for each study refer to Week 0 of 
that study; for example, Week 44 in the maintenance study refers to 44 weeks after Week 0 of 
the maintenance study, not 44 weeks after Week 0 of the induction study. 
For the primary and major secondary endpoints involving the endoscopy subscore of the Mayo 
score (eg, clinical remission, clinical response, endoscopic healing), the final reported 
endoscopic subscore will be used, as described in Section 9.2.1.
Clinical remission is the primary endpoint in both the induction and maintenance studies. 
Additionally, clinical remission is used to define some major secondary endpoints in the 
maintenance study. In this protocol, two separate definitions for clinical remission will be 
applied to the primary and major secondary endpoints of remission for both the induction and 
maintenance studies, as applicable, to accommodate the global and US-preferred definitions of 
clinical remission. These definitions of clinical remission will use Mayo score data from all 
subjects and are described below. (A complete list of definitions for efficacy endpoints is
provided in Section 9.2.2.4). 

The following global definition of clinical remission will be used for countries outside the 
United States:  a Mayo score ≤2 points, with no individual subscore >1. This definition will 
also be used to stratify subjects by clinical remission status at maintenance baseline for the 
maintenance study.

The following US-specific definition of clinical remission will be used for the United 
States:  an absolute stool number ≤3, a rectal bleeding subscore of 0, and a Mayo endoscopy 
subscore of 0 or 1. 
9.2.2.1.
Induction
9.2.2.1.1.
Primary Endpoint
The primary endpoint of the induction study is clinical remission at Week 8. 
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9.2.2.1.2.
Major Secondary Endpoints
The following are the major secondary endpoints in the induction study, which are presented in 
the order in which they will be tested:

Endoscopic healing at Week 8.

Clinical response at Week 8.

The change from induction baseline in the total score of the IBDQ at Week 8.
9.2.2.1.3.
Other Secondary Endpoints

The change from induction baseline in the Mayo score at Week 8 

The change from induction baseline in the partial Mayo score through Week 8.

Individual Mayo subscores through Week 8.

Remission at Week 8 based on a stool frequency subscore of 0 or 1, a rectal bleeding 
subscore of 0, and an endoscopy subscore of 0 or 1.

Remission at Week 8 based on a stool frequency subscore of 0, a rectal bleeding subscore of 
0, and an endoscopy subscore of 0 or 1.

Symptomatic remission at Week 8.

Normal or inactive mucosal disease at Week 8.

Clinical remission at Week 8 by biologic failure status.

Endoscopic healing at Week 8 by biologic failure status.

Clinical response at Week 8 by biologic failure status.

The change from induction baseline in each of the 4 dimensions of the IBDQ at Week 8. 

A >20-point improvement from induction baseline in the IBDQ score at Week 8. 

The change from induction baseline for each of the 8 individual subscales of the SF-36 and 
the PCS and MCS scores at Week 8.

The changes from induction baseline in the EQ-5D dimensions, EQ-5D index, and health 
state VAS scores at Week 8.

Mucosal healing at Week 8. 

The change from induction baseline in CRP through Week 8.

The change from induction baseline in fecal lactoferrin concentration through Week 8.

The change from induction baseline in fecal calprotectin concentration through Week 8.

Normalization of CRP concentration through Week 8 among subjects with abnormal CRP 
concentration at induction baseline.
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
Normalization of fecal lactoferrin concentration through Week 8 among subjects with 
abnormal fecal lactoferrin concentration at induction baseline.

Normalization of fecal calprotectin concentration through Week 8 among subjects with 
abnormal fecal calprotectin concentration at induction baseline.
9.2.2.2.
Maintenance
9.2.2.2.1.
Primary Endpoint
The primary endpoint of the maintenance study is clinical remission at Week 44.
9.2.2.2.2.
Major Secondary Endpoints
The following are the major secondary endpoints, which are presented in the order in which they 
will be tested:

Maintenance of clinical response through Week 44. 

Endoscopic healing at Week 44. 

Clinical remission and not receiving concomitant corticosteroids at Week 44.

Maintenance of clinical remission through Week 44 among the subjects who had achieved 
clinical remission at maintenance baseline.
9.2.2.2.3.
Other Secondary Endpoints

The change from maintenance baseline in the Mayo score at Week 44. 

The change from induction baseline in the Mayo score through Week 44.

Individual Mayo subscores through Week 44.

The change from maintenance baseline in the partial Mayo score over time through 
Week 44.

The change from induction baseline in the partial Mayo score over time through Week 44.

Remission at Week 44 based on a stool frequency subscore of 0 or 1, a rectal bleeding 
subscore of 0, and an endoscopy subscore of 0 or 1.

Remission at Week 44 based on a stool frequency subscore of 0, a rectal bleeding subscore 
of 0, and an endoscopy subscore of 0 or 1.

Symptomatic remission at Week 44.

Clinical remission at Week 44 by biologic failure status.

Maintenance of clinical response through Week 44 by biologic failure status.

Endoscopic healing at Week 44 by biologic failure status.

The proportion of subjects who demonstrate endoscopic healing at Week 44 among the 
subjects who had achieved endoscopic healing at maintenance baseline. 

Normal or inactive mucosal disease at Week 44.
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
Clinical remission and not receiving concomitant corticosteroids at Week 44 among the 
subjects receiving concomitant corticosteroids at maintenance baseline.

The change from maintenance baseline in corticosteroid use over time through Week 44
among the subjects receiving concomitant corticosteroids at maintenance baseline.

Subjects who are not receiving concomitant corticosteroids at Week 44 among the subjects 
who were receiving concomitant corticosteroids at maintenance baseline.

Subjects who maintained improvement in IBDQ at Week 44 from induction baseline among 
subjects who had a >20-point improvement in the total IBDQ score at maintenance baseline 
from induction baseline.

The change from maintenance baseline in the total IBDQ score and each of the 4 IBDQ 
dimensions through Week 44. 

The change from maintenance baseline in the SF-36 physical and mental component 
summary scores and the individual scale scores through Week 44.

The changes from maintenance baseline in the EQ-5D dimensions, EQ-5D index, and health 
state VAS scores through Week 44. 

Mucosal healing at Week 44. 

The change from maintenance baseline in CRP concentration over time through Week 44. 

The change from maintenance baseline in fecal lactoferrin concentration over time through 
Week 44.

The change from maintenance baseline in fecal calprotectin concentration over time through 
Week 44.

The time to loss of clinical response through Week 44.

The time to loss of clinical remission through Week 44 among subjects in clinical remission 
at maintenance baseline.
9.2.2.3.
Exploratory Endpoints

Response using the Mayo score without the PGA subscore in both induction and 
maintenance. 

Average Bristol Stool Form Scale score over time in induction.
9.2.2.4.
Efficacy Endpoint Definitions
Definitions for efficacy endpoints are as follows:

Induction baseline: Week 0 of the induction study (I-0 visit).

Maintenance baseline:  Week 0 of the maintenance study (M-0 visit).

Clinical remission (global definition):  Mayo score ≤2 points, with no individual 
subscore >1.

Clinical remission (US-specific definition):  Absolute stool number ≤3, rectal bleeding 
subscore of 0, and Mayo endoscopy subscore of 0 or 1.
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
Clinical response:  A decrease from induction baseline in the Mayo score by ≥30% and 
≥3 points, with either a decrease from baseline in the rectal bleeding subscore ≥1 or a rectal 
bleeding subscore = 0 or 1.

Endoscopic healing (ie, improvement in the endoscopic appearance of the mucosa):  
Endoscopy subscore of the Mayo score = 0 or 1.

Normal or inactive mucosal disease:  Endoscopy subscore = 0.

Mucosal healing: endoscopic healing and histologic healing.

Normalization of CRP concentration: CRP concentration <8 mg/L.

Normalization of fecal lactoferrin concentration: fecal lactoferrin
concentration 
<10 μg/mL.

Normalization of fecal calprotectin concentration: fecal calprotectin concentration 
<250 mg/kg.

Symptomatic remission:  Mayo stool frequency subscore of 0 or 1 and a rectal bleeding 
subscore of 0.
9.3.
Pharmacokinetics and Immunogenicity
9.3.1.
Evaluations
Blood samples will be used to evaluate the PK and immunogenicity of ustekinumab (antibodies 
to ustekinumab). Samples collected for analyses of serum ustekinumab concentration and 
antibodies to ustekinumab may also be used to evaluate safety or efficacy aspects that address 
concerns arising during or after the study period, for further characterization of immunogenicity 
or for the evaluation of relevant biomarkers. Genetic analyses will not be performed on these 
serum samples. Subject confidentiality will be maintained. 
Blood samples will be collected from each subject at timepoints indicated in the Time and 
Events Schedules. At visits at which serum concentration and antibodies to ustekinumab will be 
evaluated, 1 blood sample of sufficient volume can be used. Venous blood samples will be 
collected and each serum sample will be divided into 3 aliquots (1 each for PK, antibodies to 
study agent, and a back-up).
9.3.1.1.
Endpoints
Serum ustekinumab concentrations and antibodies to ustekinumab will be analyzed to assess the 
PK and immunogenicity of ustekinumab in subjects with UC treated with ustekinumab. 
9.3.2.
Analytical Procedures
9.3.2.1.
Pharmacokinetics
Serum samples will be analyzed to determine concentrations of ustekinumab using a validated, 
specific, and sensitive method by or under the supervision of the sponsor. 
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9.3.2.2.
Immunogenicity
The detection and characterization of antibodies to ustekinumab will be performed using a 
validated assay method by or under the supervision of the sponsor. All samples collected for 
detection of antibodies to ustekinumab will also be evaluated for ustekinumab serum 
concentration to enable interpretation of the antibody data.
9.3.3.
Pharmacokinetic Parameters
Serum samples will be used to evaluate various PK parameters using population PK modeling.
9.3.4.
Immunogenicity Assessments (Antibodies to Ustekinumab)
Antibodies to ustekinumab will be evaluated in serum samples collected from all subjects 
according to the Time and Events Schedules. Additionally, serum samples should also be 
collected at the final visit from subjects who are discontinued from treatment or withdrawn from 
the study. These samples will be tested by the sponsor or sponsor's designee.
Serum samples will be screened for antibodies binding to ustekinumab and the titer of confirmed 
positive samples will be reported. Other analyses may be performed to verify the stability of 
antibodies to ustekinumab and/or further characterize the immunogenicity of ustekinumab. 
9.4.
Biomarkers
Biomarker assessments will be performed to identify protein, RNA (mRNA or microRNA) 
expression patterns, and microbial activities that are relevant to ustekinumab treatment and/or 
UC, to conduct histologic and immunohistochemical assessment of disease and healing, and to 
evaluate if biomarkers can be used to predict clinical response. Biomarker assessments 
(described in further detail below) will include the evaluation of relevant markers in serum and 
feces for all subjects as specified in the Time and Events Schedules. In addition, colonic mucosal 
biopsies will be obtained at the screening, I-8, and M-44 visits. Subjects who are nonresponders 
at the I-8 visit will undergo an additional colonic mucosal biopsy at the I-16 visit; other 
biomarker samples (serum and feces) will also be collected from these subjects at the I-16 visit. 
Instructions for the collection and shipment of biomarker samples will be found in the 
Laboratory Reference Manual.
9.4.1.
Serum
Serum samples for biomarker analyses will be obtained from all subjects as specified in the Time 
and Events Schedules. Analysis of serum samples for biomarkers may include proteins 
associated with proinflammatory and anti-inflammatory effects, the recruitment and proliferation 
of cells associated with inflammation and repair, and markers associated with tissue injury or 
repair. 
9.4.2.
Fecal Biomarkers
Fecal samples will be collected from all subjects as specified in the Time and Events Schedules. 
Microbiome and associated products analysis will be conducted to evaluate the association 
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between microbial activities and ustekinumab and/or UC. The relationships between 
microbiome, metabolites, and biomarkers in other tissue samples will also be assessed. 
9.4.3.
Mucosal Biopsy RNA and Histology
Mucosal biopsy samples will be collected during endoscopy as specified in the Time and Events 
Schedules. Total RNA will be isolated and used for differential gene expression analyses to 
identify mRNA or microRNA expression patterns that are relevant to ustekinumab treatment 
and/or UC, and to evaluate markers that can predict clinical response. The biopsy samples 
collected will also be used for the histologic and immunohistochemical assessment of disease 
and healing.
9.5.
Genetic and Epigenetic (DNA) Evaluations
Genetic (encoded DNA sequence) and epigenetic (non-encoded DNA variation by promoter 
methylation, histone acetylation, and other modifications) variation may be important 
contributory factors to interindividual differences in drug disposition, response, and clinical 
outcomes. Genetic (DNA) and epigenetic factors may also serve as markers for disease 
susceptibility and prognosis and may identify population subgroups that respond differently to a 
drug.
DNA samples will be analyzed for identification of genetic and epigenetic factors to better 
understand the molecular effects of ustekinumab and/or UC, and to evaluate markers that can 
predict clinical response. Genetic (DNA) research may consist of the analysis of 1 or more 
candidate genes or analysis of the entire genome (as appropriate) in relation to ustekinumab 
and/or UC. The goal of the epigenetic component of this study is to identify epigenetic factors 
related to UC or to the PK, PD, efficacy, or tolerability of ustekinumab. 
Whole blood samples of approximately 10 mL will be collected for genetic and epigenetic 
analyses as specified in the Time and Events Schedules. Only subjects who sign the consent form 
to participate in the genetic assessment will have whole blood DNA samples collected.
9.6.
Health Economics and Medical Resource Utilization
Medical resource utilization, including UC-related hospitalizations and UC-related surgeries, 
will be collected during the induction and maintenance studies. Additionally, the potential impact 
of ustekinumab on subjects’ work limitations and daily productivity will be assessed through the 
Work Productivity and Activity Impairment Questionnaire-General Health (WPAI-GH) and the 
productivity visual analog scale (VAS), respectively. 
The WPAI-GH is a validated instrument created as a patient-reported quantitative assessment of 
the amount of absenteeism, presenteeism, and daily activity impairment attributable to general 
health. The WPAI-GH consists of 6 questions to determine employment status, hours missed 
from work due to UC, hours missed from work for other reasons, hours actually worked, the 
degree to which general health affected work productivity while at work, and the degree to which 
general health affected activities outside of work. Four scores are derived: percentage of 
absenteeism, percentage of presenteeism (reduced productivity while at work), an overall work 
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impairment score that combines absenteeism and presenteeism, and percentage of impairment in 
activities performed outside of work. Higher scores indicate greater impairment.
The productivity VAS will measure the impact of disease on subjects' daily productivity using a 
VAS (0=no impact at all to 10=impact productivity very much).
9.7.
Safety Evaluations
Details about the independent Data Monitoring Committee are provided in Section 11.12.
Any clinically relevant changes occurring during the induction and maintenance studies and the 
LTE must be recorded in the Adverse Event section of the CRF.
Any clinically significant abnormalities persisting at the end of the study or at early withdrawal 
will be followed by the investigator until resolution or until a clinically stable endpoint is 
reached or follow-up is no longer possible (eg, the subject withdraws consent, the subject is lost 
to follow-up).
The studies will include the following evaluations of safety and tolerability at the time points 
specified in the Time and Events Schedules.
Adverse Events
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, 
or the subject's legally acceptable representative) for the duration of the studies. Adverse events 
will be followed by the investigator as specified in Section 12, Adverse Event Reporting. At each 
visit, subjects (or, when appropriate, a caregiver, surrogate, or the subject's legally acceptable 
representative) will be questioned about any AEs (eg, “side effects”) occurring since the previous 
visit and the outcomes for any AEs reported at previous visits.
Clinical Laboratory Tests
Blood samples will be collected for routine hematology and blood chemistry laboratory analyses
at timepoints specified in the Time and Events Schedules.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the studies in the adverse event section of the CRF. 
The laboratory reports must be filed with the source documents.
The following tests will be performed by the central laboratory. 

Hematology panel

Hemoglobin

Hematocrit

WBC with differential

Platelet count
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
Serum chemistry panel

sodium

potassium

chloride

blood urea nitrogen (BUN)

creatinine

AST

ALT

total and direct bilirubin

alkaline phosphatase

calcium

phosphate

albumin

total protein

Pregnancy testing: Female subjects of childbearing potential will undergo a serum β-HCG 
pregnancy test at screening, and a urine pregnancy test before all study agent administration 
visits.

Serology for HIV antibody at screening. 

Serology for HCV antibody at screening. 

Serology for HBV antibody, HBsAg, anti-HBs, and anti-HBc total at screening. 
For some tests related to screening criteria, existing local or central laboratory results are 
acceptable to satisfy study requirements (eg, QuantiFERON-TB Gold test, stool pathogens) 
provided that they are obtained within the specified window; results should be retained with the 
source documents. Use of local laboratories is allowed in cases where initiation of treatment or 
safety follow-up is time sensitive and the central laboratory results are not expected to be 
available before the need to begin administration of study agent or if actions need to be taken for 
safety reasons. These laboratory results will not be entered into the CRF, but should be retained 
with the source documents.
Electrocardiogram (ECG)
A 12-lead ECG will be performed at screening. During an ECG, subjects should be in a quiet 
setting without distractions (eg, television, cell phones). Subjects should rest in a supine position 
for at least 5 minutes before ECG recording and should refrain from talking or moving arms or 
legs. If blood sample collection or vital sign measurement is scheduled for the same time point as 
ECG recording, the procedures should be performed in the following order:  ECG, vital signs, 
blood sample collection.
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Vital Signs
Vital signs (including temperature, pulse/heart rate, respiratory rate, and blood pressure) will be 
obtained before, approximately every 30 minutes during, and twice (at approximately 30-minute 
intervals) after completion of the IV infusion(s) during the induction study. Vital signs should be 
obtained before and approximately 30 minutes after every SC study agent injection.
Physical Examination
Physical examinations will be performed as specified in the Time and Events Schedules. Height 
and weight will be recorded at screening; weight will also be recorded at timepoints specified in 
the Time and Events Schedules.
Concomitant Medication Review
Concomitant medications will be reviewed at each visit.
Infusion Reactions
An infusion reaction is defined as an AE that occurs during or within 1 hour after the infusion of 
study agent, with the exception of laboratory abnormalities. Minor infusion reactions may be 
managed by slowing the rate of the IV infusion and/or treating with antihistamines and/or 
acetaminophen (paracetamol) as clinically indicated. If an IV infusion of study agent is stopped 
because of an infusion reaction and the reaction, in the opinion of the investigator, is not severe 
or does not result in a serious adverse event (SAE; Section 12.1.1), the infusion may be restarted 
with caution.
Injection Site Reaction
A study agent injection-site reaction is any adverse reaction at an SC study agent injection site. 
The injection sites will be evaluated for reactions and any injection site reactions will be 
recorded as an AE.
Allergic Reactions
Before any SC injection or IV infusion, appropriately trained personnel and medications must be 
available to treat allergic reactions, including anaphylaxis. Appropriate medical personnel must 
be in attendance at the time of the injection or infusion and for at least 30 minutes after the SC 
injection or for at least 1 hour after the start of the IV infusion.
Appropriate medical personnel must remain in close proximity to the infusion center for the 
remaining duration of the infusion, and for 1 hour after the end of the infusion in the event that 
emergency resuscitation is required. All subjects must be observed carefully for symptoms of an 
allergic reaction (eg, urticaria, itching, hives). 
If a mild or moderate allergic reaction is observed, acetaminophen, NSAIDs, and/or 
diphenhydramine may be administered. In the case of a severe allergic reaction (eg, 
anaphylaxis), SC aqueous epinephrine, corticosteroids, respiratory assistance, and other proper 
resuscitative measures are essential and must be available at the study site where the injections or 
infusions are being given.
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Subjects who experience serious adverse reactions related to an injection or infusion should be 
discontinued from further study agent administrations (Section 10.2). 
For severe reactions related to an injection or infusion, the subject may be permanently 
discontinued from further study injections at the discretion of the investigator (Section 10.2).
Subjects who experience reactions after an injection or infusion that result in 
bronchospasm with wheezing and/or dyspnea that requires ventilatory support OR that 
result in symptomatic hypotension with a decrease in systolic blood pressure >40 mm Hg or 
blood pressure <90/60 mm Hg will not be permitted to receive additional study agent.
Infections
Study agent should not be administered to a subject with a clinically important, active infection. 
Investigators are required to evaluate subjects for any signs or symptoms of infection at 
scheduled visits as specified in the Time and Events Schedules. If a subject develops a serious 
infection, including but not limited to sepsis or pneumonia, discontinuation of study agent 
administration must be considered. For an active varicella-zoster infection or a significant 
exposure to varicella-zoster infection in a subject without a history of chickenpox, study agent 
administration should be interrupted until the symptoms have resolved and no active infection is 
present. 
Early Detection of Active Tuberculosis 
To aid in the early detection of TB reactivation or new TB infection during study participation, 
subjects must be evaluated for signs and symptoms of active TB at scheduled visits (refer to 
Time and Events Schedules) or by telephone contact approximately every 8 to 12 weeks. The 
following series of questions is suggested for use during the evaluation: 

“Have you had a new cough of >14 days’ duration or a change in a chronic cough?”

“Have you had any of the following symptoms:

Persistent fever?

Unintentional weight loss?

Night sweats?”

“Have you had close contact with an individual with active TB?”  (If there is uncertainty as 
to whether a contact should be considered “close,” a physician specializing in TB should be 
consulted.)
If the evaluation raises suspicion that a subject may have TB reactivation or new TB infection, 
an immediate and thorough investigation should be undertaken, including, where possible, 
consultation with a physician specializing in TB. 
Investigators should be aware that TB reactivation in immunocompromised subjects may present 
as disseminated disease or with extrapulmonary features. Subjects with evidence of active TB 
should be referred for appropriate treatment.
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Subjects who experience close contact with an individual with active TB during the conduct of 
the study must have a repeat chest radiograph, a repeat QuantiFERON-TB Gold test, a repeat 
tuberculin skin test (Attachment 4) in countries in which the QuantiFERON-TB Gold test is not 
approved/registered or the tuberculin skin test is mandated by local health authorities, and, if 
possible, referral to a physician specializing in TB to determine the subject’s risk of developing 
active TB and whether treatment for latent TB is warranted. A tuberculin skin test is 
recommended but not required for study centers in Ukraine if tuberculin is not available. If the
QuantiFERON-TB Gold test result is indeterminate, the test should be repeated as outlined in 
Section 9.1.2. Subjects should be encouraged to return for all subsequent study visits as specified 
in the Time and Events Schedules.
Refer to Attachment 3 and Attachment 4 for details regarding QuantiFERON-TB Gold In-Tube 
and tuberculin skin testing and to Section 9.1.2 for additional details regarding TB testing during 
the study.
9.8.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the CRF or laboratory 
requisition form. Refer to the Time and Events Schedules for the timing and frequency of all 
sample collections.
Instructions for the collection, handling, and shipment of samples are found in the laboratory 
manual. 
10.
SUBJECT COMPLETION/WITHDRAWAL
10.1.
Completion
10.1.1.
Induction Study
A subject will be considered to have completed the induction study if he or she enters the 
maintenance study, or has completed the safety follow-up visit approximately 20 weeks after last 
study agent administration if he/she does not enter the maintenance study. 
10.1.2.
Maintenance Study
A subject will be considered to have completed the double-blind phase of the maintenance study 
if he or she enters the LTE, or has completed the safety follow-up visit approximately 20 weeks 
after his or her last study agent administration if he/she does not enter the LTE.
10.1.3.
Long-Term Extension
A subject will be considered to have completed the LTE if he or she has completed the final 
safety visit after the final dosing visit or the sponsor decides not to further pursue an indication 
in UC. 
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10.2.
Discontinuation of Study Agent
If a subject's study agent must be discontinued before the end of the treatment regimen, this will 
not result in automatic withdrawal of the subject from the study. 
A subject's study agent should be discontinued if:

The investigator believes that for safety reasons (eg, AE), it is in the best interest of the 
subject to discontinue study agent.

The subject becomes pregnant or plans a pregnancy within the study period. 

The subject is deemed ineligible according to the following TB screening criteria: 

A diagnosis of active TB is made.

A subject has symptoms suggestive of active TB based on follow-up assessment 
questions and/or physical examination, or has had recent close contact with a person 
with active TB, and cannot or will not continue to undergo additional evaluation. 

A subject undergoing evaluation has a chest radiograph with evidence of current active 
TB and/or a positive QuantiFERON-TB Gold test result (and/or a positive tuberculin 
skin test result in countries in which the QuantiFERON-TB Gold test is not 
approved/registered or the tuberculin skin test is mandated by local health authorities
[recommended but not required for study centers in Ukraine if tuberculin is not 
available]), unless active TB can be ruled out and appropriate treatment for latent TB 
can be initiated before the next administration of study agent and continued to 
completion. Indeterminate QuantiFERON-TB Gold test results should be handled as 
described in Section 9.1.2. Subjects with persistently indeterminate QuantiFERON-TB 
Gold test results may continue without treatment for latent TB, if active TB is ruled out, 
their chest radiograph shows no abnormality suggestive of TB (active or old, inactive 
TB) and the subject has no additional risk factors for TB as determined by the 
investigator. This determination must be promptly reported to the sponsor’s medical 
monitor and recorded in the subject's source documents and initialed by the investigator.

A subject receiving treatment for latent TB discontinues this treatment prematurely or is 
noncompliant with the therapy. 

A serious adverse reaction occurs that is related to an injection or an infusion, including an 
injection site or infusion reaction, resulting in bronchospasm with wheezing and/or dyspnea 
that requires ventilatory support OR that results in symptomatic hypotension with a decrease 
in systolic blood pressure >40 mm Hg or blood pressure <90/60 mm Hg.

Malignancy, including squamous cell skin cancer. Consideration may be given to allowing 
subjects who develop ≤2 basal cell skin cancers that are adequately treated with no evidence 
of residual disease to continue to receive study agent.

The initiation of any protocol-prohibited medications/therapies, as specified in Section 8. 

A systemic opportunistic infection.
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
The subject (or the subject’s representative) withdraws consent for administration of study 
agent.

The subject has a colectomy.
During the maintenance study, a subject who meets the criteria of clinical flare on more than 
2 occasions should be discontinued from study agent administration. 
Discontinuation of study agent administration must be considered for subjects who develop a 
severe injection site or infusion reaction or who develop a serious infection. Any subject who 
experiences a severe reaction after an injection or infusion that result in bronchospasm with 
wheezing and/or dyspnea that requires ventilatory support OR that result in symptomatic 
hypotension with a decrease in systolic blood pressure >40 mm Hg or blood pressure 
<90/60 mm Hg will not be permitted to receive additional study agent.
During the induction study, subjects who discontinue study agent (but have not terminated study 
participation) before or at the I-8 visit should complete the I-8 assessments specified in the Time 
and Events Schedule (Table 1) at the time of discontinuation and a final safety visit 
approximately 20 weeks after their last study agent administration. After Week 8, subjects who 
do not wish to continue into the maintenance study, but are willing to complete their 
participation in the induction study, should complete the I-16 assessments at the time of 
discontinuation, and a safety follow-up visit approximately 20 weeks after their last study agent 
administration.
During the maintenance study, subjects who discontinue study agent (but have not terminated
study participation) should complete the assessments specified in the Time and Events Schedule 
(Table 2) for an early termination visit, as well as a final follow-up safety visit approximately 
20 weeks after their last administration of study agent.
10.3.
Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent

Death

Sponsor decision (eg, significant noncompliance)
Before a subject is considered lost to follow-up, every reasonable effort must be made by the 
study 
site 
personnel 
to 
contact 
the 
subject 
and 
determine 
the 
reason 
for 
discontinuation/withdrawal. The measures taken to follow up must be documented.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the CRF and in the source document. Study agent assigned to the withdrawn 
subject may not be assigned to another subject. Subjects who withdraw will not be replaced.
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During the induction study, subjects who terminate their study participation before or at the I-8 
visit should complete the assessments indicated on the Time and Events Schedule for the I-8 visit 
(Table 1) at the time of termination. Subjects who terminate their study participation after the I-8 
visit but before or at the I-16 visit should complete the I-16 assessments at the time of 
termination.
During the maintenance study, subjects who terminate study participation should complete the 
assessments specified for an early termination visit on the Time and Events Schedule (Table 2).
A subject who withdraws from the study will have the following options regarding the optional
research sample(s):

The collected sample(s) will be retained and used in accordance with the subject's original 
separate informed consent for optional research samples.

The subject may withdraw consent for optional research sample(s), in which case the 
sample(s) will be destroyed and no further testing will take place. To initiate the sample 
destruction process, the investigator must notify the sponsor study site contact of withdrawal 
of consent for the optional research samples and to request sample destruction. The sponsor 
study site contact will, in turn, contact the biomarker representative to execute sample 
destruction. If requested, the investigator will receive written confirmation from the sponsor 
that the sample(s) have been destroyed.
Withdrawal From the Optional Research Samples While Remaining in the Main Study
The subject may withdraw consent for optional research samples while remaining in the study. In 
such a case, the optional research sample(s) will be destroyed. The sample destruction process 
will proceed as described above.
Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5, Long-
Term Retention of Samples for Additional Future Research). In such a case, samples will be 
destroyed after they are no longer needed for the clinical study. Details of the sample retention
for research are presented in the main ICF and in the separate ICF for optional research samples.
11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the SAP.
Descriptive statistics (eg, mean, median, standard deviation, interquartile range, minimum, and 
maximum) will be used to summarize continuous variables. Counts and percentages will be used 
to summarize categorical variables. Graphic data displays (eg, line plots) may also be used to 
summarize data.
Analyses suitable for categorical data (eg, chi-square tests, Cochran-Mantel-Haenszel chi-square 
tests, or logistic regression, as appropriate) will be used to compare the proportions of subjects 
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achieving selected endpoints (eg, clinical response). In cases of rare events, the Fisher exact test 
will be used for treatment comparisons. Continuous response parameters will be compared using 
an analysis of variance (ANOVA) or covariance (ANCOVA), unless otherwise specified. If the 
normality assumption is in question, an ANOVA or ANCOVA on the van der Waerden normal 
scores will be used.
When the endpoint is time-to-event, a log-rank or stratified log-rank test will be used. 
In this protocol, the induction and maintenance studies are considered to be 2 separate studies. 
All statistical testing will be performed at the α=0.05 (2-sided) level with appropriate multiplicity 
adjustment employed for the primary and major secondary endpoints of each respective study.
Nominal p-values will be displayed for all treatment comparisons.
11.1.
Subject Information
Demographic and baseline disease characteristic data, including UC-specific concomitant 
medications, will be summarized for all randomized subjects in the induction study and all 
enrolled subjects in the maintenance study.
11.2.
Sample Size Determination
11.2.1.
Induction Study
The sample size in the induction study is based on statistical power considerations and the 
objective of providing the primary population for the maintenance study.
Sample size/power calculations were based on the chi-square test to detect a significant 
difference for the primary endpoint of clinical remission (for both the global and US-specific 
definitions) at Week 8 between the induction ustekinumab treatment groups and placebo. 
It is assumed that the clinical remission rate based on the global definition is 19% for each 
induction ustekinumab treatment group and 7% for the placebo group. These remission rates are 
similar to other recently approved therapies in active UC.13,26,31 The clinical remission rates 
based on the US definition are assumed to be 25% for each induction ustekinumab treatment 
group and 12% for the placebo group based on data from the golimumab UC induction study 
(C0524T17). 
The treatment effect has been assumed to be the same for the 2 induction ustekinumab treatment 
groups because the data from the Phase 2b study of ustekinumab in Crohn’s disease showed 
similar levels of response across the range of doses studied.29
A step-up multiple testing procedure17 will be employed globally to control the Type 1 error. For 
the United States, the Bonferroni method will be used to control the overall Type I error rate at 
the 0.05 level (2-sided) for comparisons of the 2 induction ustekinumab treatment groups with 
placebo, with each comparison being tested at the 0.025 level (2-sided). 
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Assuming a 7% clinical remission (global definition) rate in the placebo group and 19% in each 
ustekinumab group, 135 subjects per treatment group (405 subjects in total) will provide an 
overall power of 90% using a step-up testing procedure at the α=0.05 (2-sided) level. 
Assuming a 12% clinical remission (US-specific definition) rate in the placebo group and 25% in 
each ustekinumab group, 220 subjects per treatment group (660 subjects in total) will provide 
statistical power of 90% for comparison of each ustekinumab induction treatment group versus 
placebo at a significance level of 0.025 (2-sided).
To provide a sufficient number of subjects for the primary population in the maintenance study, 
however, it is estimated that a target of 951 subjects (317 subjects per treatment group) should be 
enrolled in the induction study (Section 11.2.2). Therefore, enrollment in the induction study will 
continue until at least 951 subjects have been enrolled. Table 4 and Table 5 show the power for 
detecting a treatment difference between the ustekinumab induction treatment groups and the 
placebo group based on different proportions of subjects in clinical remission at Week 8 for the 
global and US-specific definitions with a fixed sample size of 951.
Table 4:
Power for detecting a treatment effect based on different proportions of subjects in clinical 
remission at Week 8 (global definition) with a fixed sample size of 951 subjects (317 per 
treatment group)
Proportion of Subjects in Clinical Remission at Week 8 (%)
Powera (%)
Placebo
One Ustekinumab 
Treatment Group
Other Ustekinumab 
Treatment Group
7
19
19
99
15
19
99
13
15
90
14
14
89
7
16
92
7
15
85
7
14
75
a:
Based on the Hochberg testing procedure.
Table 5:
Power for detecting a treatment effect based on different proportions of subjects in clinical 
remission at Week 8 (US-specific definition) with a fixed sample size of 951 subjects (317 per 
treatment group)
Proportion of Subjects in Clinical Remission at Week 8 (%)
Powera (%)
Placebo
Ustekinumab
12
25
97
23
92
22
86
21
79
a:
Based on α=0.025 (2-sided).
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Additionally, to ensure that there will be enough subjects from the induction study to meet the 
required number of subjects for the primary population of the maintenance study, at a designated 
timepoint near the completion of planned enrollment of the induction study, the IWRS system 
will project, based on the available data and a predefined algorithm, whether or not the target 
number of subjects for the primary population of the maintenance study will be reached, and, if 
not, how many more subjects from the induction study will need to be enrolled to reach the 
target. If the information provided by the IWRS vendor indicates that more subjects will be 
needed in the induction study, the sponsor may increase the number of subjects in the induction 
study. Of note, the only data from the induction study that will be used for this projection are the 
proportion of subjects in the induction study who have been randomized into the maintenance 
study. These data will be available only to the IWRS vendor; no sponsor personnel will have 
access. Importantly, no comparisons (blinded or unblinded) of the data from the induction study 
will be performed for this projection. Therefore, no adjustments will be made to the overall 
Type 1 error rate (α=0.05, 2-sided) for the primary and major secondary endpoint analyses.
A sample size of 951 subjects (317 per treatment group) also provides sufficient power for the 
major secondary endpoints of endoscopic healing at Week 8 and clinical response at Week 8. 
The given sample size will provide 99% power to detect a 15% difference (40% vs 25% for a 
ustekinumab dose group vs placebo) in endoscopic healing at Week 8 and to detect a 20% 
difference (50% vs 30% for each ustekinumab dose group vs placebo) in clinical response at 
Week 8 based on the Hochberg testing procedure at the α=0.05 (2-sided) level; the given sample 
size will have 96% and 99% power for the respective comparisons at the α=0.025 (2-sided) level 
for each ustekinumab dose group versus placebo according to the Bonferroni method. The 
assumptions noted above are based on the relevant clinical difference observed for other 
biologics in this indication.13,26,31
11.2.2.
Maintenance Study
The major efficacy analyses in the maintenance study will be based on the primary population, 
ie, subjects who were in clinical response to IV ustekinumab induction. Unless otherwise stated, 
the sample size/power calculations in this section refer to this population.
A fixed-sequence testing procedure, starting with the high dose group (q8w), will be used to 
control the overall Type I error rate at the 0.05 level (2-sided). As such, sample size/power 
calculations were based on the chi-square test to detect a significant difference between subjects 
receiving SC ustekinumab 90 mg q8w and those receiving placebo.
The treatment effect for the primary endpoint in the maintenance study, clinical remission at 
Week 44, was based on maintenance data from similarly designed studies of the anti-TNFα 
golimumab and of vedolizumab. In the golimumab UC maintenance study,27 the proportions of 
subjects in clinical remission (global definition) at Week 54 (among subjects in clinical response 
to golimumab induction) were 34% and 22% in the 100 mg group and the placebo group, 
respectively. In the vedolizumab UC study,13 the proportions of subjects in clinical remission 
(global definition) at Week 52 (among subjects in clinical response at Week 6) were 42% and 
16% in the vedolizumab q8w group and the placebo group, respectively. For the 
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CNTO1275UCO3001 maintenance study, it was assumed that clinical remission rates (global 
definition) at Week 44 were 40% and 20%, respectively, for the ustekinumab 90 mg SC q8w and 
placebo groups. The clinical remission rates at Week 44 based on the US definition are also 
assumed to be 40% and 20%, respectively, for the ustekinumab 90 mg SC q8w and placebo 
groups based on data from the golimumab UC maintenance study (C0524T18).
Assuming a 20% clinical remission rate (for both the global and US definitions) in the placebo 
group and 40% in the SC ustekinumab 90 mg q8w group, 109 subjects in each treatment group 
(327 subjects in total) will provide statistical power of 90% at a significance level of 0.05 
(2-sided). Table 6 shows the power for detecting a treatment difference between the SC 
ustekinumab 90 mg q8w and the placebo group based on different proportions of subjects in 
clinical remission (for both the global and US definitions) at Week 44 with a fixed sample size 
of 327. 
Table 6:
Power for detecting a treatment effect based on different proportions of subjects in clinical 
remission (both global and US definitions) at Week 44 with a fixed sample size of 327 subjects 
(109 in each treatment group)
Proportion of Subjects in Clinical Remission at Week 44 (%)
Powera (%)
Placebo
Ustekinumab
20
45
98
42
94
40
90
37
80
35
70
a: Based on testing the ustekinumab 90 mg SC q8w group versus placebo at α=0.05 (2-sided).
Table 7 shows the power for detecting a treatment difference between the ustekinumab 90 mg 
SC q8w and the placebo group for each of the major secondary endpoints with 327 subjects in 
the primary population. The assumptions about the proportion of subjects achieving each major 
secondary endpoint have been based on data from the golimumab27 and vedolizumab13
maintenance studies in subjects with moderately to severely active UC. 
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Table 7:
Power for detecting a treatment effect for each of the major secondary endpoints with 327 
subjects in the primary population (109 in each treatment group)
Major secondary endpoints
Proportion of subjects achieving 
the endpoint
Powera (%)
Placebo
Ustekinumab
Maintenance of clinical response through Week 44
25
50
97
Endoscopic healing at Week 44
25
45
88
Clinical remission and not receiving concomitant 
corticosteroids at Week 44
15
30
76
Maintenance of clinical remission through Week 44 among 
the subjects who had achieved clinical remission at 
maintenance baseline (both global and US definitions) b
25
50
65
a: Based on testing the SC ustekinumab 90 mg q8w group versus placebo at α=0.05 (2-sided).
b: It is estimated that about 37% of subjects in the primary population (40 subjects per treatment group) will be in clinical
remission at Week 0 of maintenance.
The number of subjects in the primary analysis population of the maintenance study will depend 
on the number of subjects from the following 2 groups of the induction study:  1) subjects in 
clinical response to IV ustekinumab induction at Week 8 of the induction study (Group A), and 
2) subjects who were not in clinical response to IV placebo induction at Week 8 of the induction 
study but were in clinical response at induction Week 16 after receiving an induction dose of IV 
ustekinumab at Week 8 (Group B). If the average clinical response rate to IV ustekinumab 
induction is 45%, 317 subjects in each induction treatment group (for a total of 951subjects) will 
result in about 328 subjects in the primary population of the maintenance study, assuming 15% 
attrition from the induction study to the maintenance study. However, the average clinical 
response rate to IV ustekinumab induction could range from 40% to 50% and attrition from the 
induction study to the maintenance study could range from 10% to 15%. With 317 subjects in 
each induction treatment group, the number of subjects in the primary population of the 
maintenance study could range from 290 to 385 (Table 8). 
Table 8:
Projected number of subjects in the primary population of the maintenance study  with a 
sample size of 951 subjects (317 per treatment group) in the induction study
Attrition From 
Induction Study to 
Maintenance Study
Clinical Response 
Rate to IV 
Ustekinumab 
Induction
Subjects in Group A 
Entering Maintenance
Subjects in 
Group B 
Entering 
Maintenancea
Number of Subjects 
in Primary 
Population of 
Maintenance
15%
40%
216
75
291
45%
243
85
328
50%
269
94
363
10%
40%
228
80
308
45%
257
90
347
50%
285
100
385
Group A=Subjects in clinical response to IV ustekinumab induction at induction Week 8; Group B=Subjects not in clinical 
response to IV placebo induction at induction Week 8 but in clinical response at induction Week 16 after receiving an induction 
dose of IV ustekinumab at Week 8.
a: The proportion of subjects not in clinical response to intravenous placebo induction at Week 8 of the induction study is 
assumed to be 70%.
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Additionally, as discussed in Section 11.2.1, the IWRS system will be used to project whether or 
not the target number of subjects for the primary population of the maintenance study will be 
reached based on enrollment in the induction study. If the information provided by the IWRS 
vendor indicates that more subjects will be needed in the induction study, the sponsor may 
increase the number of subjects in the induction study to make sure that enough subjects will be 
enrolled to supply the required number of subjects for the primary population of the maintenance 
study. Of note, the only data from the maintenance study that will be used for this projection are 
the number of subjects who have already entered the primary population. These data will be 
available only to the IWRS vendor; no sponsor personnel will have access. Importantly, no 
comparisons (blinded or unblinded) of the maintenance data will be performed before the 
Week 44 database lock. Therefore, no adjustments will be made to the overall Type 1 error rate 
(α=0.05, 2-sided) for the primary and major secondary endpoint analyses.
11.3.
Efficacy Analyses
In this protocol, the induction and maintenance studies are considered to be 2 separate studies. 
As such, the Type I error rate for each study is considered separately at the 0.05 level of 
significance.
11.3.1.
Induction Study
11.3.1.1.
Population for Efficacy Analyses
Unless otherwise noted, efficacy analyses will be based on all randomized subjects in the 
induction study. Subjects will be analyzed according to the treatment group to which they were 
randomized regardless of the treatment they actually received.
11.3.1.2.
Primary Analysis
The primary endpoint is clinical remission at Week 8. The definition of clinical remission (as 
well as the testing procedure) will be different for countries outside the United States and for the 
United States, as described below. Each definition of clinical remission will be based on all 
randomized subjects.
In countries outside the United States (global): Clinical remission is defined as a Mayo score 
≤2 points, with no individual subscore >1. Subjects who have a colectomy or ostomy or have 
protocol-prohibited medication changes before the I-8 visit will be considered not to be in 
clinical remission, regardless of the actual Mayo score. Subjects with a missing Mayo score (ie, 
all 4 Mayo subscores are missing) at Week 8 will be considered not to be in clinical remission. 
The comparison between each ustekinumab treatment group and the placebo group will be 
conducted using a 2-sided Cochran-Mantel-Haenszel (CMH) chi-square test stratified by 
biologic failure status (yes or no) and region (Eastern Europe, Asia, or rest of world).
A step-up multiple testing procedure17 will be employed to control the Type 1 error. For this 
procedure, if p-values for both ustekinumab treatment groups are ≤0.05, then it will be concluded 
that both ustekinumab treatment groups are effective compared with placebo. Otherwise, the 
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smaller of the 2 p-values will be compared with =0.025; if the smaller p-value is ≤0.025, then it 
will be concluded that the ustekinumab treatment group associated with the smaller of the 2 
p-values is effective compared with placebo. A positive study is defined as a statistically 
significant test for at least 1 ustekinumab treatment group.
For the United States: Clinical remission is defined as an absolute stool number ≤3, a rectal 
bleeding subscore of 0, and an Mayo endoscopy subscore of 0 or 1. The absolute stool number at 
a visit is calculated as the average number of stools per day over a 3-day period before the visit. 
Subjects who have a colectomy or ostomy or have protocol-prohibited medication changes 
before the I-8 visit will be considered not to be in clinical remission. Subjects who are missing 
the absolute stool number, rectal bleeding subscore, and Mayo endoscopy subscore at Week 8 
will also be considered not to be in clinical remission. 
The Bonferroni method will be used to control the overall Type I error rate at the 0.05 level 
(2-sided) for comparisons of the 2 ustekinumab induction treatment groups with placebo, with 
each comparison being tested at the 0.025 level (2-sided). The comparison between each 
ustekinumab treatment group and the placebo group will be based on a 2-sided CMH chi-square 
test stratified by biologic failure status and region at the 0.025 level of significance.
11.3.1.3.
Major Secondary Endpoint Analyses
The major secondary endpoint analyses in the induction study will be based on all randomized 
subjects. The major secondary endpoints of endoscopic healing (ie, improvement in the 
endoscopic appearance of the mucosa) at Week 8 and clinical response at Week 8 will be 
compared between each ustekinumab treatment group and the placebo group using a 2-sided 
CMH chi-square test stratified by biologic failure status and region. For the major secondary 
endpoint of change from induction baseline in the IBDQ score at Week 8, the treatment groups 
will be compared using ANCOVA on the van der Waerden normal scores with induction 
baseline IBDQ score, biologic failure status, region, and treatment group as covariates.
Subjects who have a colectomy or ostomy, or have protocol-prohibited medication changes 
before the I-8 visit will be considered not to have endoscopic healing and not to be in clinical 
response, and for the IBDQ score, their induction baseline value will be carried forward to 
Week 8. Subjects who have a missing Mayo endoscopy subscore at Week 8 will be considered 
not to have endoscopic healing; subjects who have all 4 Mayo subscores missing at Week 8 will 
be considered not to be in clinical response; and subjects who have a missing IBDQ score at 
Week 8 will have the last available value carried forward to Week 8.
The major secondary endpoints for a dose will be tested only if the primary endpoint for that 
dose is significant. 
Type I error control in countries outside the United States: A fixed-sequence testing 
procedure will be employed to control the overall Type 1 error rate over the 3 major secondary 
efficacy analyses at the 2-sided 0.05 significance level within a dose group. The major 
secondary endpoints for a dose will be tested only if the primary endpoint of clinical remission 
(global definition) is significant for that dose at the 2-sided 0.05 significance level, and the major 
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secondary endpoints will be tested in a hierarchical manner for that dose in the order listed in 
Section 9.2.2.1.2. A major secondary endpoint for a dose group will be tested only if that dose 
tests positive at the 2-sided 0.05 level of significance for the previous endpoint. 
Type I error control in the United States: To control the overall Type I error rate at the 0.05 
(2-sided) significance level over 2 doses, the major secondary endpoints will be tested in a 
hierarchical manner within each ustekinumab induction dose group at the 0.025 level of 
significance. More specifically, for a given ustekinumab dose group, the first major secondary 
endpoint (endoscopic healing) will be tested if the primary hypothesis (US definition of clinical 
remission) has been tested positive at the 0.025 level of significance for that dose group. Only if 
the first test for endoscopic healing is positive for the given dose group at the 0.025 level of 
significance will the second endpoint (clinical response) be tested. The third endpoint (change 
from induction baseline in the IBDQ at Week 8) will be tested only if the second test for clinical 
response is positive at the 0.025 level of significance for the given dose group.
11.3.1.4.
Other Planned Analyses
The consistency of efficacy for clinical remission at Week 8 (for both the global and US-specific 
definitions) will be examined in subgroups defined by baseline demographics, baseline clinical 
disease characteristics, baseline concomitant UC medications, UC medication history, and 
stratification variables (biologic failure status, region).
The following endpoints will be summarized and compared between each of the ustekinumab 
treatment groups and the placebo treatment group: 

The change from induction baseline in the Mayo score at Week 8 

The change from induction baseline in the partial Mayo score through Week 8.

Remission at Week 8 based on a stool frequency subscore of 0 or 1, a rectal bleeding 
subscore of 0, and an endoscopy subscore of 0 or 1.

Remission at Week 8 based on a stool frequency subscore of 0, a rectal bleeding subscore of
0, and an endoscopy subscore of 0 or 1.

Symptomatic remission at Week 8.

Normal or inactive mucosal disease at Week 8.

Endoscopic healing at Week 8 by biologic failure status.

Clinical response at Week 8 by biologic failure status.

The change from induction baseline in each of the 4 dimensions of the IBDQ at Week 8. 

A >20-point improvement from induction baseline in the IBDQ score at Week 8. 

The change from induction baseline for each of the 8 individual subscales of the SF-36 and 
the PCS and MCS scores at Week 8.

The change from induction baseline in the EQ-5D dimensions, EQ-5D index, and health 
state VAS scores at Week 8.
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
Mucosal healing at Week 8. 

The change from induction baseline in CRP through Week 8.

The change from induction baseline in fecal lactoferrin concentration through Week 8.

The change from induction baseline in fecal calprotectin concentration through Week 8.

Normalization of CRP concentration through Week 8 among subjects with abnormal CRP 
concentration at baseline.

Normalization of fecal lactoferrin concentration through Week 8 among subjects with 
abnormal fecal lactoferrin concentration at baseline.

Normalization of fecal calprotectin concentration through Week 8 among subjects with 
abnormal fecal calprotectin concentration at baseline.
Mayo subscores through Week 8 will also be summarized.
11.3.2.
Maintenance Study
11.3.2.1.
Population for Efficacy Analyses
The primary population will be all randomized subjects in the maintenance study, which consists 
of subjects in clinical response to IV ustekinumab induction as determined by the IWRS (ie, 
subjects who were in clinical response to IV ustekinumab induction at Week 8 of the induction 
study, and subjects who were not in clinical response to IV placebo induction at Week 8 of the 
induction study but were in clinical response at induction Week 16 after receiving an induction 
dose of IV ustekinumab at Week 8). The Mayo endoscopy subscore assigned by the local 
endoscopist will be used by the IWRS to calculate clinical response status. 
All efficacy analyses are based on the primary population, with the exception of selected efficacy 
summaries in nonrandomized subjects (ie, subjects in clinical response to IV placebo induction at 
Week 8 of the induction study or delayed ustekinumab responders).
For all efficacy analyses, unless otherwise specified, data will be analyzed according to the 
treatment group to which subjects were randomized, regardless of the treatment they actually 
received.
For the primary and major secondary endpoints involving clinical remission, the global 
definition of clinical remission will be used for countries outside of the United States and the 
US-specific definition will be used for the United States. 
11.3.2.2.
Primary Analysis
The primary endpoint is clinical remission at Week 44. The definition of clinical remission is 
different for countries outside the United States and for the United States, as described below. 
Each definition of clinical remission will be based on the primary population.
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In the countries outside the United States (global definition): Clinical remission is defined as 
a Mayo score ≤2 points, with no individual subscore >1. Subjects who have a colectomy or 
ostomy, discontinue study agent due to lack of therapeutic effect or due to an AE of worsening of 
UC, use a rescue medication, or have protocol-prohibited medication changes before the M-44 
visit will be considered not to be in clinical remission, regardless of the actual Mayo score. 
Subjects with a missing Mayo score (ie, all 4 Mayo subscores are missing) at Week 44 will be 
considered not to be in clinical remission.
The comparisons between each ustekinumab treatment group and the placebo group will be 
conducted using a 2-sided CMH chi-square test stratified by clinical remission status at 
maintenance baseline (yes/no as determined by the IWRS) and induction treatment (placebo IV 
[I-0] → ustekinumab ~6 mg/kg IV [I-8], ustekinumab 130 mg IV [I-0], or ustekinumab ~6 mg/kg 
IV [I-0]). ]).  
A fixed-sequence testing procedure will be used to control the overall Type I error rate at the 
0.05 level for the primary endpoint. Specifically, the high maintenance dose group (ustekinumab 
90 mg SC q8w) will first be compared with the placebo maintenance dose group at the 2-sided 
0.05 level of significance. Only if this test is positive will the low maintenance dose group 
(ustekinumab 90 mg SC q12w) be compared with the placebo maintenance dose group at the 
2-sided 0.05 level of significance.
The study will be considered positive if the test involving the high maintenance dose group 
(ustekinumab 90 mg SC q8w) is positive, regardless of the result of the test for the low 
maintenance dose group (ustekinumab 90 mg SC q12w).
For the United States: Clinical remission is defined as an absolute stool number ≤3, a rectal 
bleeding subscore of 0, and a Mayo endoscopy subscore of 0 or 1. The absolute stool number at a 
visit is calculated as the average number of stools per day over a 3-day period before the visit.
Subjects who have a colectomy or ostomy, discontinue study agent due to lack of therapeutic 
effect or due to an AE of worsening of UC, use a rescue medication, or have protocol-prohibited 
medication changes before the M-44 visit will be considered not to be in clinical remission. 
Subjects who are missing absolute stool number, rectal bleeding subscore, and Mayo endoscopy 
subscore at Week 44 will be considered not to be in clinical remission.
The comparison between each ustekinumab treatment group and the placebo group will be 
conducted using a 2-sided CMH chi-square test stratified by clinical remission status (as 
determined by the IWRS) at maintenance baseline and induction treatment.
A fixed-sequence testing procedure will be employed for the United States to strongly control the 
overall Type 1 error rate at the 0.05 level across the primary and all 4 major secondary endpoints 
and across the 2 ustekinumab doses, starting with the high maintenance dose group (ustekinumab 
90 mg SC q8w) of the primary endpoint. The exact testing procedure will be detailed in the SAP 
before the Week 44 DBL in the maintenance study. The study will be considered positive if the 
test involving the high maintenance dose group is positive.
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11.3.2.3.
Major Secondary Endpoint Analyses
The major secondary endpoint analyses will be based on the primary population. 
Except for the fourth major secondary endpoint of maintenance of clinical remission, analyses of 
major secondary endpoints will be conducted using a 2-sided CMH chi-square test stratified by 
clinical remission status at maintenance baseline (as determined by the IWRS) and induction 
treatment. For the fourth major secondary endpoint, a 2-sided CMH chi-square test stratified by 
induction treatment will be used. Note that, for the United States, for the fourth major secondary 
endpoint of maintenance of clinical remission through Week 44 among the subjects who had 
achieved clinical remission at maintenance baseline, the US-specific definition of clinical 
remission should also be used to determine whether or not a subject had achieved clinical 
remission at maintenance baseline. 
Subjects who have a colectomy or ostomy, discontinue study agent due to lack of therapeutic 
effect or due to an AE of worsening of UC, use a rescue medication, or have protocol-prohibited 
medication changes before the M-44 visit will be considered not to have achieved the respective 
endpoints. At Week 44, subjects who have a missing Mayo endoscopy subscore will be 
considered not to have endoscopic healing; subjects who have all 4 Mayo subscores missing will 
be considered not to be in clinical response or clinical remission (for the global definition of 
remission). For the US-specific definition of clinical remission, subjects who are missing the 
absolute stool number, rectal bleeding subscore, and Mayo endoscopy subscore at Week 44 will 
be considered not to be in clinical remission. Subjects who lose clinical response at any time 
before Week 44 will be considered not to be in clinical response through Week 44.
Type I error control in countries outside the United States:  A fixed-sequence testing 
procedure will be employed to control the overall Type 1 error rate over the 4 major secondary 
efficacy analyses at the (2-sided) 0.05 significance level within a dose group. The major 
secondary endpoints for a dose will be tested only if the primary endpoint is significant for that 
dose, and the major secondary endpoints will be tested in a hierarchical manner for that dose in 
the order listed in Section 9.2.2.2.2. A major secondary endpoint for a dose group will be tested 
only if that dose tests positive at the 2-sided 0.05 level of significance for the previous endpoint. 
Type I error control in the United States:  A US-specific testing procedure will be employed 
to strongly control the overall Type 1 error rate at the 0.05 level across all of the primary and 
major secondary endpoints over 2 ustekinumab doses. The exact testing procedure will be 
determined after the results of the Phase 3 maintenance study of ustekinumab in Crohn’s disease 
are available, and will be described in the SAP before the Week 44 DBL in the maintenance 
study.
11.3.2.4.
Other Planned Analyses
The consistency of efficacy for clinical remission at Week 44 (for both the global and US-
specific definitions) will be examined in subgroups defined by baseline demographics, baseline 
clinical disease characteristics, baseline concomitant UC medications, UC medication history, 
stratification variables, biologic failure status, and region.
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The following endpoints will be summarized and compared between each of the ustekinumab 
treatment groups and the placebo treatment group. 

The change from maintenance baseline in the Mayo score at Week 44. 

The change from maintenance baseline in the partial Mayo score over time through 
Week 44.

Remission at Week 44 based on a stool frequency subscore of 0 or 1, a rectal bleeding 
subscore of 0, and an endoscopy subscore of 0 or 1.

Remission at Week 44 based on a stool frequency subscore of 0, a rectal bleeding subscore 
of 0, and an endoscopy subscore of 0 or 1.

Symptomatic remission at Week 44.

Maintenance of symptomatic remission through Week 44 among the subjects who had 
achieved symptomatic remission at maintenance baseline.

Endoscopic healing at Week 44 by biologic failure status.

Maintenance of clinical response through Week 44 by biologic failure status.

The proportion of subjects who demonstrate endoscopic healing at Week 44 among the 
subjects who had achieved endoscopic healing at maintenance baseline. 

Normal or inactive mucosal disease at Week 44.

Clinical remission and not receiving concomitant corticosteroids at Week 44 among the 
subjects receiving concomitant corticosteroids at maintenance baseline.

The change from maintenance baseline in corticosteroid use over time through Week 44 
among the subjects receiving concomitant corticosteroids at maintenance baseline.

Subjects who are not receiving concomitant corticosteroids at Week 44 among the subjects 
who were receiving concomitant corticosteroids at maintenance baseline.

Subjects who maintained improvement in IBDQ at Week 44 from induction baseline among 
subjects with a >20-point improvement in the total IBDQ score at maintenance baseline. 

The change from maintenance baseline in the total IBDQ score and each of the 4 IBDQ 
dimensions through Week 44. 

The change from maintenance baseline in the SF-36 physical and mental component 
summary scores and the individual scale scores through Week 44.

The changes from maintenance baseline in the EQ-5D dimensions, EQ-5D index, and health 
state VAS scores through Week 44. 

Mucosal healing at Week 44. 

The change from maintenance baseline in CRP concentration over time through Week 44. 

The change from maintenance baseline in fecal lactoferrin concentration over time through 
Week 44.

The change from maintenance baseline in fecal calprotectin concentration over time through 
Week 44.
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
The time to loss of clinical response through Week 44. 

The time to loss of clinical remission (global definition) through Week 44 among subjects 
who had achieved clinical remission (global definition) at maintenance baseline.

The time to loss of clinical remission (US-specific definition) through Week 44 among 
subjects who had achieved clinical remission (US-specific definition) at maintenance 
baseline.
In addition, the following endpoints will be summarized:

The change from induction baseline in the Mayo score over time through Week 44.

The change from induction baseline in the partial Mayo score over time through Week 44.

Mayo subscores through Week 44. 
11.3.3.
Exploratory Analyses
Exploratory analyses will be conducted in the induction and maintenance studies for the endpoint
of response using the Mayo score stool without the PGA subscore. 
Analyses of the average Bristol Stool Form Scale score over time in the induction study will be 
conducted.
11.3.4.
Criteria for Endpoints 
11.3.4.1.
Induction Study
The induction study will be considered positive if at least one of the ustekinumab induction 
treatment groups shows a statistically significant difference versus placebo for the induction 
primary endpoint of clinical remission at Week 8 by the global definition. The global definition 
of clinical remission is based on the Mayo score and is defined as a Mayo score ≤2 points, with 
no individual subscore >1.
The induction study will be considered positive for the United States if at least one of the 
ustekinumab induction treatment groups shows a statistically significant difference versus 
placebo for the induction primary endpoint of clinical remission at Week 8 by the US-specific 
definition. The US-specific definition of clinical remission comprises the following: an absolute 
stool number ≤ 3, a rectal bleeding subscore of 0, and a Mayo endoscopy subscore of 0 or 1. 
A significant testing (taking the testing procedure into account) in one or more of the major 
secondary endpoints of endoscopic healing, clinical response, or the change from induction 
baseline in the IBDQ score (all at Week 8) will be considered confirmative evidence of the 
efficacy of ustekinumab induction therapy.
The major secondary endpoint of endoscopic healing at Week 8 is based on the endoscopy 
subscore of the Mayo score. Endoscopic healing is defined as an endoscopy subscore of 0 or 1.
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The major secondary endpoint of clinical response at Week 8 is based on the Mayo score. 
Clinical response is defined as a decrease from induction baseline in the Mayo score by ≥30% 
and ≥3 points, with either a decrease from induction baseline in the rectal bleeding subscore of 
≥1 or a rectal bleeding subscore of 0 or 1. 
The major secondary endpoint of the change from induction baseline in the IBDQ score at 
Week 8 is based on a 32-item questionnaire18 for subjects with IBD. The change is calculated as 
the IBDQ score at Week 8 minus the induction baseline IBDQ score.
11.3.4.2.
Maintenance Study
The maintenance study will be considered positive if the test involving the high maintenance 
dose group (ustekinumab 90 mg SC q8w) shows a statistically significant difference versus 
placebo for the maintenance primary endpoint, clinical remission at Week 44 (global definition 
for the countries outside the United States and US-specific definition for the United States).
A significant testing (taking the testing procedure into account) in one or more of the major 
secondary endpoints (Section 9.2.2.2.2) will be considered confirmative evidence of the efficacy 
of ustekinumab maintenance therapy. The definitions of clinical remission, clinical response, and 
endoscopic healing are provided in Section 11.3.4.1.
11.4.
Pharmacokinetic Analyses
Serum ustekinumab concentrations will be summarized for each treatment group over time using 
descriptive statistics. All concentrations below the lowest quantifiable concentration or missing 
data will be labeled as such in the concentration data presentations. Concentrations below the 
lower quantifiable concentration will be treated as zero in the summary statistics.
Median serum ustekinumab concentration time profiles will be plotted after the first dose of 
ustekinumab.
A population PK analysis using a nonlinear mixed-effects model will be used to characterize the 
PK of ustekinumab. The influence of important covariates on the population PK parameter 
estimates may be evaluated. Details will be provided in a population PK analysis plan, and 
results of the population PK analysis will be presented in a separate technical report.
Subjects will be excluded from the PK analysis if their data do not allow for accurate PK 
assessment (eg, incomplete administration of the study agent; missing dosing or sampling time 
information).
11.5.
Immunogenicity Analyses
The incidence and titers of antibodies to ustekinumab will be summarized for all subjects who 
receive a dose of ustekinumab and have appropriate samples for detection of antibodies to 
ustekinumab (ie, subjects with at least 1 sample obtained after their first dose of ustekinumab).
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11.6.
Pharmacokinetic/Pharmacodynamic Analyses
The relationship between serum ustekinumab concentration and efficacy will be explored. If 
feasible, an exposure-response model may be developed to describe further characterize such 
relationships.
11.7.
Biomarkers Analysis
Changes in the concentration of individual serum markers from baseline to the selected 
posttreatment time points will be summarized. RNA analyses and additional analyses such as 
histology assessment and microbiome analysis will be performed. Biomarker analyses are 
considered exploratory and will be summarized in a separate technical report.
11.8.
Genetic and Epigenetic (DNA) Analysis
Genetic and epigenetic (DNA) analyses will be conducted only in subjects who sign the consent 
form to participate in the genetics and epigenetic assessments. These analyses are considered 
exploratory and will be summarized in a separate technical report. 
11.9.
Health Economics and Medical Resource Utilization Analyses
The potential pharmacoeconomic benefits of ustekinumab treatment will be examined by 
comparing the difference in direct medical resource utilization and drivers of indirect costs 
among treatment groups. These comparisons will be based on data through Week 44 such as UC-
related hospitalizations and surgeries, medical visits, daily productivity, and time lost from work.
Health economics and medical resource utilization data will be descriptively summarized by 
treatment group.
11.10. Safety Analyses
Safety analyses will be provided separately for the induction and maintenance studies and will be 
based on subjects who received at least 1 dose of study agent in each respective study. 
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). All reported adverse events 
with onset during the treatment phase of each study (ie, treatment-emergent adverse events, and 
adverse events that have worsened since baseline of each study) will be included in the analysis
of each respective study. For each adverse event, the percentage of subjects who experience at 
least 1 occurrence of the given event will be summarized by treatment group.
Analyses of AEs in this study will include:

Frequency and type of AEs.

Frequency and type of SAEs.

Frequency and type of reasonably related AEs.

Frequency and type of AEs leading to discontinuation of study agent.
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
Frequency of infusion reactions (induction study only).

Frequency of injection-site reactions.

Frequency and type of infections, including infections requiring oral or parenteral 
antimicrobial treatment.

Frequency and type of serious infections.
Listings of subjects with SAEs and AEs leading to discontinuation of study agent will also be 
provided. Any deaths, malignancies, or major cardiovascular events will either be presented in a 
listing or described in the clinical study report.
Clinical Laboratory Tests
The following summaries of clinical laboratory tests will be used to assess the safety of subjects 
in this study:

Box plots of the observed values and changes from baseline over time for selected clinical 
laboratory parameters.

Summary of maximum National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) toxicity grade for postbaseline laboratory values.
Listings of subjects with any abnormal postbaseline laboratory values of CTCAE grade ≥2 will 
also be provided.
11.11. Interim Analysis
11.11.1.
Induction Study
A futility analysis based on the primary endpoint of clinical remission (global definition) at 
Week 8 will be conducted when 30% of randomized subjects have either completed the I-8 visit 
or have terminated study participation before Week 8. The whole study may be stopped for 
futility when the conditional power (ie, the probability of success at the end of the study, given 
the data at the interim analysis) on both ustekinumab doses is less than a prespecified cutoff. The 
DMC will review the interim analysis results and form a recommendation on whether or not to 
stop the trial for futility. The sponsor decision committee will then review the DMC’s 
recommendation and make a final decision.
This futility analysis will result in minimal loss in power (≤2% when the treatment effect is in 
the expected range of 10% to 12%) and will not affect the overall Type I error rate (α=0.05, 
2-sided) for the primary endpoint analysis. 
For the futility analysis, the induction treatment assignment information will be unblinded for the 
first 30% of randomized subjects in the trial (the induction treatment assignment for the 
remaining subjects and the maintenance treatment assignment information for all subjects will 
remain blinded at this time). To protect the integrity of the study, the unblinding of the treatment 
assignments for the futility analysis will be handled by an external statistical support group. 
Details about the futility analysis will be specified in the SAP or IAP before the time at which 
the futility analysis is performed.
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11.11.2.
Maintenance Study
No interim analysis is planned for the maintenance study. 
11.12. Data Monitoring Committee
A DMC will be established to monitor data on an ongoing basis to ensure the continuing safety 
of the subjects enrolled in this protocol. The committee will meet periodically to review safety 
data. After the review, the DMC will make recommendations regarding the continuation of the 
study. The same DMC will also review the interim analysis results from the induction study and 
form a recommendation to the sponsor on whether or not to stop the trial for futility. Details will 
be provided in a separate DMC charter.
The DMC will consist of at least one medical expert in the relevant therapeutic area and at least 
one statistician. The DMC responsibilities, authorities, and procedures will be documented in its 
charter.
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not 
related to that medicinal (investigational or non-investigational) product (definition per 
International Conference on Harmonisation [ICH]).
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
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Serious Adverse Event
An SAE, based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for 
Human Use, is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening (The subject was at risk of death at the time of the event. It does not refer 
to an event that hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is medically important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For ustekinumab, the expectedness of an 
adverse event will be determined by whether or not it is listed in the IB.
Adverse Event Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2.
Adverse Events Associated with the Study Population
Anticipated events are events that are considered common for the study population defined in 
this protocol and, when determined to be serious, should be reported by the investigator as 
described in Section 12.3.2. Anticipated events will be recorded and reported as described in 
Attachment 6.
12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
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Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria
An assessment of severity grade will be made using the following general categorical 
descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation; 
prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study agent that may require expedited reporting and/or 
safety evaluation include, but are not limited to:

Overdose of a sponsor study agent

Suspected abuse/misuse of a sponsor study agent

Inadvertent or accidental exposure to a sponsor study agent

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study agent, eg, name confusion)
Special reporting situations should be recorded in the CRF. Any special reporting situation that 
meets the criteria of an SAE should be recorded on the SAE page of the CRF.
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12.3.
Procedures
12.3.1.
All Adverse Events
All adverse events and special reporting situations, whether serious or nonserious, will be 
reported from the time a signed and dated ICF is obtained until completion of the subject's last 
study-related procedure (which may include contact for follow-up of safety). SAEs, including 
those spontaneously reported to the investigator within 20 weeks after the last dose of study 
agent, must be reported using the Serious Adverse Event Form. The sponsor will evaluate any 
safety information that is spontaneously reported by an investigator beyond the time frame 
specified in the protocol.
Anticipated events will be recorded and reported as described in Attachment 6.
All adverse events, regardless of seriousness, severity, or presumed relationship to study agent, 
must be recorded using medical terminology in the source document and the CRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection"). Investigators must record in the CRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) suspected unexpected serious adverse reactions (SUSARs). The 
investigator (or sponsor where required) must report SUSARs to the appropriate IEC/IRB that 
approved the protocol unless otherwise required and documented by the IEC/IRB. A SUSAR will 
be reported to regulatory authorities unblinded. Participating investigators and IEC/IRB will 
receive a blinded SUSAR summary, unless otherwise specified.
Subjects (or their designees, if appropriate) must be provided with a "study wallet card" 
indicating, but not limited to, the following information:

Study number

Statement, in the local language(s), that the subject is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical staff only)

Study site number

Subject number 
12.3.2.
Serious Adverse Events
All SAEs occurring during the study must be reported to the appropriate sponsor contact person 
by study-site personnel within 24 hours of their knowledge of the event.
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Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event 
Form, which must be completed and signed by a physician from the study site, and transmitted to 
the sponsor within 24 hours. The initial and follow-up reports of an SAE should be made by 
facsimile (fax).
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject's participation in the study, must be followed until any of the 
following occurs:

The event resolves.

The event stabilizes.

The event returns to baseline, if a baseline value/status is available.

The event can be attributed to agents other than the study agent or to factors unrelated to 
study conduct.

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts).
Suspected transmission of an infectious agent by a medicinal product will be reported as an SAE.
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a subject's participation in a study must be reported as an SAE, except hospitalizations 
for the following:

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons 
such as performance of an endoscopy).

Surgery or procedure planned before entry into the study (must be documented in the CRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not 
be considered SAEs. Any adverse event that results in a prolongation of the originally 
planned hospitalization is to be reported as a new SAE.
The cause of death of a subject in a study, whether or not the event is expected or associated with 
the study agent, is considered an SAE.
Lack of improvement in the condition/indication under investigation is not an AE unless it meets 
the criteria for an SAE (eg, hospitalization). Hospitalization due to disease progression or 
hospitalization due to lack of improvement in the condition/indication under investigation is 
considered an SAE.
12.3.3.
Pregnancy
All initial reports of pregnancy must be reported to the sponsor by the study-site personnel
within 24 hours of their knowledge of the event using the appropriate pregnancy notification 
form. Abnormal pregnancy outcomes (eg, spontaneous abortion, stillbirth, congenital anomaly) 
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are considered SAEs and must be reported using the Serious Adverse Event Form. Any subject 
who becomes pregnant during the study must discontinue further study treatment. 
Because the effect of the study agent on sperm is unknown, pregnancies in partners of male 
subjects included in the study must be reported by the study-site personnel within 24 hours of their 
knowledge of the event using the appropriate pregnancy notification form.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
12.3.4.
Events of Special Interest
Any newly identified malignancy or case of active TB occurring after the first administration of 
study agent(s) in subjects participating in this clinical study must be reported by the investigator 
according to the procedures in Section 12.3.2. Investigators are also advised that active TB is 
considered a reportable disease in most countries. These events are to be considered serious only 
if they meet the definition of an SAE.
12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed on the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with an SAE, the study-site personnel must report the PQC to the 
sponsor according to the SAE reporting timelines (refer to Section 12.3.2, Serious Adverse 
Events). A sample of the suspected product should be maintained for further investigation if 
requested by the sponsor.
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13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed on the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY AGENT INFORMATION
14.1.
Physical Description of Study Agent(s)
14.1.1.
Induction Study
Ustekinumab 5 mg/mL final vialed product (FVP) (IV) is supplied for this study as a single-use, 
sterile solution in 30 mL vials with 1 dose strength (ie, 130 mg in 26 mL nominal volume). No 
preservatives are present. It will be manufactured and provided under the responsibility of the 
sponsor. Refer to the IB for a list of excipients.
Placebo for FVP (IV) is supplied as a single-use, sterile solution in 30 mL vials with a 26 mL 
nominal volume. The composition of the placebo is 10 mM histidine, 8.5% (w/v) sucrose, 0.04% 
(w/v) polysorbate 80, 0.4 mg/mL L-methionine, and 20 µg/mL EDTA disodium salt, dihydrate at 
pH 6.0. 
Placebo administrations will have the same appearance as the respective ustekinumab 
administrations.
14.1.2.
Maintenance Study
Ustekinumab is supplied as sterile liquid for SC injection in a single-use prefilled syringe (PFS). 
Each single-use PFS contains 90 mg (1 mL fill of liquid) ustekinumab in an aqueous medium of 
L-histidine, L-histidine monohydrochloride monohydrate, sucrose, and polysorbate 80 at pH 6.0. 
No preservatives are present.
Placebo is supplied as a sterile liquid for SC injection at a fill volume of 1.0 mL in a single-use 
PFS. Each PFS contains L-histidine, sucrose, and polysorbate 80 at pH 6.0.
Placebo administrations will have the same appearance as the respective ustekinumab 
administrations.
The needle cover on the PFS contains dry natural rubber (a derivative of latex), which may cause 
allergic reactions in individuals sensitive to latex.
Details regarding the study agents are provided in the investigational product manual. 
14.2.
Packaging
The investigational supplies will be uniquely packaged to assure that they are appropriately 
managed throughout the supply chain process.
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The study agent will be packaged in individual subject kits. Each kit will consist of a single vial 
or PFS packaged inside a protective outer carton.
14.3.
Labeling
Study agent labels will contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage
All study agent must be stored at controlled temperatures ranging from 36°F to 46°F (2°C to
8°C), not frozen, and protected from light. Vigorous shaking of the product should be avoided. 
Prior to administration, the product should be inspected visually for particulate matter and 
discoloration. If discoloration (other than a slight yellow color), visible opaque particles, or other 
foreign particles are observed in the solution, the product should not be used.
Study agent in glass vials and PFS will be ready to use. Study agent will be prepared according 
to the subject’s treatment assignment (and weight for weight-range-based doses). The pharmacist 
(or designated personnel) who is blinded to treatment will prepare the required volume of study 
agent using the appropriate number of vials.
Aseptic procedures must be used during the preparation and administration of the study material. 
Exposure to direct sunlight should be avoided during preparation and administration.
Refer to the Site Investigational Product Procedures Manual and/or Investigational Product 
Preparation Instructions (ie, pharmacy manual) for additional guidance on study agent
preparation, handling, and storage.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study agent received at the site is inventoried 
and accounted for throughout the study. The study agent administered to the subject must be 
documented on the drug accountability form. All study agent will be stored and disposed of 
according to the sponsor's instructions. Study-site personnel must not combine contents of the 
study agent containers.
Study agent must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study agent must be available for verification by the sponsor's 
study site monitor during on-site monitoring visits. The return of unused study agent or used 
returned study agent for destruction will be documented on the applicable drug return form. 
When the study site is an authorized destruction unit and/or is using an offsite authorized 
destruction company for destruction, verification and documentation must also be noted on the 
applicable drug return form. Destruction documentation, verifying the destruction, needs to be in 
place. 
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Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes. The immediate destruction of these drug supplies 
should be documented in the drug accountability records on site.
Study agent should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study agent will be supplied only 
to subjects participating in the study. Returned study agent must not be dispensed again, even to 
the same subject. Study agent may not be relabeled or reassigned for use by other subjects. The 
investigator agrees neither to dispense the study agent from, nor store it at, any site other than the 
study sites agreed upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Investigator Site File (includes protocol and IB)

Investigational Product Binder

Central Laboratory Manual 

eCRF completion instructions

IWRS Manual

Patient recruitment materials

Subject study card

Informed consent form

Mayo diaries
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential adverse events of the study, and provide their consent voluntarily will be enrolled.
The total blood volume to be collected is considered to be an acceptable amount of blood to be 
collected over this time period from the population in this study based upon the standard of the 
American Red Cross (1 pint/473 mL of blood for donation). 
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16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

IB (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the ICF, applicable recruiting materials, and 
subject compensation programs, and the sponsor has received a copy of this approval. This 
approval letter must be dated and must clearly identify the IEC/IRB and the documents being 
approved.
Approval for the collection of optional samples for research and for the corresponding ICF must 
be obtained from the IEC/IRB. Approval for the protocol can be obtained independent of this 
optional research component.
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During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the IB and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the 
study agent

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study. The 
reapproval should be documented in writing (excluding the ones that are purely administrative, 
with no consequences for subjects, data, or study conduct).
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion.
16.2.3.
Informed Consent
Each subject must give written consent according to local requirements after the nature of the 
study has been fully explained. The ICF(s) must be signed before performance of any study-
related activity. The ICF(s) that is used must be approved by both the sponsor and by the 
reviewing IEC/IRB and be in a language that the subject can read and understand. The informed 
consent should be in accordance with principles that originated in the Declaration of Helsinki, 
current ICH and GCP guidelines, applicable regulatory requirements, and sponsor policy.
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Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Subjects will be informed that their participation is voluntary and that they may withdraw 
consent to participate at any time. They will be informed that choosing not to participate will not 
affect the care the subject will receive for the treatment of his or her UC. Subjects will be told 
that alternative treatments are available if they refuse to take part and that such refusal will not 
prejudice future treatment. Finally, they will be told that the investigator will maintain a subject 
identification register for the purposes of long-term follow-up if needed and that their records 
may be accessed by health authorities and authorized sponsor personnel without violating the 
confidentiality of the subject, to the extent permitted by the applicable law(s) or regulations. By 
signing the ICF, the subject is authorizing such access, and agrees to allow his or her study 
physician to recontact the subject for the purpose of obtaining consent for additional safety 
evaluations, if needed.
The subject will be given sufficient time to read the ICF and the opportunity to ask questions. 
After this explanation and before entry into the study, consent should be appropriately recorded 
by means of the subject's personally dated signature. After having obtained the consent, a copy of 
the ICF must be given to the subject.
Subjects will be asked for consent to provide optional samples for research (where local 
regulations permit). After informed consent for the study is appropriately obtained, the subject 
will be asked to sign and personally date a separate ICF indicating agreement to participate in the 
optional research component. Refusal to participate in the optional research will not result in 
ineligibility for the study. A copy of this signed ICF will be given to the subject.
Subjects must be able to read and write and give informed consent without assistance. A subject 
who is unable to read or write is not eligible to participate in the study.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential.
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his or her original 
medical records (source data/documents) for study-related monitoring, audit, IEC/IRB review, 
and regulatory inspection. This consent also addresses the transfer of the data to other entities 
and to other countries.
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The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Biomarker, DNA, and PK research is not conducted under standards appropriate for the return of 
data to subjects. In addition, the sponsor cannot make decisions as to the significance of any 
findings resulting from exploratory research. Therefore, exploratory research data will not be 
returned to subjects or investigators, unless required by law or local regulations. Privacy and 
confidentiality of data generated in the future on stored samples will be protected by the same 
standards applicable to all other clinical data.
16.2.5.
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand ustekinumab, to 
understand UC, to understand differential drug responders, to identify biomarkers capable of 
predicting ustekinumab response in UC, and to develop tests/assays related to ustekinumab and 
UC. The research may begin at any time during the study or the post-study storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 10.3, Withdrawal From the Study (Withdrawal From the Use 
of Samples in Future Research).
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product, unless explicitly addressed as a specific ethical 
consideration in Section 16.1, Study-Specific Design Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IRB (and IEC where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
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representative (see Contact Information page(s) provided separately). Except in emergency 
situations, this contact should be made before implementing any departure from the protocol. In 
all cases, contact with the sponsor must be made as soon as possible to discuss the situation and 
agree on an appropriate course of action. The data recorded in the CRF and source documents 
will reflect any departure from the protocol, and the source documents will describe this 
departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study agent to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated clinical trial agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)
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
Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification
and date of birth. In cases where the subject is not randomized into the study, the date seen and 
date of birth will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documentation must be available for the following to confirm data 
collected in the CRF: subject identification, eligibility, and study identification; study discussion 
and date of signed informed consent; dates of visits; results of safety and efficacy parameters as 
required by the protocol; record of all adverse events and follow-up of adverse events; 
concomitant medication; drug receipt/dispensing/return records; study agent administration 
information; and date of study completion and reason for early discontinuation of study agent or 
withdrawal from the study, if applicable. 
In addition, the author of an entry in the source documents should be identifiable.
At a minimum, the type and level of detail of source data available for a subject should be 
consistent with that commonly recorded at the study site as a basis for standard medical care. 
Specific details required as source data for the study will be reviewed with the investigator 
before the study and will be described in the monitoring guidelines (or other equivalent 
document).
The minimum source documentation requirements for Section 4.1, Inclusion Criteria, and 
Section 4.2, Exclusion Criteria, that specify a need for documented medical history are as 
follows:

Referral letter from treating physician or

Complete history of medical notes at the site

Discharge summaries
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Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents.
17.5.
Case Report Form Completion
Case report forms are provided for each subject in electronic format. 
Electronic Data Capture (eDC) will be used for this study. The study data will be transcribed by 
study-site personnel from the source documents onto an electronic CRF, and transmitted in a 
secure manner to the sponsor within the timeframe agreed upon between the sponsor and the 
study site. The electronic file will be considered to be the CRF.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the subject's source documentation. All data relating to the 
study must be recorded in CRFs prepared by the sponsor. Data must be entered into CRFs in 
English. Study site personnel must complete the CRF as soon as possible after a subject visit, and 
the forms should be available for review at the next scheduled monitoring visit.
The investigator must verify that all data entries in the CRFs are accurate and correct.
All CRF entries, corrections, and alterations must be made by the investigator or other authorized 
study-site personnel. If necessary, queries will be generated in the eDC tool. The investigator or 
study-site personnel must adjust the CRF (if applicable) and complete the query. 
If corrections to a CRF are needed after the initial entry into the CRF, this can be done in 
3 different ways:

Study site personnel can make corrections in the eDC tool at their own initiative or as a 
response to an auto query (generated by the eDC tool).

Study site manager can generate a query for resolution by the study-site personnel.

Clinical data manager can generate a query for resolution by the study-site personnel.
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, periodic monitoring visits by the sponsor or delegate, and 
direct transmission of clinical laboratory data from a central laboratory into the sponsor's data 
base. Written instructions will be provided for collection, handling, storage, and shipment of 
samples. 
Guidelines for CRF completion will be provided and reviewed with study-site personnel before 
the start of the study.
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The sponsor will review CRFs for accuracy and completeness during on-site monitoring visits 
and after transmission to the sponsor; any discrepancies will be resolved with the investigator or 
designee, as appropriate. After upload of the data into the study database, they will be verified 
for accuracy and consistency with the data sources. 
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRFs 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
17.8.
Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the 
monitor will compare the data entered into the CRFs with the hospital or clinic records (source 
documents). The nature and location of all source documents will be identified to ensure that all 
sources of original data required to complete the CRF are known to the sponsor and study-site 
personnel and are accessible for verification by the sponsor study-site contact. If electronic 
records are maintained at the study site, the method of verification must be discussed with the 
study-site personnel. 
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Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the CRF are consistent with the original source data. Findings 
from this review of CRFs and source documents will be discussed with the study-site personnel. 
The sponsor expects that, during monitoring visits, the relevant study-site personnel will be 
available, the source documentation will be accessible, and a suitable environment will be 
provided for review of study-related documents. The monitor will meet with the investigator on a 
regular basis during the study to provide feedback on the study conduct.
17.9.
Study Completion/Termination
17.9.1.
Study Completion
The study is considered completed with the last visit for the last subject participating in the LTE. 
The final data from the study site will be sent to the sponsor (or designee) after completion of the 
final subject visit at that study site, in the time frame specified in the Clinical Trial Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study agent development
17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection and comparison with the CRFs. Subject 
privacy must, however, be respected. The investigator and study-site personnel are responsible 
for being present and available for consultation during routinely scheduled study-site audit visits 
conducted by the sponsor or its designees. 
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Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding ustekinumab or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including pharmacogenomic or exploratory biomarker
research data, generated as a result of this study, are considered confidential and remain the sole 
property of the sponsor. The investigator agrees to maintain this information in confidence and 
use this information only to accomplish this study, and will not use it for other purposes without 
the sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of ustekinumab, and thus may be 
disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain CRF data from all study sites that participated in the study. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Results of pharmacogenomic or 
exploratory biomarker analyses, performed after the Clinical Study Report has been issued, will 
be reported in a separate report and will not require a revision of the Clinical Study Report. 
Study subject identifiers will not be used in publication of results. Any work created in 
connection with the performance of the study and contained in the data that can benefit from 
copyright protection (except any publication by the investigator as provided for below) shall be 
the property of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
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should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study
have been submitted for publication, within 12 months of the availability of the final data (tables, 
listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law.
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REFERENCES
1.
Ahern PP , Schiering C, Buonocore S, et al. Interleukin-23 drives intestinal inflammation through direct 
activity on T cells. Immunity. 2010; 33(2):279-288. 
2.
Anderson CA, Boucher G, Lees CW, et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, 
increasing the number of confirmed associations to 47. Nat Genet. 2011; 43(3):246-252. 
3.
Baron JH, Connell AM, Lennard-Jones JE. Variation between observers in describing mucosal appearances in 
proctocolitis. Brit Med J. 1964; 1:89-92. 
4.
Baumgart DC, Sandborn WJ. Crohn’s disease. Lancet. 2012; 380:1590-1605. 
5.
Berg DJ, Davidson N, Kühn R, et al. Enterocolitis and colon cancer in interleukin-10-deficient mice are 
associated with aberrant cytokine production and CD4(+) TH1-like responses. J Clin Invest. 1996; 98:1010-
1020.
6.
Brant SR. Promises, delivery, and challenges of inflammatory bowel disease risk gene discovery. Clin 
Gastroenterol Hepatol. 2013; 11(1):22-26.
7.
Buderus S, Boone J, Lyerly D, Lentze MJ. Fecal lactoferrin:  a new parameter to monitor infliximab therapy. 
Dig Dis Sci. 2004; 49(6):1036-1039.
8.
Colombel J-F, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and 
remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology. 2007; 132:52–65. 
9.
Costa F, Mumolo MG, Ceccarelli L, et al. Calprotectin is a stronger predictive marker of relapse in ulcerative 
colitis than in Crohn’s disease. Gut. 2005; 54:364-368. 
10.
Danese S, Fiocchi C. Ulcerative colitis. N Engl J Med. 2011; 365:1715-1725. 
11.
Davidson NJ, Hudak SA, Lesley RE, Menon S, Leach MW, Rennick DM. IL-12, but not IFN-gamma, plays a 
major role in sustaining the chronic phase of colitis in IL-10-deficient mice. J Immunol. 1998; 161:3143–3149.
12.
Dove LS, Lembo A, Randall CW, et al. Eluxadoline benefits patients with irritable bowel syndrome with 
diarrhea in a Phase 2 study. Gastroenterology. 2013; 145:329–338. 
13.
Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative 
colitis. N Engl J Med. 2013; 369:699-710.
14.
Geremia A, Biancheri P, Allan P, Corazza GR, Di Sabatino A. Innate and adaptive immunity in inflammatory 
bowel disease. Autoimmun Rev. 2014; 13:3-10. 
15.
Granlund AV, Flatberg A, Østvik AE, et al. Whole genome gene expression meta-analysis of inflammatory 
bowel disease colon mucosa demonstrates lack of major differences between Crohn's disease and ulcerative 
colitis. PLoS One. 2013; 8(2):e56818. 
16.
Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I 
randomised trial. Lancet. 2002; 359:1541-1549. 
17.
Hochberg Y. A sharper Bonferroni for multiple tests of significance. Biometrika. 1988; 75(4):800-802. 
18.
Irvine EJ, Feagan B, Rochon J, et al. Quality of life:  a valid and reliable measure of therapeutic efficacy in the 
treatment of inflammatory bowel disease. Canadian Crohn’s Relapse Prevention Trial Study Group. 
Gastroenterology. 1994; 106(2):287-296. 
19.
Izcue A, Hue S, Buonocore S, et al. Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent 
colitis. Immunity. 2008; 28(4):559-570. 
20.
Jostins L, Ripke S, Weersma RK, et al. Host-microbe interactions have shaped the genetic architecture of 
inflammatory bowel disease. Nature. 2012; 491(7422):119-124. 
21.
Kane SV, Sandborn WJ, Rufo PA et al. Fecal lactoferrin is a sensitive and specific marker in identifying 
intestinal inflammation. Am J Gastroenterol. 2003; 98(6);1309-1314. 
22.
Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol. 
1997; 32(9):920–924. 
23.
Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol. 2014; 14(5):329-42. 
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24.
Neurath MF, Fuss I, Kelsall BL, Stuber E, Strober W. Antibodies to interleukin 12 abrogate established 
experimental colitis in mice. J Exp Med. 1995; 182(5):1281-1290. 
25.
Sandborn WJ, Feagan BG, Fedorak RN, et al; Ustekinumab Crohn's Disease Study Group. A randomized trial 
of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn's 
disease. Gastroenterology. 2008; 135(4):1130-1141.
26.
Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golimumab induces clinical response and remission 
in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014; 146:85-95. 
27.
Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golimumab maintains clinical response in patients 
with moderate-to-severe ulcerative colitis. Gastroenterology. 2014; 146:96-109. 
28.
Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn’s 
disease. N Engl J Med. 2013; 369:711-721.
29.
Sandborn WJ, Gasink C, Gao L-L, et al, for the CERTIFI Study Group. Ustekinumab induction and 
maintenance therapy in refractory Crohn’s disease. N Engl J Med. 2012; 367:1519-1528. 
30.
Sandborn WJ, Rutgeerts P, Enns R. Adalimumab induction therapy for Crohn disease previously treated with 
infliximab: a randomized trial. Ann Intern Med. 2007; 146(12):829-838. 
31.
Sandborn WJ, Van Assche G, Reinisch W, et al. Adalimumab induces and maintains clinical remission in 
patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2012; 142:257–265
32.
Talley NJ, Abreu MT, Achkar JP, et al. An evidence-based systematic review on medical therapies for 
inflammatory bowel disease. Am J Gastroenterol. 2011; 106 Suppl 1:S2-S25. 
33.
Travis SP, Schnell D, Krzeski P, et al. Developing an instrument to assess the endoscopic severity of ulcerative
colitis: the Ulcerative Colitis Endoscopic Index of Severity (UCEIS). Gut. 2012; 61:535-542. 
34.
Truelove SC, Witts LJ. Cortisone in ulcerative colitis: final report on a therapeutic trial. Brit Med J. 1955; 
2:1041-1048. 
35.
Uhlig HH, McKenzie BS, Hue S, et al. Differential activity of IL-12 and Il-23 in mucosal and systemic innate 
immune pathology. Immunity. 2006; 25:309-318. 
36.
Ware JE, Kosinski M, Keller SD. Interpretation:  Norm-Based. In:  SF-36 Physical and Mental Health 
Summary Scales:  A User’s Manual. Boston, MA:  The Health Institute; 1994:8:1-8:42. 
37.
Ware JE Jr, Sherbourne CD. The MOS 36 item short form health survey (SF 36), I:  conceptual framework and 
item selection. Med Care. 1992; 30(6):473 483. 
38.
Yen D, Cheung J, Scheerens H, et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation 
via IL-17 and IL-6. J Clin Invest. 2006; 116(5):1310-1316. 
39.
Yu LZ, Wang HY, Yang SP, et al. Expression of interleukin-22/STAT3 signaling pathway in ulcerative colitis 
and related carcinogenesis. World J Gastroenterol. 2013; 19(17):2638-2649. 
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ATTACHMENTS
Attachment 1:
Definition of Inadequate Initial Response, Loss of Response, or Intolerance to TNF 
Antagonist Therapies (Infliximab, Adalimumab, Golimumab, or Approved Biosimilars for 
Infliximab or Adalimumab) or Vedolizumab
The criteria for inadequate initial response, response followed by loss of response, or intolerance to 
infliximab, adalimumab, golimumab (or approved biosimilars for infliximab or adalimumab), or 
vedolizumab are described in items I, II, and III, below.
I.
Inadequate initial response to at least 8 weeks of therapy with infliximab, adalimumab, or 
golimumab (or approved biosimilars for infliximab or adalimumab), or vedolizumab 
(primary nonresponse)
Eligible subjects must satisfy criteria A, B, and C.
A.
Have received induction doses of:

REMICADE (infliximab; 3 intravenous [IV] doses 5 mg/kg) at Weeks 0, 2, 
and 6 (or approved biosimilar for infliximab)
OR

Humira (adalimumab; subcutaneous [SC] doses of 160 mg at Week 0 and 
80 mg at Week 2 followed by a dose 40 mg every 2 weeks) or approved 
biosimilar for adalimumab
OR

SIMPONI (golimumab; SC doses of 200 mg at Week 0 and 100 mg at Week 2, 
followed by 50 or 100 mg every 4 weeks)
OR

Entyvio (vedolizumab; IV doses of 300 mg at Weeks 0, 2, and 6)
AND
B.
Did not initially respond to these induction doses of infliximab, adalimumab, 
golimumab
(or approved biosimilars for infliximab or adalimumab), or 
vedolizumab, as evidenced by the presence of at least 1 of the following signs or 
symptoms related to persistence of ulcerative colitis (UC), as assessed by a treating 
physician:

Lack of improvement or worsening in stool frequency

Lack of improvement or worsening in rectal bleeding

Lack of improvement or worsening in daily abdominal pain

Lack of improvement or worsening in urgency

Lack of improvement or worsening in the endoscopic appearance of the colonic 
mucosa
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These signs and symptoms of UC must have occurred 2 weeks after receiving the last 
induction dose of infliximab, adalimumab, golimumab (or approved biosimilars for 
infliximab or adalimumab), or vedolizumab and are offered only as a benchmark of the 
minimally acceptable criteria required to designate a subject as having had an inadequate 
initial response to infliximab, adalimumab, golimumab (or approved biosimilars for 
infliximab or adalimumab), or vedolizumab. 
AND
C.
Have documentation available to the investigator that meets the following 2 
requirements:

Provides the dates and doses of the failed infliximab, adalimumab, golimumab
(or approved biosimilars for infliximab or adalimumab), or vedolizumab 
induction therapy.

Documents that the subject had persistence of disease activity following 
infliximab, adalimumab, golimumab (or approved biosimilars for infliximab or 
adalimumab), or vedolizumab induction therapy.
Examples of acceptable documents include medical records, letter provided by a referring 
physician, or other “reason for referral” documents (eg, insurance authorization form).
II.
Initial response followed by loss of response to current or prior therapy with infliximab, 
adalimumab, golimumab (or approved biosimilars for infliximab or adalimumab), or 
vedolizumab (secondary nonresponse)
Eligible subjects must satisfy criteria A, B, C, and D.
A.
Initially responded to induction therapy
AND
B.
Have received at least 2 maintenance doses of:

Infliximab (at a dose 5 mg/kg, or approved biosimilar for infliximab)
or

Adalimumab (at a dose 40 mg, or approved biosimilar for adalimumab) 
or

Golimumab (at a dose of fmg) 
or

Vedolizumab (at a dose 300 mg)
AND
C.
Have or had at least 1 of the following signs or symptoms related to recurrence of 
UC, as assessed by a treating physician:

Worsening in stool frequency

Worsening in rectal bleeding

Worsening in daily abdominal pain
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
Worsening in urgency.

Worsening in the endoscopic appearance of the colonic mucosa.
These signs and symptoms of UC must have occurred 2 weeks after receiving the last 
maintenance dose of infliximab, adalimumab, golimumab (or approved biosimilars for 
infliximab or adalimumab), or vedolizumab and are offered only as a benchmark of the 
minimally acceptable criteria required to designate a subject as having lost response to 
infliximab, adalimumab, golimumab (or approved biosimilars for infliximab or 
adalimumab), or vedolizumab therapy.
AND
D.
Have documentation available to the investigator that meets the following 2 
requirements:

Provides the dates and doses of the failed infliximab, adalimumab, golimumab
(or approved biosimilars for infliximab or adalimumab), or vedolizumab 
maintenance therapy.

Documents that the subject had recurrence of disease activity despite infliximab, 
adalimumab, 
golimumab
(or 
approved 
biosimilars 
for 
infliximab 
or 
adalimumab), or vedolizumab maintenance therapy.
Examples of acceptable documents include medical records, letter provided by a referring 
physician, or other “reason for referral” documents (eg, insurance authorization form).
III.
Current or prior intolerance to therapy with infliximab, adalimumab, golimumab (or 
approved biosimilars for infliximab or adalimumab), or vedolizumab.
Eligible subjects must satisfy criteria A and B.
A.
Have had an adverse reaction that meets 1 of the following 3 criteria:  1) significant 
acute 
infusion/administration 
reaction; 
2) 
significant 
delayed 
infusion/administration reaction (eg, delayed hypersensitivity or serum-sickness-like 
reaction); or 3) significant injection site reaction. Definitions of these 3 criteria are 
provided below. 
Adverse reactions must have followed 1 dose of infliximab, adalimumab, 
golimumab (or approved biosimilars for infliximab or adalimumab), or vedolizumab 
and, in the treating physician’s opinion, precluded continued use of the therapy.
1)
A significant acute infusion/administration reaction is defined as an adverse 
reaction that was:

Manifested through 1 of the following symptoms.
a.
Fever greater than 100F (37.8C)
b.
Chills or rigors
c.
Itching
d.
Rash
e.
Flushing
f.
Urticaria or angioedema
g.
Breathing difficulties (eg, dyspnea, chest paint or tightness, 
shortness of breath, wheezing, stridor)
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h.
Clinical hypotension (eg, pallor, diaphoresis, faintness, syncope), 
blood pressure <90 mm Hg systolic and 60 mm Hg diastolic, or a 
systemic or orthostatic drop in systolic blood pressure >20 mm 
Hg.
and 

Occurred 24 hours after infusion/administration of infliximab, 
adalimumab, golimumab (or approved biosimilars for infliximab or 
adalimumab), or vedolizumab.
and 

Was considered related to the infusion/administration of infliximab, 
adalimumab, golimumab (or approved biosimilars for infliximab or 
adalimumab), or vedolizumab.
2)
A significant delayed infusion/administration reaction is defined as an 
adverse reaction that:

Was manifested through 1 or more of the following symptoms:
a.
Myalgias
b.
Arthralgias
c.
Fever greater than 100F (37.8C).
d.
Malaise
e.
Rash
and

Occurred >24 hours and <15 days after infusion/administration of 
infliximab, adalimumab, golimumab (or approved biosimilars for 
infliximab or adalimumab), or vedolizumab.
and

Was considered related to the infusion/administration of infliximab, 
adalimumab, golimumab (or approved biosimilars for infliximab or 
adalimumab), or vedolizumab.
3)
A significant injection site reaction is defined as an adverse reaction that:

Was manifested through 1 or more of the following symptoms:
a.
Significant bruising
b.
Erythema
c.
Hemorrhage
d.
Irritation
e.
Pain
f.
Pruritus
g.
“Injection site reaction”
and

Occurred within 24 hours of an SC injection of adalimumab (or approved 
biosimilar for adalimumab) or golimumab
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and

Was considered related to the injection.
B.
Have documentation available to the investigator that meets the following 2 
requirements:

Provides the date of discontinuation of infliximab, adalimumab, golimumab (or 
approved biosimilars for infliximab or adalimumab), or vedolizumab.

Documents that the subject had intolerance to infliximab, adalimumab, 
golimumab (or approved biosimilars for infliximab or adalimumab), or 
vedolizumab.
Examples of acceptable documents include medical records, letter provided by a referring 
physician, or other “reason for referral” documents (eg, insurance authorization form).
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Attachment 2: Definition of Inadequate Response to or Intolerance of Corticosteroids or AZA/6-MP and 
Corticosteroid Dependence
CORTICOSTEROIDS
Subjects have failed to respond to corticosteroids if they have had evidence of an initial inadequate 
response, recurrent disease, or a relapse despite receiving at least 0.75 mg/kg/day or >40 mg/day of 
prednisone (or corticosteroid equivalent, given orally or intravenously) for 2 weeks; or ≥9 mg/day of 
budesonide or ≥5 mg/day of beclomethasone dipropionate given orally for at least 4 weeks.
Subjects are intolerant of corticosteroids if:

They have developed clinically significant adverse events (eg, osteonecrosis or osteoporosis, 
psychosis, uncontrolled diabetes) unresponsive to dose reduction that, in the judgment of the 
investigator, precluded the use of corticosteroids to treat ulcerative colitis (UC). 
OR

They have a medical condition that precludes the use of corticosteroids as a treatment for UC.
Subjects are corticosteroid dependent if they have failed to successfully taper their corticosteroid (ie, 
had a flare of disease) within 3 months of starting therapy, or if a relapse occurs within 3 months after 
stopping corticosteroids or if they are unable to discontinue these agents without flare within 3 months 
after starting them.
6-MERCAPTOPURINE (6-MP) OR AZATHIOPRINE (AZA): 
Subjects have failed to respond to 6-MP or AZA if they have had evidence of an initial inadequate 
response, recurrent disease, or a relapse despite receiving: 

At least 3 months of therapy with 1 mg/kg/day of 6-MP or 2 mg/kg/day of AZA.
OR

A lower dosage of 6-MP or AZA when country or local guidelines specify a different treatment 
regimen. (In such an event, the country or local guidelines needs to be included in the source 
document).
OR

The dosage of 6-MP or AZA confirmed to be therapeutic for the subject with whole blood 
thioguanine nucleotide levels >200 pmole/8 x 108 RBCs. 
OR

The highest tolerated dosage due to leukopenia, elevated liver enzymes, or nausea. 
Subjects are intolerant of 6-MP or AZA if: 

They have developed clinically significant adverse events (eg, pancreatitis, arthritis accompanied by 
high fever and/or rash, leukopenia, or persistently elevated liver enzymes) unresponsive to dose 
reduction that, in the judgment of the investigator, precluded the use of 6-MP or AZA to treat UC 
within the past 5 years.
OR

They have a medical condition that precludes the use of 6-MP or AZA. 
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Attachment 3:
QuantiFERON-TB Gold Testing
The QuantiFERON-TB Gold test is one of the interferon-(IFN-) based blood assays for TB screening (Cellestis, 
2009). It utilizes the recently identified M. tuberculosis-specific antigens ESAT-6 and CFP-10 in the standard 
format, as well as TB7.7 (p4) in the In-Tube format, to detect in vitro cell-mediated immune responses in infected 
individuals. The QuantiFERON-TB Gold assay measures the amount of IFN-produced by sensitized T-cells when 
stimulated with the synthetic M. tuberculosis-specific antigens. In M. tuberculosis-infected persons, sensitized 
T lymphocytes will secrete IFN-in response to stimulation with the M. tuberculosis-specific antigens and, thus, the 
QuantiFERON-TB Gold test should be positive. Because the antigens used in the test are specific to M. tuberculosis
and not found in BCG, the test is not confounded by BCG vaccination, unlike the tuberculin skin test. However, 
there is some cross-reactivity with the 3 Mycobacterium species, M. kansasii, M. marinum, and M. szulgai. Thus, a 
positive test could be the result of infection with one of these 3 species of Mycobacterium, in the absence of M. 
tuberculosis infection.
In a study of the QuantiFERON-TB Gold test (standard format) in subjects with active TB, sensitivity has been 
shown to be approximately 89% (Mori et al, 2004). Specificity of the test in healthy BCG-vaccinated individuals has 
been demonstrated to be more than 98%. In contrast, the sensitivity and specificity of the tuberculin skin test was 
noted to be only about 66% and 35% in a study of Japanese patients with active TB and healthy BCG-vaccinated 
young adults, respectively. However, sensitivity and specificity of the tuberculin skin test depend on the population 
being studied, and the tuberculin skin test performs best in healthy young adults who have not been BCG-
vaccinated.
Data from a limited number of published studies examining the performance of the QuantiFERON-TB Gold assay in 
immunosuppressed populations suggest that the sensitivity of the QuantiFERON-TB Gold test is better than the 
tuberculin skin test even in immunosuppressed patients (Ferrara et al, 2005; Kobashi et al, 2007; Matulis et al, 
2008). The ability of IFN--based tests to detect latent infection has been more difficult to study due to the lack of a 
gold standard diagnostic test; however, several TB outbreak studies have demonstrated that the tests correlated 
better than the tuberculin skin test with the degree of exposure that contacts had to the index TB case (Brock et al, 
2004; Ewer et al, 2003). In addition, TB contact tracing studies have shown that patients who had a positive 
QuantiFERON-TB Gold test result and were not treated for latent TB infection were much more likely to develop 
active TB during longitudinal follow-up than those who had a positive tuberculin skin test and a negative 
QuantiFERON-TB Gold test result (Higuchi et al, 2007; Diel et al, 2008).
Although the performance of the new IFN--based blood tests for active or latent M. tuberculosis infection have not 
been well validated in the immunosuppressed population, experts believe these new tests will be at least as, if not 
more, sensitive, and definitely more specific, than the tuberculin skin test (Barnes, 2004; personal communication, 
April, 2008 TB Advisory Board).
Performing the QuantiFERON-TB Gold Test
The QuantiFERON-TB Gold test In-Tube format will be provided for this study. The In-Tube format contains 1 
additional M. tuberculosis-specific antigen, TB7.7 (p4), which is thought to increase the specificity of the test. 
To perform the test using the In-Tube format, blood is drawn through standard venipuncture into supplied tubes that 
already contain the M. tuberculosis-specific antigens. Approximately 3 tubes will be needed per subject, each 
requiring 1 mL of blood. One tube contains the M. tuberculosis-specific antigens, while the remaining tubes contain 
positive and negative control reagents. Thorough mixing of the blood with the antigens is necessary prior to 
incubation. The blood is then incubated for 16 to 24 hours at 37C, after which tubes are centrifuged for 
approximately 15 minutes at 2000 to 3000 g. Following centrifugation, plasma is harvested from each tube, frozen, 
and shipped on dry ice to the laboratory. The laboratory will perform an ELISA to quantify the amount of IFN-
present in the plasma using spectrophotometry and computer software analysis.
The laboratory will analyze and report results for each subject, and sites will be informed of the results. Subjects 
who have an indeterminate result should have the test repeated.
Adherence to Local Guidelines
Local country guidelines for immunocompromised patients should be consulted for acceptable antituberculous 
treatment regimens for latent TB. If no local country guidelines for immunocompromised patients exist, US 
guidelines must be followed.
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In countries in which the QuantiFERON-TB Gold test is not considered approved/registered, a tuberculin skin test is 
additionally required. In Ukraine, the tuberculin skin test is recommended but not required if tuberculin is not 
available.
References
Barnes PF. Diagnosing latent tuberculosis infection:  Turning glitter to gold [editorial]. Amer J Respir Crit Care 
Med. 2004;170:5-6.
Brock I, Weldingh K, Lillebaek T, et al. Comparison of tuberculin skin test and new specific blood test in 
tuberculosis contacts. Am J Respir Crit Care Med. 2004;170:65-69.
Cellestis. QuantiFERON-TB Gold clinicians guide and QuantiFERON-TB Gold In-Tube Method package insert. 
Downloaded from www.cellestis.com, February 2009.
Diel R, Loddenkemper R, Meywald-Walter K, Niemann S, Nienhaus A. Predictive value of a whole blood IFN-
assay for the development of active tuberculosis disease after recent infection with mycobacterium tuberculosis. Am 
J Respir Crit Care Med. 2008;177:1164-1170.
Ewer K, Deeks J, Alvarez L, et al. Comparison of T-cell-based assay with tuberculin skin test for diagnosis of 
Mycobacterium tuberculosis infection in a school tuberculosis outbreak. Lancet. 2003;361:1168-73.
Ferrara G, Losi M, Meacci M, et al. Routine hospital use of a new commercial whole blood interferon-assay for 
the diagnosis of tuberculosis infection. Am J Respir Crit Care Med. 2005; 172:631-635.
Higuchi K, Nobuyuki H, Mori T, Sekiya Y. Use of QuantiFERON-TB Gold to investigate tuberculosis contacts in a 
high school. Respirology. 2007;12:88-92.
Kobashi Y, Mouri K, Obase Y, et al. Clinical evaluation of QuantiFERON TB-2G test for immunocompromised 
patients. Eur Respir J. 2007; 30:945-950.
Matulis G, Jüni P, Villiger PM, Gadola SD. Detection of latent tuberculosis in immunosuppressed patients with 
autoimmune diseases: performance of a Mycobacterium tuberculosis antigen-specific interferon assay. Ann Rheum 
Dis. 2008;67:84-90
Mori T, Sakatani M, Yamagishi F, et al. Specific detection of tuberculosis infection:  An interferon--based assay 
using new antigens. Am J Respir Crit Care Med. 2004;170:59-64.
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Attachment 4:
Tuberculin Skin Testing
Administering the Mantoux Tuberculin Skin Test
The Mantoux tuberculin skin test (CDC, 2000) is the standard method of identifying persons infected with 
Mycobacterium tuberculosis. Multiple puncture tests (Tine and Heaf) should not be used to determine whether a 
person is infected because the amount of tuberculin injected intradermally cannot be precisely controlled. Tuberculin 
skin testing is both safe and reliable throughout the course of pregnancy. The Mantoux tuberculin test is performed 
by placing an intradermal injection of 0.1 mL of tuberculin into the inner surface of the forearm. The test must be 
performed with tuberculin that has at least the same strength as either 5 tuberculin units (TU) of standard purified 
protein derivative (PPD)-S or 2 TU of PPD-RT 23, Statens Seruminstitut, as recommended by the World Health 
Organization. PPD strengths of 1 TU or 250 TU are not acceptable (Menzies, 2000). Using a disposable tuberculin 
syringe with the needle bevel facing upward, the injection should be made just beneath the surface of the skin. This 
should produce a discrete, pale elevation of the skin (a wheal) 6 mm to 10 mm in diameter. To prevent needle-stick 
injuries, needles should not be recapped, purposely bent or broken, removed from disposable syringes, or otherwise 
manipulated by hand. After they are used, disposable needles and syringes should be placed in puncture-resistant 
containers for disposal. Institutional guidelines regarding universal precautions for infection control (eg, the use of 
gloves) should be followed. A trained health care worker, preferably the investigator, should read the reaction to the 
Mantoux test 48 to 72 hours after the injection. Subjects should never be allowed to read their own tuberculin skin 
test results. If a subject fails to show up for the scheduled reading, a positive reaction may still be measurable up to 
1 week after testing. However, if a subject who fails to return within 72 hours has a negative test, tuberculin testing 
should be repeated. The area of induration (palpable raised hardened area) around the site of injection is the reaction 
to tuberculin. For standardization, the diameter of the induration should be measured transversely (perpendicular) to 
the long axis of the forearm. Erythema (redness) should not be measured. All reactions should be recorded in 
millimeters, even those classified as negative.
Interpreting the Tuberculin Skin Test Results
In the US and many other countries, the most conservative definition of positivity for the tuberculin skin test is 
reserved for immunocompromised patients, and this definition is to be applied in this study to maximize the 
likelihood of detecting latent TB, even though the subjects may not be immunocompromised at baseline.
In the US and Canada, an induration of 5 mm or greater in response to the intradermal tuberculin skin test is 
considered to be a positive result and evidence for either latent or active TB.
In countries outside the US and Canada, country-specific guidelines for immunocompromised patients should be 
consulted for the interpretation of tuberculin skin test results. If no local country guidelines for 
immunocompromised patients exist, US guidelines must be followed. 
Treatment of Latent Tuberculosis
Local country guidelines for immunocompromised patients should be consulted for acceptable antituberculous 
treatment regimens for latent TB. If no local country guidelines for immunocompromised patients exist, US 
guidelines must be followed.
In Ukraine, the tuberculin skin test is recommended but not required if tuberculin is not available.
References
Centers for Disease Control and Prevention. Core curriculum on tuberculosis:  What the clinician should know 
(Fourth Edition). Atlanta, GA:  Department of Health and Human Services; Centers for Disease Control and 
Prevention; National Center for HIV, STD, and TB Prevention; Division of Tuberculosis Elimination; 2000:25-86. 
Menzies RI. Tuberculin skin testing. In:  Reichman LB, Hershfield ES (eds). Tuberculosis, a comprehensive 
international approach. 2nd ed. New York, NY:  Marcel Dekker, Inc; 2000:279-322.
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Attachment 5:
Mayo Score
Mayo scoring system for assessment of ulcerative colitis activity
Stool frequencya
0 = Normal number of stools for this patient
1 = 1-2 stools more than normal
2 = 3-4 stools more than normal
3 = 5 or more stools more than normal
Rectal bleedingb
0 = No blood seen
1 = Streaks of blood with stool less than half the time
2 = Obvious blood with stool most of the time
3 = Blood alone passed
Findings of endoscopy
0 = Normal or inactive disease
1 = Mild disease (erythema, decreased vascular pattern, mild friability)
2 = Moderate disease (marked erythema, absent vascular pattern, friability, erosions)
3 = Severe disease (spontaneous bleeding, ulceration)
Physician’s global assessmentc
0 = Normal
1 = Mild disease
2 = Moderate disease
3 = Severe disease
a At the screening visit, each person indicates the number of stools he/she passed in a 24-hour period when in 
remission or before his/her UC diagnosis, thereby serving as his/her own control to establish the degree of 
abnormality of stool frequency.
b The daily bleeding score represents the most severe bleeding of the day.
c The physician’s global assessment acknowledges the 3 other criteria, the patient’s recall of abdominal 
discomfort and general sense of well-being, and other observations, such as physical findings and the 
patient’s performance status.
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Attachment 6:
Anticipated Events
Anticipated Event
An anticipated event is an adverse event (serious or nonserious) that commonly occurs as a consequence 
of the underlying disease or condition under investigation (disease related) or background regimen.
For the purposes of this study the following events will be considered anticipated events:
Adverse Events Associated with the Study Population

Adverse events related to symptoms of UC

Adverse events related to worsening or progression of UC
Reporting of Anticipated Events
These events will be captured on the CRF and in the database, and will be reported to the sponsor as 
described in Section 12.3.1, All Adverse Events. Any event that meets serious adverse event criteria will 
be reported to the sponsor within the appropriate timeline as described in Section 12.3.2, Serious Adverse 
Events. These anticipated events are exempt from expedited reporting as individual single cases to Health 
Authorities. However if based on an aggregate review, it is determined that an anticipated event is 
possibly related to study drug, the sponsor will report these events in an expedited manner.
Anticipated Event Review Committee (ARC)
An Anticipated Event Review Committee (ARC) will be established to perform reviews of prespecified 
anticipated events at an aggregate level. The ARC is a safety committee within the sponsor’s organization 
that is independent of the sponsor’s study team. The ARC will meet to aid in the recommendation to the 
sponsor’s study team as to whether there is a reasonable possibility that an anticipated event is related to 
the study drug.
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and threshold to 
trigger an aggregate analysis of anticipated events will be provided in a separate Anticipated Events 
Safety Monitoring Plan (ASMP).
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INVESTIGATOR AGREEMENT
LAST PAGE
NCT02407236


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 30 April 2020
Janssen Research & Development *
Clinical Protocol
COVID-19 Appendix
A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter 
Study to Evaluate the Safety and Efficacy of Ustekinumab Induction and Maintenance 
Therapy in Subjects with Moderately to Severely Active Ulcerative Colitis
UNIFI
Protocol CNTO1275UCO3001; Phase 3
STELARA  (ustekinumab)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen Biologics,
BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen Sciences Ireland
UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term “sponsor” is used
throughout the protocol to represent these various legal entities; the sponsor is identified on the Contact
Information page that accompanies the protocol.
United States (US) sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
Status:
Approved  
Date:
30 April 2020
Prepared by:
Janssen Research & Development, LLC  
EDMS number:
EDMS-RIM-38086, 1.0
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF PROTOCOL
CNTO1275UCO3001
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT02407236


COVID-19 Appendix
STELARA (ustekinumab)
Clinical Protocol CNTO1275UCO3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved,  Date: 30 April 2020
COVID-19 APPENDIX
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, self-isolation/quarantine by participants and 
study-site personnel; travel restrictions/limited access to public places, including hospitals; study 
site personnel being reassigned to critical tasks. 
In alignment with recent health authority guidance, the sponsor is providing options for study 
related participant management in the event of disruption to the conduct of the study. This guidance 
does not supersede any local or government requirements or the clinical judgement of the 
investigator to protect the health and well-being of participants and site staff. If, at any time, a 
participant’s safety is considered to be at risk, study intervention will be discontinued, and study 
follow-up will be conducted.
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent 
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each 
contact, participants will be interviewed to collect safety data. Key efficacy endpoint assessments 
should be performed if required and as feasible. Participants will also be questioned regarding 
general health status to fulfill any physical examination requirement. 
Every effort should be made to adhere to protocol-specified assessments for participants on study 
intervention, including follow up. Modifications to protocol-required assessments may be 
permitted via COVID-19 Appendix after consultation with the participant, investigator, and the 
sponsor. Missed assessments/visits will be captured in the clinical trial management system for 
protocol deviations. Discontinuations of study interventions and withdrawal from the study should 
be documented with the prefix “COVID-19-related” in the case report form (CRF). 
The sponsor will continue to monitor the conduct and progress of the clinical study, and any 
changes will be communicated to the sites and to the health authorities according to local guidance.  
If a participant has tested positive for COVID 19, the investigator should contact the sponsor’s 
responsible medical officer to discuss plans for study intervention and follow-up. Modifications 
made to the study conduct as a result of the COVID-19 pandemic should be summarized in the 
clinical study report.


COVID-19 Appendix
STELARA (ustekinumab)
Clinical Protocol CNTO1275UCO3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Approved,  Date: 30 April 2020
ADDITIONAL ELEMENTS, WHERE APPLICABLE:

Certain protocol-mandated visits to the study site may not be possible during the COVID-19 
outbreak. Therefore, temporary measures may be implemented if considered appropriate by 
the sponsor and investigator to maintain continuity of participant care and study integrity. 
Certain measures, such as those listed below, may be necessary and should be instituted in 
accordance with applicable (including local) laws, regulations, guidelines, and procedures:
o
remote (eg, by phone / telemedicine) or in-person, off-site (eg, in-home) interactions 
between site staff (or designees) and participants for study procedures e.g. those related 
to safety monitoring / efficacy evaluation / study intervention storage and 
administration (including training where pertinent)
o
procurement of study intervention by participants (or designee) or shipment of study 
intervention from the study site directly to participants for at home administration 
(including the potential for self-administration of study intervention)
o
laboratory assessments using a suitably accredited local laboratory; for selected 
measures (eg, urine pregnancy), home testing may be employed
o
other procedures, eg, imaging, may be conducted at an appropriate facility

Missed assessments/visits will be captured in the clinical trial management system for 
protocol deviations.  Discontinuations of study interventions and withdrawal from the 
study should be documented with the prefix “COVID-19-related” in the case report form 
(CRF).  
o
other relevant study data elements impacted by the pandemic should also be 
documented / labeled as “COVID-19-related” in CRFs and / or other study systems, 
as directed by detailed sponsor guidance. These may include missed / delayed / 
modified study visits / assessments / dosing, and instances where temporary 
measures such as those above are implemented.  

The sponsor will evaluate the totality of impact of COVID-19 on collection of key study 
data and additional data analyses will be outlined in study SAP(s). 

Precaution: for those who may carry a higher risk for severe COVID-19 illness (eg, those 
aged over 65 years), follow guidance from local health authorities when weighing the 
potential benefits and risks during participation in the study. 



SAP_001.pdf: 
1
Approved, Date: 25 July 2018
Janssen Research & Development *
Statistical Analysis Plan
For the Maintenance Study
A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter 
Protocol to Evaluate the Safety and Efficacy of Ustekinumab Induction and Maintenance 
Therapy in Subjects with Moderately to Severely Active Ulcerative Colitis
UNIFI
Protocol CNTO1275UCO3001; Phase 3
AMENDMENT 1
CNTO1275  (CNTO1275)
Status:
Approved  
Date:
25 July 2018
Prepared by:
Janssen Research & Development, LLC  
Document No.: EDMS-ERI-128681086
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
NCT02407236


CNTO1275  (Ustekinumab)
Statistical Analysis Plan CNTO1275UCO3001: Maintenance Amendment 1
2
Approved, Date: 25 July 2018
AMENDMENT HISTORY
This analysis plan was modified to implement the following changes:
1) The following new analyses have been added:
a) Major secondary endpoints will be evaluated for the following subgroups:
CRP and Fecal Biomarkers (calprotecin and lactoferrin), both at Week 0 of the 
induction study and at Week 0 of the maintenance study

CRP (≤3 mg/L, >3 mg/L)

CRP (≤ median, > median)

CRP (≤10 mg/L, >10 mg/L)

Fecal calprotectin (≤250 mg/kg, >250 mg/kg)

Fecal lactoferrin (≤7.24 µg/g, >7.24 µg/g)
Induction baseline Weight (≤ 1st quartile, >1st quartile and ≤ 2nd quartile, >2nd 
quartile and ≤ 3rd quartile, >3rd quartile)
b) Apart from those subgroup analyses by biologic failure status that were prespecified for 
the primary and the first 2 major secondary endpoints, subgroup analyses based on 
biologic failure status will also be performed for the 3rd and 4th major secondary 
endpoints as well as for the mucosal healing endpoint.
c) Primary and major secondary endpoints as well as mucosal healing endpoint will be 
evaluated based on the following biologic failure profiles: subjects who were biologic-
naïve, subjects who were biologic failures to at least 1 anti-TNF (regardless of 
vedolizumab), and subjects who were biologic failures to both anti-TNF and 
vedolizumab. These subpopulations were identified as they represent the general 
treatment pathway for patients with UC and indicate progressively more refractory 
disease.
d) Sensitivity analyses will be performed for mucosal healing at Week 44 and histologic 
healing at Week 44 by considering subjects with an unevaluable biopsy at Week 44 as 
nonresponders.
e) The following IBDQ endpoints will be analyzed:

A >20-point improvement from induction baseline in the IBDQ score at Week 44. 

A ≥16-point improvement from induction baseline in the IBDQ score at Week 44. 

IBDQ remission at Week 44

Maintenance of IBDQ remission among subjects with IBDQ remission at the 
maintenance baseline.
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CNTO1275  (Ustekinumab)
Statistical Analysis Plan CNTO1275UCO3001: Maintenance Amendment 1
3
Approved, Date: 25 July 2018
f)
The following endpoints will be analyzed based on the endoscopy subscore assigned by 
the local endoscopist:

Normal or inactive mucosal disease at Week 44 

Mucosal healing at Week 44 
g) The following endpoints will be summarized based on the Non-randomized Analysis Set.

Corticosteroid-free clinical remission at Week 44

Mucosal healing at Week 44
In addition, maintenance of clinical response through Week 44, instead of clinical response 
at Week 44, will be summarized based on the Non-randomized Analysis Set
h) The following endpoints will be analyzed:

Subjects with a UC-related hospitalization and/or surgery through Week 44

The time to the first UC-related hospitalization or surgery through Week 44 
2) The definition of rescue medication was clarified.
3) Minor errors were noted and corrected.
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CNTO1275  (Ustekinumab)
Statistical Analysis Plan CNTO1275UCO3001: Maintenance Amendment 1
4
Approved, Date: 25 July 2018
TABLE OF CONTENTS
AMENDMENT HISTORY.............................................................................................................................. 2
TABLE OF CONTENTS ............................................................................................................................... 4
LIST OF IN-TEXT TABLES.......................................................................................................................... 5
LIST OF IN-TEXT FIGURES ........................................................................................................................ 5
ABBREVIATIONS ........................................................................................................................................ 6
1.
INTRODUCTION.................................................................................................................................. 7
1.1.
Trial Objectives ................................................................................................................................ 7
1.2.
Trial Design ...................................................................................................................................... 7
1.3.
Statistical Hypotheses for Trial Objectives..................................................................................... 13
1.4.
Randomization and Blinding .......................................................................................................... 13
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 15
2.1.
Visit Windows................................................................................................................................. 15
2.2.
Baseline Measurements................................................................................................................. 15
2.3.
Analysis Sets.................................................................................................................................. 15
2.3.1.
Efficacy Analysis Sets................................................................................................................. 15
2.3.2.
Safety Analysis Set..................................................................................................................... 15
2.3.3.
Pharmacokinetics Analysis Set .................................................................................................. 16
2.4.
Definition of Subgroups.................................................................................................................. 16
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 18
4.
SUBJECT INFORMATION................................................................................................................ 18
4.1.
Demographics and Baseline Characteristics ................................................................................. 19
4.2.
Prior and Concomitant Medications ............................................................................................... 19
4.3.
Disposition Information................................................................................................................... 19
4.4.
Treatment Compliance................................................................................................................... 19
4.5.
Extent of Exposure......................................................................................................................... 19
4.6.
Protocol Deviations ........................................................................................................................ 20
5.
EFFICACY ......................................................................................................................................... 20
5.1.
Analysis Specifications................................................................................................................... 20
5.1.1.
Data Handling Rules................................................................................................................... 20
5.1.1.1.
Treatment Failure .................................................................................................................... 20
5.1.1.2.
Missing Data............................................................................................................................ 22
5.2.
Primary Efficacy Endpoint.............................................................................................................. 22
5.2.1.
Definitions ................................................................................................................................... 22
5.2.1.1.
Mayo Score.............................................................................................................................. 22
5.2.1.2.
Clinical Remission ................................................................................................................... 25
5.2.2.
Analysis Methods........................................................................................................................ 25
5.2.3.
Sample Size Justification............................................................................................................ 26
5.2.4.
Subgroup Analyses..................................................................................................................... 28
5.2.5.
Sensitivity Analysis ..................................................................................................................... 29
5.3.
Major Secondary Endpoints........................................................................................................... 31
5.3.1.
Definitions ................................................................................................................................... 31
5.3.2.
Analysis Methods........................................................................................................................ 32
5.3.3.
Subgroup Analyses..................................................................................................................... 34
5.4.
Other Efficacy Endpoints................................................................................................................ 35
5.4.1.
Endpoints.................................................................................................................................... 35
5.4.1.1.
Clinical Endpoints .................................................................................................................... 35
5.4.1.2.
CRP and Fecal Biomarkers..................................................................................................... 37
5.4.1.3.
Patient Reported Outcomes .................................................................................................... 38
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CNTO1275  (Ustekinumab)
Statistical Analysis Plan CNTO1275UCO3001: Maintenance Amendment 1
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Approved, Date: 25 July 2018
5.4.2.
Definitions ................................................................................................................................... 39
5.4.3.
Analysis Methods for Other Efficacy Endpoints ......................................................................... 41
5.5.
Efficacy Endpoints in Other Populations........................................................................................ 42
5.6.
Exploratory Endpoints.................................................................................................................... 42
5.6.1.
Clinical Endpoints ....................................................................................................................... 42
5.6.2.
Definitions ................................................................................................................................... 42
5.6.3.
Analysis Methods........................................................................................................................ 43
6.
SAFETY............................................................................................................................................. 43
6.1.
Adverse Events .............................................................................................................................. 44
6.2.
Clinical Laboratory Tests................................................................................................................ 45
6.3.
Vital Signs ...................................................................................................................................... 46
7.
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................... 47
7.1.
Pharmacokinetics........................................................................................................................... 47
7.2.
Immune Response......................................................................................................................... 47
7.3.
Pharmacodynamics........................................................................................................................ 48
8.
HEALTH ECONOMICS ..................................................................................................................... 48
REFERENCES............................................................................................................................................ 51
ATTACHMENTS......................................................................................................................................... 52
ATTACHMENT 1: MAYO SCORE ............................................................................................................. 52
ATTACHMENT 2: GRADING CRITERIA FOR THE HISTOLOGICAL EVALUATION OF 
DISEASE ACTIVITY IN ULCERATIVE COLITIS.............................................................................. 53
ATTACHMENT 3: UCEIS........................................................................................................................... 54
ATTACHMENT 4: LIST OF PRIMARY AND MAJOR SECONDARY ENDPOINTS IN THE 
ORDER OF THE US-SPECIFIC TESTING ....................................................................................... 55
LIST OF IN-TEXT TABLES
Table 1:
Power for detecting a treatment effect based on different proportions of subjects in 
clinical remission (both global and US definitions) at Week 44 with a fixed sample size 
of 327 subjects (109 in each treatment group) ......................................................................... 27
Table 2:
Power for detecting a treatment effect for each of the major secondary endpoints with 
327 subjects in the primary population (109 in each treatment group) .................................... 27
Table 3:
Projected number of subjects in the primary population of the maintenance study with 
a sample size of 951 subjects (317 per treatment group) in the induction study ..................... 28
Table 4:
Grading Criteria for Clinical Laboratory Tests [CTCAE Version 4.03]...................................... 46
LIST OF IN-TEXT FIGURES
Figure 1:
Overall schema for CNTO1275UCO3001 protocol .................................................................... 8
Figure 2:
Schema for the CNTO1275UCO3001 maintenance study....................................................... 10
Figure 3:
Global testing procedure for primary and major secondary endpoints..................................... 33
Figure 4:
US-specific testing procedure for the primary and major secondary endpoints....................... 34
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ABBREVIATIONS
6-MP
6-mercaptopurine
AE 
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical Classification
AZA
Azathioprine
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CRF
case report form
CRP
C-reactive protein
CSR
Clinical Study Report
DBL
database lock
DMC
Data Monitoring Committee
ECG
Electrocardiogram
eCRF
electronic case report form
EQ-5D
EuroQoL-5D Health Questionnaire
EQ-VAS
EQ Visual Analogue scale
FDA
Food and Drug Administration
IBDQ
Inflammatory Bowel Disease Questionnaire
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ITT
Intent-to-Treat
IV
Intravenous
IWRS
interactive web response system
LOCF
last observation carried forward
LTE
long term extension
MAR
missing at random
MCS
mental component summary
MedDRA
Medical Dictionary for Regulatory Activities
MTX
methotrexate
NCI-CTC
National Cancer Institute’s Common Terminology Criteria
PCS
physical component summary
PD
Pharmacodynamic
PI
principal investigator
PK
pharmacokinetic(s)
SAE
serious adverse event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SD
standard deviation
SF-36
36-item Short Form Health Survey
SUA
serious unexpected associated adverse reaction
TNF
more tumor necrosis factor
UC
ulcerative colitis
UCEIS
Ulcerative Colitis Endoscopic Index of Severity
WHO
World Health Organization
WPAI-GH
Work Productivity and Activity Impairment Questionnaire-General Health
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1.
INTRODUCTION
This Statistical Analysis Plan contains definitions of analysis sets, derived variables, and 
statistical methods for all planned analyses of the maintenance study in protocol 
CNTO1275UCO3001. The analyses for the induction study in this protocol will be provided 
in a separate induction SAP.
1.1.
Trial Objectives
The primary objectives of the maintenance study in protocol CNTO1275UCO3001 are:

To evaluate clinical remission for subcutaneous (SC) maintenance regimens of ustekinumab 
in subjects with moderately to severely active ulcerative colitis (UC) induced into clinical 
response with ustekinumab.

To evaluate the safety of SC maintenance regimens of ustekinumab in subjects with 
moderately to severely active UC induced into clinical response with ustekinumab.
The secondary objectives are:

To evaluate the efficacy of ustekinumab in maintaining clinical response in subjects induced 
into clinical response with ustekinumab.

To evaluate endoscopic healing (i.e., improvement in the endoscopic appearance of the 
mucosa) in subjects induced into clinical response with ustekinumab.

To evaluate the efficacy of ustekinumab in achieving corticosteroid-free clinical remission 
in subjects induced into clinical response with ustekinumab.

To evaluate the efficacy of ustekinumab in maintaining clinical remission in subjects 
induced into clinical remission with ustekinumab. 

To evaluate the efficacy of ustekinumab treatment on mucosal healing (i.e., endoscopic 
healing and histologic healing).

To evaluate the impact of SC ustekinumab on disease-specific health-related quality of life. 

To evaluate the efficacy of maintenance therapy with SC ustekinumab by biologic failure 
status. 

To evaluate the pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD) of 
ustekinumab induction therapy in subjects with moderately to severely active UC, including 
changes in C-reactive protein (CRP), fecal calprotectin, fecal lactoferrin, and other PD 
biomarkers.
1.2.
Trial Design
The Phase 3 development program for ustekinumab in the treatment of UC will be conducted 
under a single protocol but will be designed and analyzed as 2 separate studies, an induction 
study and a maintenance study. Both studies will be Phase 3, randomized, double-blind, placebo-
controlled, parallel-group, multicenter studies of ustekinumab in subjects with moderately to 
severely active UC. The induction study will target subjects with moderately to severely active 
UC who have demonstrated an inadequate response or failure to tolerate conventional or biologic 
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therapy. The maintenance study will be a randomized withdrawal study targeting subjects with 
moderately to severely active UC who have demonstrated a clinical response to induction 
treatment with IV ustekinumab. Overall, the program will evaluate ustekinumab treatment in 
subjects with moderately to severely active UC through at least 1 year of induction and 
maintenance therapy; after completion of the maintenance study through Week 44, a long-term 
extension study will follow eligible subjects for an additional 3 years. 
Overall schema for CNTO1275UCO3001 protocol is shown in Figure 1.
Figure 1:
Overall schema for CNTO1275UCO3001 protocol
The target population is men or women 18 years of age or older with moderately to severely 
active UC, as defined by a Mayo score of 6 to 12, inclusive, at Week 0 of the induction study, 
including an endoscopy subscore ≥2 as assessed by the central reader. Subjects must not be at 
imminent risk of colectomy. 
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A broad subject population will be evaluated and will include both subjects who have failed 
biologic therapy and those who have not: 

Subjects may be biologic failures, i.e., have received treatment with 1 or more tumor 
necrosis factor (TNF) antagonists or vedolizumab at a dose approved for the treatment of 
UC, and either did not respond initially, responded initially but then lost response, or were 
intolerant to the medication. A minimum of 40% and a maximum of 50% of the total subject 
population in the induction study will be biologic failures. 

Subjects may be biologic-naive or may have been exposed to biologic therapy but not
demonstrated an inadequate response or intolerance to treatment with a biologic agent (i.e., a 
TNF antagonist or vedolizumab). These subjects must have demonstrated an inadequate 
response to, or have failed to tolerate, at least 1 of the following conventional UC therapies:  
oral or intravenous (IV) corticosteroids or the immunomodulators azathioprine (AZA) or 
6-mercaptopurine (6-MP). Subjects who have demonstrated corticosteroid dependence (i.e., 
an inability to successfully taper corticosteroids without a return of the symptoms of UC) are 
also eligible for entry into the study. 
Induction Study
In the induction study, a target of 951 subjects will be randomized in a 1:1:1 ratio to receive 1 of 
the following 3 treatment regimens at Week 0 (I-0):  Placebo IV, Ustekinumab 130 mg IV, and 
Weight-range-based ustekinumab doses approximating ustekinumab 6 mg/kg IV (i.e., 
ustekinumab ~6 mg/kg IV). At Week 8 (I-8), subjects who are in clinical response are eligible to 
enter the maintenance study; subjects who are not in clinical response will receive ustekinumab 
as follows:

Subjects who are randomized to placebo at Week 0 will receive 1 dose of ustekinumab 
~6 mg/kg IV plus placebo SC (to maintain the blind) at I-8. 

Subjects who are randomized to ustekinumab at Week 0 will receive 1 dose of ustekinumab 
90 mg SC plus placebo IV (to maintain the blind) at I-8. 
At Week 16 of the induction study, the subjects who are not in clinical response at I- 8 will be re-
evaluated for clinical response. Subjects who achieve clinical response at I-16 are eligible to 
enter the maintenance study. All subjects in the induction study who do not enter the 
maintenance study will have a safety follow-up visit approximately 20 weeks after their last 
administration of study agent
Maintenance Study
In the randomized-withdrawal maintenance study, all subjects enrolled will be responders to 
study agent administered in the induction study. The schema for the maintenance study is shown 
in Figure 2. 
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Figure 2:
Schema for the CNTO1275UCO3001 maintenance study
Subjects who are in clinical response to IV ustekinumab during induction will comprise the 
primary population in the maintenance study; this population will include the following:

Subjects who are randomized to receive ustekinumab at Week 0 of the induction study and 
are in clinical response at I-8. 

Subjects who are randomized to receive placebo at Week 0 of the induction study and are 
not in clinical response at I-8, but are in clinical response at I-16 after receiving an induction 
dose of IV ustekinumab (~6 mg/kg) at I-8.
Note that subjects who are delayed clinical responders to ustekinumab induction (i.e., the 
subjects who are randomized to ustekinumab at Week 0 of the induction study, not in clinical 
response at I- 8 but are in clinical response at I- 16 after receiving 1 dose of ustekinumab 90 mg 
SC at I-8) will not be included in the primary population.
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A target of 327 subjects who are in clinical response to IV ustekinumab induction will be 
randomized in a 1:1:1 ratio to 1 of 3 treatment groups at the maintenance Week 0/baseline (M-0) 
visit of the maintenance study: 

Placebo SC.

Ustekinumab 90 mg SC every 12 weeks (q12w).

Ustekinumab 90 mg SC q8w.
Eligible subjects will be allocated to a treatment group using a permuted block randomization 
with clinical remission status at maintenance baseline (yes/no), oral corticosteroid use at 
maintenance baseline (yes/no), and induction treatment (placebo IV [I-0]→ ustekinumab 
~6 mg/kg IV [I-8], ustekinumab 130 mg IV [I-0], or ustekinumab ~6 mg/kg IV [I-0]) as 
stratification variables. 
Additional subjects entering the maintenance study will include the following; these subjects will 
not be part of the primary population:

Subjects who are in clinical response to placebo IV induction will receive placebo SC. 

Subjects who are delayed responders to ustekinumab induction will receive ustekinumab 
90 mg SC q8w.
All subjects will receive their assigned dose of SC study agent at the M-0 visit. Thereafter, to 
maintain the blind, all subjects will receive study agent at all scheduled study agent 
administration visits. Subjects will be assessed for clinical flare at every visit and, if loss of 
response is confirmed (based on the Mayo score that includes the endoscopy subscore assigned 
by the local endoscopist), may be eligible for rescue medication. See the protocol for more 
details.
Concomitant medical therapy for UC must have been stable from the I-0 visit through the 
M-0 visit unless, in the judgment of the investigator, the therapy had to be discontinued or 
reduced in dose because of toxicity or medical necessity. Subjects who initiated or increased the 
dose of a UC-specific medication (or any restricted/prohibited medication) during the induction 
study are prohibited from entering the maintenance study.
With the exception of corticosteroids, which should be tapered, UC-specific medical therapies 
(i.e., oral 5-ASA compounds, or the immunomodulators 6-MP, AZA, or methotrexate [MTX]) 
must be maintained at stable doses through M-44 unless investigator judgment requires that the 
therapy be discontinued or the dose reduced because of toxicity or medical necessity, or unless 
there is a documented loss of response that makes the subject eligible for rescue medication. 
Corticosteroids will be tapered beginning at the M-0 visit for all subjects who enter the 
maintenance study. 
The primary endpoint of the maintenance study is clinical remission at Week 44. The major 
secondary endpoints are (presented in the order in which they will be tested):  maintenance of 
clinical response through Week 44; endoscopic healing at Week 44; clinical remission and not 
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receiving concomitant corticosteroids at Week 44; and maintenance of clinical remission through 
Week 44 among the subjects who had achieved clinical remission at maintenance baseline.
The primary database lock (DBL) will occur when all subjects in the maintenance study have 
either completed the M-44 visit or have terminated study participation before M-44. No interim 
analysis is planned during the maintenance study.
Long Term Extension
Subjects who complete the safety and efficacy evaluations at Week 44 and who may benefit 
from continued treatment, in the opinion of the investigator, will have the opportunity to 
participate in the long term extension (LTE). The LTE begins after the assessments listed for the 
M-44 visit (i.e., the last assessments in the maintenance study) have been completed and will 
continue through Week 220 or until the sponsor decides not to pursue an indication in UC, 
whichever occurs first. 
Subjects will continue to receive the same treatment regimen during the LTE that they were 
receiving at the end of the maintenance study (either placebo or ustekinumab 90 mg SC q8w or 
q12w), with the first dose in the LTE being administered at Week 48. The study blind will be 
maintained during the LTE until the last subject in the maintenance study has completed the 
M-44 visit evaluations and the Week 44 analyses have been completed. After the study is 
unblinded to the investigative sites, subjects receiving placebo will be terminated from study 
participation, and subjects receiving ustekinumab will continue to receive ustekinumab, but will 
have their study visits scheduled to coincide with their dose regimen (either q8w or q12w, as 
appropriate for their dose regimen).
During the LTE, all subjects will be assessed for worsening of disease activity based on the 
clinical judgment of the investigator. Subjects in the primary population whose UC disease 
activity worsens will be eligible for a dose adjustment as follows:

Placebo SC → ustekinumab 90 mg SC q8w

Ustekinumab 90 mg SC q12w → ustekinumab 90 mg SC q8w

Ustekinumab 90 mg SC q8w → continue on ustekinumab 90 mg SC q8w
The first visit at which a subject can be considered for a dose adjustment is at Week 56. Subjects 
will be allowed 1 dose adjustment during the LTE. The interactive web response system (IWRS) 
will ensure that SC ustekinumab is not administered more frequently than q8w.
Subjects who are not in the primary population (i.e., induction placebo responders, delayed 
ustekinumab responders) will not be eligible for a dose adjustment during the LTE.
Any subject who has not shown improvement in his or her UC disease activity by 16 weeks after 
worsening of their UC disease activity (as assessed by the investigator) will be discontinued from 
further study agent administration.
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During the LTE, all concomitant medications, including UC-specific medications (with the 
exception of the prohibited medications listed in Section 8.1.1.1.2 of the protocol), may be 
administered at the discretion of the investigator. 
Efficacy evaluations during the LTE will generally be based on the partial Mayo score, markers 
of inflammation (i.e. CRP, fecal lactoferrin and calprotectin), and corticosteroid use. Selected 
patient-reported outcomes (PRO) and health economics data will also be collected. All study 
evaluations to be performed during the LTE are listed in the Time and Events Schedule of the 
protocol.
The final DBL will occur when all subjects have either completed the M-220 visit or have 
terminated study participation before M-220. One or more additional DBLs may occur between 
Week 44 and Week 220 for publication purposes or for regulatory requirements.
Unless stated otherwise, the procedures in the following sections are all described in the 
context of the maintenance study, and the analysis time points are in reference to Week 0 of 
the maintenance study. For example, Week 44 of the endpoints refers to 44 weeks after 
Week 0 of the maintenance study, not 44 weeks after Week 0 of the induction study. 
Week X of the induction study will be denoted as I-X.
1.3.
Statistical Hypotheses for Trial Objectives
The primary endpoint is clinical remission at Week 44 among subjects with moderately to 
severely active UC who were responders to IV ustekinumab induction.  The null hypothesis to be 
tested is that there is no difference between ustekinumab maintenance therapy (90 mg SC q8w or 
90 mg SC q12w) and placebo in achieving clinical remission at Week 44.
1.4.
Randomization and Blinding
Randomization and Treatment Allocation
Treatment allocation of this study will be performed using a centralized IWRS. At Week 0 upon 
a subject’s entry into the maintenance study, subjects in the primary population (i.e., the subjects 
who were in clinical response to IV ustekinumab during the induction) will be randomized to 
1 of 3 treatment groups (placebo SC, ustekinumab 90 mg SC q8w, or ustekinumab 90 mg 
SC q12w) using a permuted block randomization with clinical remission status at maintenance 
baseline (yes/no), oral corticosteroid use at maintenance baseline (yes/no), and induction 
treatment (placebo IV [I-0]→ ustekinumab ~6 mg/kg IV [I-8], ustekinumab 130 mg IV [I-0], or 
ustekinumab ~6 mg/kg IV [I-0]) as stratification variables. Other subject populations will not be 
randomized, but will be assigned to treatment at Week 0 upon a subject’s entry into the 
maintenance study as described in Section 1.2. A computer-generated randomization schedule 
will be prepared under the supervision of the sponsor.
At each call to the IWRS for a treatment allocation, the IWRS will assign a treatment code that 
will dictate the treatment assignment and matching study agent kit for each subject. The 
requestor must use his or her own personal identification number when contacting the IWRS.
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The values of the stratification factors in the IWRS that are used for the Week 0 randomization 
for a subject will not be changed once the subject is randomized. Dose adjustment in the LTE is 
based on the status of worsening of UC disease activity assessed by the investigator. The status 
of worsening of UC disease activity cannot be changed once the subject has requested a dose 
adjustment.
Blinding
The sponsor will be blinded to maintenance treatment assignment until after the Week 44 
database lock has occurred. Treatment assignment blinding will be maintained for investigative 
sites, site monitors, and subjects participating in this protocol until the Week 44 analyses for the 
maintenance study have been completed. 
To maintain the study blind, the study agent container will have a label containing the study 
name, medication number, and reference number. A tear-off label is designed to be separated 
from the study agent container, and attached to the subject's source documents. The label will not 
identify the study agent in the container. The medication number will be entered in the case 
report form (CRF) when the drug is dispensed. The study agents will be identical in appearance 
and packaging.
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual subject. The date and reason for the unblinding will be documented in the appropriate 
section of the CRF and in the source document. The documentation received from the IWRS 
indicating the code break will be retained with the subject's source documents in a secure 
manner. Subjects who had their treatment assignment unblinded by the investigator will be 
discontinued from study agent.
Data that may potentially unblind the treatment assignment (i.e., study agent serum 
concentrations, antibodies to study agent, and treatment allocation) will be handled through the 
Secure Data Office to ensure that the integrity of the blind is maintained and the potential for 
bias is minimized. 
The postbaseline results of CRP, fecal lactoferrin, and fecal calprotectin tests performed by the 
central laboratory will be blinded to the investigative sites. If an investigative site requests these 
data, it will be provided to them after the Week 44 analyses for the maintenance study have been 
completed. 
Additionally, a given subject’s treatment assignment may be unblinded to the sponsor, the 
Independent Ethics Committee/Institutional Review Board (IEC/IRB), and site personnel to 
fulfill regulatory reporting requirements for serious unexpected associated adverse reactions 
(SUAs). 
A separate code-break procedure will be available for use by J&J Global Medical Safety group 
to allow for unblinding of individual subjects to comply with specific requests from regulatory or 
health authorities.
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An independent DMC will regularly review unblinded safety data. The same DMC will also 
review the interim analysis results from the induction study and form a recommendation to the 
sponsor per the pre-specified decision rules detailed in the Interim Analysis Plan. The committee 
and its statistical support group will have access to unblinded treatment information. They will 
not divulge any information to the Sponsor that may potentially unblind an individual subject’s 
treatment group.
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Visit Windows
Unless otherwise specified, actual scheduled visits will be used for over time summaries and 
listings with no visit windows applied.
2.2.
Baseline Measurements
Unless otherwise specified, the baseline measurement for each parameter is defined as the closest 
measurement taken prior to or on the same day as the Week 0 study agent administration in the 
maintenance study.
2.3.
Analysis Sets
2.3.1.
Efficacy Analysis Sets
Unless otherwise specified, all efficacy analyses will be based on the intent-to-treat (ITT) 
principle. Therefore, subjects will be analyzed according to the treatment group to which they 
were assigned regardless of the treatment they actually received.
The Primary Efficacy Analysis Set consists of all subjects randomized at Week 0 of this 
maintenance study, that is, subjects in clinical response to IV ustekinumab induction as 
determined by the IWRS (i.e., subjects who are in clinical response to IV ustekinumab induction 
at I-8, or subjects who are not in clinical response to IV placebo induction at I-8 but are in 
clinical response at I-16 after receiving an induction dose of IV ustekinumab at I-8). Some
prespecified efficacy analyses will also be conducted in the Non-randomized Analysis Set,
which includes:

Subjects in clinical response to placebo IV induction dosing at I-8.

Subjects who are delayed responders to ustekinumab induction.
2.3.2.
Safety Analysis Set
All subjects who receive at least 1 administration of study agent in this maintenance study will 
be included in the Safety Analysis Set, which includes subjects who are randomized and 
subjects who are not randomized. Some prespecified safety analyses will also be conducted in 
the Randomized Safety Analysis Set, which includes subjects in the Safety Analysis Set who 
are randomized at Week 0 of this maintenance study. Subjects will be analyzed according to the 
treatment group to which they were assigned regardless of the treatment they actually received. 
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2.3.3.
Pharmacokinetics Analysis Set
PK summaries will be provided for the PK Analysis Set (i.e., subjects who receive at least 
1 administration of study agent [either ustekinumab or placebo] in this maintenance study and
receive at least one administration of ustekinumab in the induction study). Some prespecified PK 
analyses will also be conducted in the Randomized PK Analysis Set, which includes subjects in 
the PK Analysis Set who are randomized at Week 0 of this maintenance study.  Subjects will be 
analyzed according to the treatment group to which they were assigned regardless of the 
treatment they actually received.
2.4.
Definition of Subgroups
The consistency of treatment effect for the primary endpoint will be evaluated for subgroups 
based on demographics and baseline UC clinical disease characteristics, UC-related concomitant 
medication usage, and UC-related medication history, all at Week 0 of the induction study, as 
well as maintenance stratification factors and UC clinical disease characteristics at Week 0 of the 
maintenance study, when the number of subjects within each level of the subgroup permits.
Demographics at Week 0 of the induction study

Gender (male, female)

Race (Caucasian, non-Caucasian)

Age (≤ median age, > median age) 

Weight (≤ 1st quartile, >1st quartile and ≤ 2nd quartile, >2nd quartile and ≤ 3rd quartile, 
>3rd quartile) 

Smoking status (nonsmoker, prior smoker, current smoker)

Region 

Asia: Japan, South Korea 

Eastern Europe: Belarus, Bulgaria, Czech Republic, Hungary, Poland, Romania, Russia, 
Serbia, Slovakia, Ukraine 

Rest of World: Australia, Austria, Belgium, Canada, Denmark, France, Germany, Israel,
Italy, Netherlands, New Zealand, United Kingdom, United States
Baseline UC clinical disease characteristics at Week 0 of the induction study

UC disease duration (≤ 5 years, > 5 years to ≤ 15 years, > 15 years)

Extent of disease (limited, extensive)

Severity of UC disease (moderate: 6≤ Mayo score ≤ 10, severe: Mayo score >10)

Extraintestinal manifestations (absent, present)

CRP (≤3 mg/L, >3 mg/L)

CRP (≤ median, > median)

CRP (≤10 mg/L, >10 mg/L)
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
Fecal calprotectin (≤250 mg/kg, >250 mg/kg)

Fecal lactoferrin (≤7.24 µg/g, >7.24 µg/g)
UC-related concomitant medications at Week 0 of the induction study

Oral 5-ASA compounds (receiving, not receiving)

Oral corticosteroids including budesonide and beclomethasone dipropionate (receiving, not 
receiving) 

6-MP/AZA/MTX (receiving, not receiving)

Oral corticosteroids and (6-MP/AZA/MTX) (receiving, not receiving)

Oral corticosteroids or (6-MP/AZA/MTX) (receiving, not receiving)
UC-related medication history at Week 0 of the induction study

Refractory or intolerant to 6-MP/AZA (yes, no)

Refractory, dependent or intolerant to oral or IV corticosteroids (yes, no)

Refractory, dependent, or intolerant to oral or IV corticosteroids, but not refractory or 
intolerant to 6-MP/AZA (yes, no)

Refractory, dependent or intolerant to oral or IV corticosteroids, and refractory or intolerant 
to 6-MP/AZA (yes, no)

Biologic failure status (yes, no)

Subjects with biologic failure

Primary nonresponse, secondary nonresponse, or intolerance to 
o
At least one anti-TNF (yes, no)
o
Anti-TNF only (yes, no)
o
Vedolizumab (yes, no)
o
Vedolizumab and at least one anti-TNF (yes, no)

For subjects with biologic failure to anti-TNF only
o
Primary nonresponse (yes, no)
o
Secondary nonresponse (yes, no)
o
Intolerance (yes, no)

Subjects without biologic failure (naïve, bio-experienced [but not documented failure])
Stratification variables for the maintenance study

Clinical remission status at maintenance baseline as determined by the IWRS (yes, no)

Induction treatment (placebo IV [I-0] → ustekinumab ~6 mg/kg IV [I-8], ustekinumab 
130 mg IV [I-0], ustekinumab ~6 mg/kg IV [I-0])

Oral corticosteroid use at maintenance baseline as recorded in the IWRS (yes, no)
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UC clinical disease characteristics at Week 0 of the maintenance study

Endoscopic healing status (yes, no)

CRP (≤3 mg/L, >3 mg/L)

CRP (≤ median, > median)

CRP (≤10 mg/L, >10 mg/L)

Fecal calprotectin (≤250 mg/kg, >250 mg/kg)

Fecal lactoferrin (≤7.24 µg/g, >7.24 µg/g)
In addition, the consistency of treatment effect for the major secondary endpoints will be 
evaluated for the following subgroups, when the number of subjects within each level of the 
subgroup permits.
CRP and Fecal Biomarkers (calprotecin and lactoferrin), both at Week 0 of the induction 
study and at Week 0 of the maintenance study

CRP (≤3 mg/L, >3 mg/L)

CRP (≤ median, > median)

CRP (≤10 mg/L, >10 mg/L)

Fecal calprotectin (≤250 mg/kg, >250 mg/kg)

Fecal lactoferrin (≤7.24 µg/g, >7.24 µg/g)
Induction baseline Weight (≤ 1st quartile, >1st quartile and ≤ 2nd quartile, >2nd quartile and 
≤3rd quartile, >3rd quartile)
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
No interim analysis is planned for the maintenance study. 
A DMC will be established to monitor data on an ongoing basis to ensure the continuing safety 
of the subjects enrolled in this protocol. As mentioned in Section 1.4, the committee will meet 
periodically to review unblinded safety data. The same DMC will also review the interim 
analysis results from the induction study and form a recommendation to the sponsor per the pre-
specified decision rules detailed in the Interim Analysis Plan. The DMC roles and 
responsibilities, and the general procedures of the DMC review are defined and documented in 
the DMC Charter. 
4.
SUBJECT INFORMATION
Descriptive statistics (mean, standard deviation, median, interquartile range, minimum and 
maximum) will be provided for continuous variables. Counts and percentages will be provided 
for categorical variables. No formal statistical analyses for treatment comparisons will be 
performed. 
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4.1.
Demographics and Baseline Characteristics
To assess the comparability of subjects, the following data will be summarized by treatment 
group for all subjects enrolled in the maintenance study:

Demographic data at I-0 (i.e., age, gender [male, female], race [White, Black or African 
American, Asian, American Indian or Alaska Native, Native Hawaiian or Other Pacific 
Islander, Other], weight, height, and region [Asia, Eastern Europe, Rest of World])

Disease characteristics at I-0 (i.e., UC disease duration, extent of disease [limited, 
extensive], Mayo score, severity of UC disease [moderate: 6≤ Mayo score ≤10, severe: 
Mayo score >10], extraintestinal manifestations [absent, present], CRP, fecal calprotectin,
fecal lactoferrin, abnormal CRP (>3 mg/L), abnormal fecal calprotectin (>250 mg/kg), 
abnormal fecal lactoferrin (>7.24 µg/g)

Smoking status at I-0 (nonsmoker, prior smoker, current smoker)

Past medical history and current diagnoses at I-0

Disease characteristics at M-0 (i.e., Mayo score, CRP, abnormal CRP [>3 mg/L], fecal 
calprotectin, abnormal fecal calprotectin (>250 mg/kg), fecal lactoferrin, abnormal fecal 
lactoferrin (>7.24 µg/g), clinical remission status [yes, no], endoscopic healing [yes, no])
4.2.
Prior and Concomitant Medications
Summaries of UC medication history (i.e., subjects who took medications for UC and their 
length of exposure prior to I-0), UC-related concomitant medications at I-0, UC-related non-
biologic medication history at I-0 (i.e., history of response to or tolerance of 6-MP/AZA and 
history of response to, dependence or tolerance of corticosteroids) and UC-related biologic 
medication history at I-0 will be provided for all subjects enrolled in the maintenance study.   
4.3.
Disposition Information
Subjects who discontinued study agent prior to Week 44 along with the reasons for 
discontinuation, and subjects who terminated study participation prior to Week 44 along with the 
reasons for termination, will be summarized by treatment group for all subjects enrolled in the 
maintenance study. In addition, listings of the subjects who discontinued study agent and the 
subjects who terminated study participation prior to Week 44 will be provided.
4.4.
Treatment Compliance
The number of subjects receiving each scheduled administration through Week 44 will be 
summarized for all subjects enrolled in the maintenance study. In addition, a listing of subjects 
who were assigned treatment but were never treated and a listing of subjects who were unblinded 
prior to Week 44 during the maintenance study will be provided.
4.5.
Extent of Exposure
The cumulative dose of ustekinumab received will be summarized by treatment group through 
Week 44 based on the Safety Analysis Set. In addition, the number of administrations of study 
agent and the average duration of follow-up (weeks) will be summarized through Week 44 by 
treatment group for all subjects in the Safety Analysis Set as part of the safety tables.
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4.6.
Protocol Deviations
Subjects with a major protocol deviation through Week 44 will be summarized for all subjects 
enrolled in the maintenance study. In addition, subjects who did not meet study entry criteria will 
be further summarized by category (UC disease criteria, Medication criteria, Laboratory criteria, 
Medical history criteria and other). A listing of subjects who have a major protocol deviation and 
a more detailed listing of subjects who do not meet study entry criteria will be provided. 
5.
EFFICACY
Descriptive statistics (e.g., mean, median, SD, IQ range, minimum, and maximum) will be used
to summarize continuous variables. Counts and percentages will be used to summarize 
categorical variables. Graphical data displays (e.g., line plots) may also be used to summarize the 
data.
Analyses suitable for categorical data (e.g., chi-square tests, Cochran-Mantel-Haenszel chi-
square tests, or logistic regression, as appropriate) will be used to compare the proportions of 
subjects achieving selected endpoints (e.g., clinical remission). In cases of rare events, Fisher’s 
exact test will be used for treatment comparisons. Continuous response parameters will be 
compared using an analysis of variance (ANOVA) or covariance (ANCOVA), unless otherwise 
specified. If the normality assumption is in question, an ANOVA or ANCOVA on the van der 
Waerden normal scores will be used.
Nominal p-values will be presented for all analyses unless specified otherwise. 
5.1.
Analysis Specifications
5.1.1.
Data Handling Rules
5.1.1.1.
Treatment Failure
Subjects who have any of the following events are considered to be a treatment failure from the 
time of event onward:

An ostomy or colectomy (partial or total)

Discontinue study agent due to lack of therapeutic effect or due to an AE of worsening of 
UC

Use a rescue medication after clinical flare as defined in protocol Section 3.1.2.1

A prohibited change in UC medication:

Initiation of restricted or prohibited medications or therapies as defined in the protocol 
(see protocol Section 8.1.1.1), except for antibiotics used to treat UC, TPN, and 
apheresis. 

Increase in the dose of oral corticosteroids (excluding budesonide and beclomethasone 
dipropionate) > 5 mg/day (prednisone equivalent) above the baseline dose (Week 0 of 
the maintenance study) for more than 7 days after the Week 32 visit (i.e., approximately 
90 days prior to Week 44) due to worsening of disease. This includes initiation of oral 
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corticosteroids due to worsening of disease that lasts for more than 7 days after the 
Week 32 visit for subjects who were not receiving oral corticosteroids at Week 0 of the 
maintenance study.

Increase in the dose of oral budesonide > 3 mg/day above the baseline dose (Week 0 of 
the maintenance study) for more than 7 days after the Week 32 visit (i.e., approximately 
90 days prior to Week 44) due to worsening of disease. This includes initiation of oral 
budesonide due to worsening of disease that lasts for more than 7 days after the 
Week 32 visit for subjects who were not receiving oral budesonide at Week 0 of the 
maintenance study.

Increase in the dose of oral beclomethasone dipropionate > 5 mg/day above the baseline 
dose (Week 0 of the maintenance study) for more than 7 days after the Week 32 visit 
(i.e., approximately 90 days prior to Week 44) due to worsening of disease. This 
includes initiation of oral beclomethasone dipropionate due to worsening of disease that 
lasts for more than 7 days after the Week 32 visit for subjects who were not receiving 
oral beclomethasone dipropionate at Week 0 of the maintenance study.

Increase in the dose of oral corticosteroids (excluding budesonide and beclomethasone 
dipropionate) > 5 mg/day (prednisone equivalent) above the baseline dose (Week 0 of 
the maintenance study) for more than 28 days after the Week 32 visit (i.e., 
approximately 90 days prior to Week 44) due to reasons other than worsening of 
disease. This includes initiation of oral corticosteroids due to reasons other than 
worsening of disease that lasts for more than 28 days after the Week 32 visit for 
subjects who were not receiving oral corticosteroids at Week 0 of the maintenance 
study.

Increase in the dose of oral budesonide > 3 mg/day (prednisone equivalent) above the 
baseline dose (Week 0 of the maintenance study) for more than 28 days after the 
Week 32 visit (i.e., approximately 90 days prior to Week 44) due to reasons other than 
worsening of disease. This includes initiation of oral budesonide due to reasons other 
than worsening of disease that lasts for more than 28 days after the Week 32 visit for 
subjects who were not receiving oral budesonide at Week 0 of the maintenance study.

Increase in the dose of oral beclomethasone > 5 mg/day (prednisone equivalent) above 
the baseline dose (Week 0 of the maintenance study) for more than 28 days after the 
Week 32 visit (i.e., approximately 90 days prior to Week 44) due to reasons other than 
worsening of disease. This includes initiation of oral beclomethasone dipropionate due 
to reasons other than worsening of disease that lasts for more than 28 days after the 
Week 32 visit for subjects who were not receiving oral beclomethasone dipropionate at 
Week 0 of the maintenance study.

Any switch among oral budesonide, oral beclomethasone dipropionate or other oral 
corticosteroids (excluding prednisone equivalent changes) due to worsening of disease.

Initiation of oral 5-ASA compounds due to worsening of disease.

Increase above baseline in the dosage of oral 5-ASA compounds due to worsening of 
disease.

Change from one oral 5-ASA compound to another 5-ASA compound due to worsening 
of disease.
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
Initiation of 6-MP/AZA/MTX due to worsening of disease.

Increase above baseline in the dosage of 6-MP/AZA/MTX due to worsening of disease.

Any switch between 6-MP/AZA and MTX due to worsening of disease.
Following a clinical flare, any initiation or increase in the dose of 6-MP/AZA/MTX, oral 
budesonide > 3 mg/day, oral beclomethasone dipropionate > 5 mg/day, or oral corticosteroids 
(excluding budesonide and beclomethasone dipropionate) > 5 mg/day (prednisone equivalent) 
above the dose received at maintenance baseline was considered a rescue medication.
For dichotomous endpoints, subjects who have a treatment failure are considered as not 
achieving the respective endpoints. For continuous endpoints, subjects who have a treatment 
failure have their induction baseline values carried forward from the time of the treatment failure 
onwards. 
5.1.1.2.
Missing Data
For subjects with missing data, unless otherwise specified, the last observation will be carried 
forward for continuous endpoints, with the exception of the Mayo and partial Mayo scores 
(defined in Section 5.2.1.1), where the last available Mayo subscores will be carried forward. For 
dichotomous endpoints, subjects with missing data will be considered as not achieving the 
respective endpoints. More detailed descriptions of missing data for the Mayo score, IBDQ and 
SF-36 will be provided later in the document. Note that treatment failure rules override 
missing data rules. This means that if a subject has an event of treatment failure, induction 
baseline values will be assigned from the point of treatment failure onward for continuous 
endpoints, and subjects will be considered as not achieving the respective endpoints for 
dichotomous endpoints, regardless of whether the data were observed or missing.
5.2.
Primary Efficacy Endpoint
The primary endpoint is clinical remission at Week 44, which is derived from the Mayo score.  
5.2.1.
Definitions
5.2.1.1.
Mayo Score
The Mayo score (Schroeder et al, 1987)8 was developed from the criteria of Truelove and Witts 
(1955)10 for mild, moderate, and severe UC; and from the criteria of Baron et al (1964)1 for 
grading the mucosal appearance.  The Mayo score consists of the following 4 subscores:

Stool frequency

Rectal bleeding

Findings of endoscopy

Physician’s global assessment (PGA)
Each subscore is rated on a scale from 0 to 3, indicating normal to severe activity, as defined in 
Attachment 1.
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The Mayo score is calculated as the sum of the 4 subscores of stool frequency, rectal bleeding, 
physician’s global assessment, and the findings of endoscopy.  Thus, the Mayo score may take 
on values in the range of 0 to 12.  The partial Mayo score, which is the Mayo score without 
taking into account the findings of endoscopy, is calculated as the sum of the stool frequency, 
rectal bleeding, and physician’s global assessment subscores, and may take on values from 0 to 
9. The modified Mayo score, which is the Mayo score without the PGA subscore, is calculated 
as the sum of the stool frequency, rectal bleeding, and endoscopy subscores, and may take on 
values from 0 to 9.  
The Mayo score can be calculated when at least 1 of the 4 subscores is available. If 1 or more of 
the 4 Mayo subscores is missing at a specific visit, but not all 4 subscores are missing, the last 
available value for each missing subscore will be carried forward to compute a full Mayo score 
(where the full Mayo score is scheduled to be collected). When the Mayo score cannot be 
calculated (i.e., all 4 subscores are missing), then the Mayo score is considered to be missing. 
Similarly, if 1 or more of the following 3 Mayo subscores (stool frequency subscore, rectal 
bleeding subscore, and PGA subscore) is missing at a specific visit, but not all 3 subscores are 
missing, the last available value for each missing subscore will be carried forward to compute a 
partial Mayo score. If all 3 subscores are missing at a specific visit, the partial Mayo score will 
be considered missing at that visit. The modified Mayo score (the sum of stool frequency 
subscore, rectal bleeding subscore, and endoscopy subscore) will be calculated in a similar 
fashion.
Stool Frequency and Rectal Bleeding Subscores
The eCRFs capture seven days of rectal bleeding data and the number of stools per day prior to 
each visit at which the partial Mayo score or Mayo score is collected. Sites are instructed to 
check the boxes next to the 3 days for which are used to calculate stool frequency and rectal 
bleeding subscores.  Absolute stool number is the average of the daily stool number over the 
three days, and rectal bleeding subscores is calculated using the average rectal bleeding number 
for the three days based on the criteria in Attachment 1. At the screening visit, each person 
indicates the number of stools he/she passed in a 24-hour period when in remission or before 
his/her UC diagnosis. The stool frequency subscore will be calculated based on the criteria in 
Attachment 1 by subtracting the number of stools when in remission or prior to UC from the 
absolute stool number.
Sites are directed to use the most recent 3 consecutive days within the week prior to the visit and 
are directed to exclude the following:

The day medications were taken for constipation, diarrhea or irregularity

The day of a procedure or preparation for procedure (e.g. enema, other laxatives, or clear 
liquid diet) that would affect stool frequency and/or blood content of the stool

The 48 hours after the use of antimotility agents (i.e. diphenoxylate hydrochloride with 
atropine sulfate or loperamide)

The 48 hours immediately following a colonoscopy
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If three consecutive days are not available, the sites are instructed to choose two consecutive 
days and the closest nonconsecutive day. If two consecutive days are not available, then three 
nonconsecutive days closest to the visit should be chosen. If 3 days (within the week prior to the 
indicated visit) that meet the criteria defined above are not available, then the absolute stool 
number, stool frequency subscore and rectal bleeding subscore cannot be calculated and will be 
missing in the eCRF.
Endoscopy Subscore
The endoscopic findings will be based on the criteria of the Mayo endoscopy subscore described 
in Attachment 1. The endoscopic subscore will be assessed by the investigator (i.e., local 
endoscopist) during the endoscopy procedure and by a central reader reviewing a video of the 
endoscopy. The central readers will be blinded to the local endoscopist subscores, treatment 
assignment, and study visit (except for the initial or the final endoscopy videos when the central 
readers know that these videos are or are not from the screening visit). 
If the local endoscopist and the central reader agree on the endoscopic subscore, the agreed score 
will be the final reported endoscopic subscore.  If there is a discrepancy between the local 
endoscopist and the central reader subscores, the video endoscopy will be submitted to a second 
central reader designated for adjudication. The adjudicator will be blinded to the scores of the 
local and first central reader. From the three Mayo endoscopic subscores, the score with which 
two readers agree will be reported as the final Mayo endoscopic subscore. In the unlikely event 
that no two readers agree on the Mayo endoscopic subscore, the median score of the three 
completed reads (i.e., local read, central read #1 and central read #2 designated for adjudication) 
will be chosen as the final reported endoscopic subscore. 
The final reported endoscopic subscore at screening will be used to determine eligibility (i.e., 
Mayo endoscopy subscore ≥2) and to calculate the baseline Mayo score. Further details 
regarding video acquisition, standardization, readings, and data transfer are provided in the 
Imaging Charter.
Unless otherwise specified, the analysis of endpoints related to the endoscopy subscore, 
including the Mayo score, will be based on the final reported endoscopic subscore. If the 
final reported endoscopic subscore is not available, the corresponding central endoscopy score 
(central read #1) will be used, if available. If the central endoscopy score (central read #1) is also 
missing, then the local endoscopy score will be used, if available. If the local endoscopy score is 
also not available, then the endoscopy subscore for the analysis will be left missing. 
The central reader will perform a friability assessment for each endoscopy (sigmoidoscopy or 
colonoscopy) received by providing a response to the following question: “Is hemorrhage 
detected with incidental trauma caused by the endoscopic procedure?” If friability is present, the 
central reader will also provide a confidence level (High or Low) when evaluating friability.
Further details are provided in the Imaging Charter.
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Physician’s Global Assessment Subscore
The physician’s global assessment acknowledges the 3 other Mayo subscores, the patient’s recall 
of abdominal discomfort and general sense of well-being, and other observations, such as 
physical findings and the patient’s performance status.
5.2.1.2.
Clinical Remission
The definition of the primary endpoint of clinical remission will be different for countries outside 
the United States and for the United States. Each definition of clinical remission will be applied 
to all subjects in the efficacy analysis populations.
The global definition of clinical remission is (for countries outside the United States): A Mayo 
score ≤2 points, with no individual subscore >1. In addition to the clinical remission status based 
on the Mayo score, treatment failure rules will be applied to determine the final clinical 
remission status for a subject. Subjects who have a treatment failure (see Section 5.1.1.1) prior to 
Week 44 will be considered not to be in clinical remission at Week 44, regardless of the actual 
computation of clinical remission based on the Mayo score. Subjects who have all 4 Mayo 
subscores missing at Week 44 will be considered not to be in clinical remission. 
The US-specific definition of clinical remission is: An absolute stool number ≤3, a Mayo rectal
bleeding subscore of 0, and a Mayo endoscopy subscore of 0 or 1. The Absolute stool number as 
defined in Section 5.2.1.1 is the average of the daily stool number over the three days.  Subjects 
who have a treatment failure (see Section 5.1.1.1) prior to Week 44 will be considered not to be 
in clinical remission regardless of the actual computation of clinical remission based on the 
Mayo score. Subjects who are missing all three Mayo components pertaining to the primary 
endpoint (i.e., the absolute stool number, rectal bleeding subscore, and Mayo endoscopy 
subscore) at Week 44 will be considered not to be in clinical remission.
5.2.2.
Analysis Methods
The primary analysis will be based on the Primary Efficacy Analysis Set.  
The proportions of subjects in clinical remission will be compared between each ustekinumab 
treatment group and the placebo group using a Cochran-Mantel-Haenszel (CMH) chi-square test 
stratified by clinical remission status at baseline (yes/no as determined by the IWRS) and 
induction treatment (placebo IV [I-0] → ustekinumab ~6 mg/kg IV [I-8], ustekinumab 130 mg 
IV [I-0], or ustekinumab ~6 mg/kg IV [I-0]).  Summaries of the proportion of subjects in clinical 
remission by treatment group, the adjusted treatment difference (with Cochran-Mantel-Haenszel 
weight) between each ustekinumab treatment group and the placebo group, as well as the 
associated 95% confidence interval, will be provided.
The multiple testing procedure to control the Type 1 error will be different for the United States 
and the countries outside the United States, as described below.
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Type I error control in countries outside the United States (global testing procedure): A 
fixed-sequence testing procedure will be used to control the overall Type I error rate at the 
0.05 level for the primary endpoint.  Specifically, the high maintenance dose group 
(i.e., ustekinumab 90 mg SC q8w) will be considered significant if its p-value is < 0.05. The low 
maintenance dose group (ustekinumab 90 mg SC q12w) will be significant if the p-value for both 
high and low maintenance dose groups are < 0.05. The study will be considered positive if the 
test involving the high maintenance dose group (ustekinumab 90 mg SC q8w) shows a 
statistically significant difference versus placebo for the primary endpoint of clinical remission at 
Week 44, regardless of the result of the test for the low maintenance dose (ustekinumab 90 mg 
SC q12w).
Type I error control in the United States (US-specific testing procedure): A fixed-sequence 
testing procedure will be employed for the United States to strongly control the overall Type 1 
error rate at the 0.05 level across the primary and all 4 major secondary endpoints and across the 
2 ustekinumab doses, starting with the high maintenance dose group (ustekinumab 90 mg SC 
q8w) of the primary endpoint. The exact testing procedure is detailed in Section 5.3.2. The study 
will be considered positive if the test involving the high maintenance dose group (ustekinumab 
90 mg SC q8w) is positive for clinical remission at Week 44.
5.2.3.
Sample Size Justification
The major efficacy analyses in the maintenance study will be based on the primary population, 
i.e., subjects who were in clinical response to IV ustekinumab induction. Unless otherwise stated, 
the sample size/power calculations in this section refer to this population.
For both global and US-specific testing procedures, a fixed-sequence testing procedure, starting 
with the high dose group (q8w), will be used to control the overall Type I error rate at the 
0.05 level (2-sided). Therefore, sample size/power calculations were based on the chi-square test 
to detect a significant difference between subjects receiving SC ustekinumab 90 mg q8w and 
those receiving placebo. 
The definition of the primary endpoint of clinical remission will be different for countries outside 
the United States and for the United States, as described in Section 5.2.1.2.
The treatment effect for the global definition of the primary endpoint of clinical remission at 
Week 44 in the maintenance study, was based on maintenance data from similarly designed 
studies of the anti-TNFα golimumab and of vedolizumab.7,3 In the golimumab UC maintenance 
study, the proportions of subjects in clinical remission (based on the global definition) at 
Week 54 (among subjects in clinical response to golimumab induction) were 34% and 22% in 
the 100 mg group and the placebo group, respectively. In the vedolizumab UC study, the 
proportions of subjects in clinical remission (based on the global definition) at Week 52 (among 
subjects in clinical response at Week 6) were 42% and 16% in the vedolizumab q8w group and 
the placebo group, respectively. For the CNTO1275UCO3001 maintenance study, it was 
assumed that clinical remission rates (based on the global definition) at Week 44 were 40% and 
20%, respectively, for the ustekinumab 90 mg SC q8w and placebo groups. The clinical 
remission rates at Week 44 based on the US definition are also assumed to be 40% and 20%, 
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respectively, for the ustekinumab 90 mg SC q8w and placebo groups based on data from the 
golimumab UC maintenance study (C0524T18).
Assuming a 20% clinical remission rate (for both global and US definitions) in the placebo group 
and 40% in the SC ustekinumab 90 mg q8w group, 109 subjects in each treatment group 
(327 subjects in total) will provide statistical power of 90% at a significance level of 0.05 
(2-sided). Table 1 shows the power for detecting a treatment difference between the SC 
ustekinumab 90 mg q8w and the placebo group based on different proportions of subjects in 
clinical remission (for both the global and US definitions) at Week 44 with a fixed sample size 
of 327. 
Table 1:
Power for detecting a treatment effect based on different proportions of subjects in clinical 
remission (both global and US definitions) at Week 44 with a fixed sample size of 327 subjects 
(109 in each treatment group)
Proportion of Subjects in Clinical Remission at Week 44 (%)
Powera (%)
Placebo
Ustekinumab
20
45
98
42
94
40
90
37
80
35
70
a: Based on testing the ustekinumab 90 mg SC q8w group versus placebo at α=0.05 (2-sided).
Table 2 shows the power for detecting a treatment difference between the ustekinumab 90 mg 
SC q8w and the placebo group for each of the major secondary endpoints with 327 subjects in 
the primary population.  The assumptions about the proportion of subjects achieving each major 
secondary endpoint have been based on data from the golimumab7 and vedolizumab3
maintenance studies in subjects with moderately to severely active UC. 
Table 2:
Power for detecting a treatment effect for each of the major secondary endpoints with 327 
subjects in the primary population (109 in each treatment group)
Major secondary endpoints
Proportion of subjects achieving 
the endpoint
Powera (%)
Placebo
Ustekinumab
Maintenance of clinical response through Week 44
25
50
97
Endoscopic healing at Week 44
25
45
88
Clinical 
remission 
and 
not 
receiving 
concomitant 
corticosteroids at Week 44
15
30
76
Maintenance of clinical remission through Week 44 among 
the subjects who had achieved clinical remission at 
maintenance baseline (both global and US definitions) b
25
50
65
a: Based on testing the SC ustekinumab 90 mg q8w group versus placebo at α=0.05 (2-sided).
b: It is estimated that about 37% of subjects in the primary population (40 subjects per treatment group) will be in clinical
remission at Week 0 of maintenance.
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The number of subjects in the primary analysis population of the maintenance study will depend 
on the number of subjects from the following 2 groups of the induction study:  1) subjects in 
clinical response to IV ustekinumab induction at Week 8 of the induction study (Group A), and 
2) subjects who were not in clinical response to IV placebo induction at Week 8 of the induction 
study but were in clinical response at induction Week 16 after receiving an induction dose of 
IV ustekinumab at Week 8 (Group B). If the average clinical response rate to IV ustekinumab 
induction is 45%, 317 subjects in each induction treatment group (for a total of 951subjects) will 
result in about 328 subjects in the primary population of the maintenance study, assuming 
15% attrition from the induction study to the maintenance study. However, the average clinical 
response rate to IV ustekinumab induction could range from 40% to 50% and attrition from the 
induction study to the maintenance study could range from 10% to 15%. With 317 subjects in 
each induction treatment group, the number of subjects in the primary population of the 
maintenance study could range from 290 to 385 (Table 3). 
Table 3:
Projected number of subjects in the primary population of the maintenance study with a sample 
size of 951 subjects (317 per treatment group) in the induction study
Attrition 
From 
Induction Study to 
Maintenance Study
Clinical 
Response 
Rate 
to 
IV 
Ustekinumab 
Induction
Subjects in Group A 
Entering Maintenance
Subjects 
in 
Group B 
Entering 
Maintenancea
Number of Subjects 
in 
Primary 
Population 
of 
Maintenance
15%
40%
216
75
291
45%
243
85
328
50%
269
94
363
10%
40%
228
80
308
45%
257
90
347
50%
285
100
385
Group A=Subjects in clinical response to IV ustekinumab induction at induction Week 8; Group B=Subjects not in clinical 
response to IV placebo induction at induction Week 8 but in clinical response at induction Week 16 after receiving an induction 
dose of IV ustekinumab at Week 8.
a: The proportion of subjects not in clinical response to intravenous placebo induction at Week 8 of the induction study is 
assumed to be 70%.
5.2.4.
Subgroup Analyses
The consistency of treatment effect for the primary endpoint will be evaluated for the subgroups 
defined in Section 2.4.  For each of these subgroups, the odds ratio of each ustekinumab dose 
group vs placebo and the associated 95% confidence interval will be provided.  The odds ratios 
and confidence intervals will be provided based on the logistic regression model that includes 
factors for treatment group, clinical remission status at baseline and induction treatment (for the 
subgroup analyses based on clinical remission status at baseline or induction treatment factor, the 
corresponding factor will not be included in the model).
Subgroup analyses will also be performed for Japanese subjects. These analyses will be included 
in a separate report to support the submission in Japan.
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5.2.5.
Sensitivity Analysis
To examine the robustness of the primary analysis, sensitivity analyses will be conducted for the 
primary endpoint of clinical remission (for both global and US-specific definitions) at Week 44
based on observed case, worst case, and multiple imputation method as described below.
1.
Sensitivity Analysis 1 (Observed case):  exclude subjects with missing Mayo data at 
Week 44 and have not had an event of treatment failure prior to Week 44. 

For the global definition, subjects with missing data are those who are missing all four 
Mayo subscores.

For the US-specific definition, subjects with missing data are those who are missing all 
three Mayo components pertaining to the primary endpoint (i.e., the average stool 
number, rectal bleeding subscore, and Mayo endoscopy subscore).
2.
Sensitivity Analysis 2 (nonresponder if any missing subscore): subjects with missing data 
for any of the Mayo components pertaining to the primary endpoint (i.e., the four Mayo 
subscores for the global definition and the average stool number, Mayo rectal bleeding 
subscore, and Mayo endoscopy subscore for the US-specific definition) at Week 44 are 
considered not to be in clinical remission.
3.
Sensitivity Analysis 3 (Multiple imputation): 
1)
Any missing Mayo components pertaining to the primary endpoint at Week 44 will be 
imputed 5 times to generate 5 complete data sets using the Markov chain Monte Carlo 
method, assuming missing at random (MAR) and a multivariate normal distribution.
The following variables will be included in the imputation model: Mayo subscores at 
Week 0 of an induction study and at Week 0 and Week 44 of the maintenance study, 
induction dose factor and the maintenance treatment group. 
2)
Before the multiple imputation method is applied, the Mayo data after treatment failure 
will be set to missing. For each multiple-imputed data set, each subject’s clinical 
remission status at Week 44 will be calculated.  
3)
Each of the 5 resulting data sets will be analyzed using a logistic regression model with 
treatment group, baseline Mayo score (for global definition) or baseline modified Mayo 
score (for US-specific definition), and induction treatment as covariates. The modified 
Mayo score was used as the baseline disease activity measure for the US-specific 
definition of clinical remission as it contains the same Mayo components as those for 
the US-specific definition of clinical remission
4)
The results from the 5 data sets will be combined to produce inferential results.
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4.
Sensitivity Analysis 4 (Worst case): subjects receiving placebo who have a missing Mayo 
score at Week 44 and have not had an event of treatment failure prior to Week 44 (as 
defined in Sensitivity Analysis 1) will be considered to be in clinical remission, and subjects 
receiving ustekinumab who have a missing Mayo score at Week 44 will be considered not to 
be in clinical remission.
In addition, the following sensitivity analyses will be performed:
5.
Sensitivity Analysis 5 (“modified ITT” analysis): excludes subjects who are randomized but 
not treated.  
6.
Sensitivity analysis 6 (Per-Protocol analysis): Excludes  subjects with at least 1 of the 
following deviations that might affect efficacy: 1) subjects who are found to have Crohn's 
disease instead of UC, 2) subjects who are randomized, but do not receive study agent,  3) 
subjects who are a treatment failure in the induction study, 4) subjects who are  excluded in 
the Per-Protocol analysis in the induction study, 5) subjects who are randomized to the 
placebo group at Week 0 but receive a  ustekinumab injection at any administration visit 
through Week 44 or subjects who are randomized to one of the ustekinumab groups at 
Week 0 but receive only placebo through Week 44 , 6) subjects who are not in clinical 
response on entry into the maintenance study based on the final reported endoscopy score 
and the eCRF Mayo score data, or have other deviations that will be identified and 
documented prior to unblinding. 
7.
Sensitivity analysis 7 (logistic regression): The primary endpoint will be analyzed using a 
logistic regression model. 
1)
For the global definition, the primary endpoint will be analyzed based on a logistic 
regression model with maintenance baseline Mayo score, induction treatment, and 
maintenance treatment group as covariates.
2)
For the US-specific definition, the primary endpoint will be analyzed based on a logistic 
regression model with maintenance baseline modified Mayo score, induction treatment, 
and maintenance treatment group as covariates.
8.
Sensitivity Analysis 8 (clinical remission based on local endoscopy subscores): the primary 
analysis will be repeated with clinical remission derived based on local endoscopy 
subscores, instead of the final reported endoscopic subscores.
The following sensitivity analyses will be performed for the US-specific definition of clinical 
remission:
9.
Sensitivity Analysis 9 (nonresponder if friability present on endoscopy): subjects with 
friability at Week 44 are considered not to have achieved clinical remission. Note that 
subjects with missing friability or a friability that cannot be determined will be considered 
not to have friability.
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10. Sensitivity Analysis 10 (Tipping Point Analysis): the adjusted treatment difference (with
Cochran-Mantel-Haenszel weight) in proportion of subjects in clinical remission at Week 44
between each ustekinumab group and placebo group and the corresponding p-values will be 
provided for possible scenarios of remission status for subjects with missing data (0%-100% 
of subjects in clinical remission, in increments of at least 10%, for the placebo and the 
ustekinumab group).
The same treatment failure rules as were used in the primary analysis will be applied. For 
Sensitivity Analyses 5 through 9, the same missing data rules as are used in the primary analysis 
will also be applied. Note that treatment failure rules override the missing data rules. Subjects 
who have a treatment failure prior to Week 44 are considered not to be in clinical remission at 
Week 44, regardless of the observed or missing data.
5.3.
Major Secondary Endpoints
The following are the major secondary endpoints, presented in the order in which they will be 
tested:  
1.
Maintenance of clinical response through Week 44; 
2.
Endoscopic healing at Week 44; 
3.
Clinical remission and not receiving concomitant corticosteroids (corticosteroid-free clinical 
remission) at Week 44;
4.
Maintenance of clinical remission through Week 44 among the subjects who had achieved 
clinical remission at maintenance baseline
5.3.1.
Definitions

Clinical response is defined as a decrease from induction baseline in the Mayo score by 
≥30% and ≥3 points, with either a decrease from induction baseline in the rectal bleeding 
subscore ≥1 or a rectal bleeding subscore = 0 or 1.

Endoscopic healing (i.e., improvement in the endoscopic appearance of the mucosa) is 
defined as endoscopy subscore of the Mayo score = 0 or 1.

Clinical remission is defined in Section 5.2.1.2. Two separate definitions for clinical 
remission will be applied to accommodate the global and US-preferred definitions of clinical 
remission. Note that, for the United States, for the fourth major secondary endpoint 
(maintenance of clinical remission through Week 44 among the subjects who had achieved 
clinical remission at maintenance baseline), the US-specific definition of clinical remission 
should also be used to determine whether or not a subject had achieved clinical remission at 
maintenance baseline.  
Treatment failure and missing data rules will be applied to each of these major secondary 
endpoints. Subjects who have a treatment failure prior to the M-44 visit will be considered not to 
have achieved the respective endpoints. At Week 44, subjects who have a missing Mayo 
endoscopy subscore will be considered not to have endoscopic healing; subjects who have all 
4 Mayo subscores missing will be considered not to be in clinical response or clinical remission 
(for the global definition of remission). For the US-specific definition of clinical remission, 
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subjects who are missing the average stool number, rectal bleeding subscore, and Mayo 
endoscopy subscore at Week 44 will be considered not to be in clinical remission. For subjects 
without corticosteroid information at Week 44, the last available corticosteroid dose will be 
carried forward to Week 44.
5.3.2.
Analysis Methods
The major secondary endpoint analyses will be based on the Primary Efficacy Analysis Set. 
Except for the fourth major secondary endpoint of maintenance of clinical remission, analyses of 
major secondary endpoints will be conducted using a CMH chi-square test stratified by clinical 
remission status at maintenance baseline (yes/no as determined by the IWRS) and induction 
treatment. For the fourth major secondary endpoint, a CMH chi-square test stratified by 
induction treatment will be used. Summaries of the proportion of subjects by treatment group, 
the adjusted treatment difference (with Cochran-Mantel-Haenszel weight) between each 
ustekinumab treatment group and the placebo group, as well as the associated 95% confidence 
interval, will be provided for all the major secondary endpoints.
The United States and the global regions will employ a different multiple testing strategy as 
described below to control the overall Type I error.
Type I error control in countries outside the United States (global testing procedure):  A 
hierarchical testing procedure as shown in Figure 3 will be employed to control the overall Type 
1 error rate over the 4 major secondary efficacy analyses at the (2-sided) 0.05 significance level 
within a dose group. A major secondary endpoint for a dose group will be considered significant
only if both the previous endpoints in the hierarchy and current endpoint test positive at the 
2-sided 0.05 level of significance. If an endpoint is not significant, all subsequent tests in the 
hierarchy will be considered not to be significant. Nominal p-values will be reported for all 
analyses.
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Figure 3:
Global testing procedure for primary and major secondary endpoints
Type I error control in the United States (US-specific testing procedure):  A hierarchical 
testing procedure as shown Figure 4 (and listed in Attachment 4) will be employed for the United 
States to strongly control the overall Type 1 error rate at the 0.05 level across the primary and all 
4 major secondary endpoints and across the 2 ustekinumab doses.
An endpoint will be 
considered significant only if both the previous endpoints in the hierarchy and current endpoint
test positive at the 2-sided 0.05 level of significance. If an endpoint is not significant, all 
subsequent tests in the hierarchy will be considered not to be significant. Nominal p-values will 
be reported for all analyses.
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Figure 4:
US-specific testing procedure for the primary and major secondary endpoints
5.3.3.
Subgroup Analyses
The primary and major secondary endpoints will be analyzed using a CMH chi-square test
described above based on the following subgroups, when the number of subjects within each 
level of the subgroup permits. Summaries of the proportion of subjects by treatment group, the 
adjusted treatment difference (with Cochran-Mantel-Haenszel weight) between each 
ustekinumab treatment group and the placebo group, as well as the associated 95% confidence 
interval, will be provided
CRP and Fecal Biomarkers (calprotecin and lactoferrin), both at Week 0 of the induction 
study and at Week 0 of the maintenance study

CRP (≤3 mg/L, >3 mg/L)

CRP (≤ median, > median)

CRP (≤10 mg/L, >10 mg/L)
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
Fecal calprotectin (≤250 mg/kg, >250 mg/kg)

Fecal lactoferrin (≤7.24 µg/g, >7.24 µg/g)
Induction baseline Weight (≤ 1st quartile, >1st quartile and ≤ 2nd quartile, >2nd quartile and 
≤3rd quartile, >3rd quartile)
5.4.
Other Efficacy Endpoints
Regardless of the significance of the endpoints in the hierarchical testing procedures described 
above, the testing of the other endpoints in the following sections will proceed.  These endpoints 
will not be adjusted for multiplicity, and statements of significance for these endpoints will be 
based on nominal p-values. 
5.4.1.
Endpoints
5.4.1.1.
Clinical Endpoints
The following endpoints will be summarized and compared between each of the ustekinumab 
treatment groups and the placebo treatment group:

The change from maintenance baseline in the Mayo score at Week 44. 

The change from maintenance baseline in the partial Mayo score over time through 
Week 44.

The change from maintenance baseline in the modified Mayo score (i.e., Mayo score 
without the PGA) at Week 44.

Partial Mayo remission over time through Week 44.

Durable partial Mayo remission through Week 44.

Clinical remission (global definition) at Week 44 with a rectal bleeding subscore of 0.

Remission at Week 44 based on a stool frequency subscore of 0 or 1, a rectal bleeding 
subscore of 0, and an endoscopy subscore of 0 or 1.

Remission at Week 44 based on a stool frequency subscore of 0, a rectal bleeding subscore 
of 0, and an endoscopy subscore of 0 or 1.

Remission at Week 44 based on a stool frequency subscore of 0 or 1, a rectal bleeding 
subscore of 0, and an endoscopy subscore of 0 or 1 (Nonresponder if friability present on 
endoscopy).

Remission at Week 44 based on a stool frequency subscore of 0, a rectal bleeding subscore 
of 0, and an endoscopy subscore of 0 or 1 (Nonresponder if friability present on endoscopy).

Symptomatic remission through Week 44.

Maintenance of symptomatic remission through Week 44 among the subjects who had 
achieved symptomatic remission at maintenance baseline.

Endoscopic healing at Week 44 among the subjects who had achieved endoscopic healing at 
maintenance baseline. 
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
Histologic healing at Week 44.

Endoscopic healing at Week 44 (Nonresponder if friability present on endoscopy).

Mucosal healing at Week 44. 

Mucosal healing at Week 44 (Nonresponder if friability present on endoscopy).

Normal or inactive mucosal disease at Week 44.

Subjects in clinical response and not receiving corticosteroids at Week 44.

The change from maintenance baseline in the average daily prednisone-equivalent 
corticosteroid dose (excluding budesonide and beclomethasone dipropionate) over time 
through Week 44 among the subjects who were receiving concomitant corticosteroids at 
maintenance baseline.

Subjects who are not receiving concomitant corticosteroids at Week 44 among the subjects 
who were receiving concomitant corticosteroids at maintenance baseline.

Subjects who were not receiving corticosteroids for at least 90 days prior to Week 44 among 
subjects who were receiving corticosteroids at maintenance baseline.

Subjects who were not receiving corticosteroids for at least 30 days prior to Week 44 among 
subjects who were receiving corticosteroids at maintenance baseline.

The time to loss of clinical response through Week 44. 

Clinical response through Week 44 based on the Mayo score that includes the endoscopy 
subscore assigned by the local endoscopist.

Endoscopic healing at Week 44 based on the endoscopy subscore assigned by the local 
endoscopist.

Normal or inactive mucosal disease at Week 44 based on the endoscopy subscore assigned 
by the local endoscopist.

Mucosal healing at Week 44 based on the endoscopy subscore assigned by the local 
endoscopist.

Endoscopic healing at Week 44 by biologic failure status. 

Maintenance of clinical response through Week 44 by biologic failure status.

Mucosal healing at Week 44 by biologic failure status
In addition, primary and major secondary endpoints as well as mucosal healing endpoint will be 
evaluated based on the following biologic failure profiles: subjects who were biologic-naïve, 
subjects who were biologic failures to at least 1 anti-TNF (regardless of vedolizumab), and 
subjects who were biologic failures to both anti-TNF and vedolizumab, when the number of 
subjects within each subpopulation permits. Furthermore, Sensitivity analyses will be performed 
for mucosal healing at Week 44 and histologic healing at Week 44 by considering subjects with 
an unevaluable biopsy at Week 44 as nonresponders.
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The following endpoints will be summarized and compared for both global and US-specific 
definitions of clinical remission:

Subjects in clinical remission at Week 44 and not receiving corticosteroids for at least 
90 days prior to Week 44.

Subjects in clinical remission at Week 44 and not receiving corticosteroids for at least 
30 days prior to Week 44.

Subjects in clinical remission at Week 44 and not receiving corticosteroids at Week 44 
among the subjects receiving concomitant corticosteroids at maintenance baseline.

Subjects in clinical remission at Week 44 and not receiving corticosteroids for at least 
90 days prior to Week 44 among the subjects receiving concomitant corticosteroids at 
maintenance baseline.

Subjects in clinical remission at Week 44 and not receiving corticosteroids for at least 
30 days prior to Week 44 among the subjects receiving concomitant corticosteroids at 
maintenance baseline.

The time to loss of clinical remission through Week 44 among subjects who had achieved 
clinical remission at maintenance baseline.

Clinical remission at Week 44 by biologic failure status.

Corticosteroid-free clinical remission at Week 44 by biologic failure status

Maintenance of clinical remission through Week 44 among the subjects who had achieved 
clinical remission at maintenance baseline by biologic failure status.
In addition, the following endpoints will be summarized:

The change from induction baseline in the Mayo score over time through Week 44.

The change from induction baseline in the partial Mayo score over time through Week 44.

Mayo subscores through Week 44. 

Clinical remission (both global and US-specific definitions) at Week 44 by investigative
site.
5.4.1.2.
CRP and Fecal Biomarkers
The following endpoints will be summarized and compared between each of the ustekinumab 
treatment groups and the placebo treatment group. 

The change from maintenance baseline in CRP concentration over time through Week 44. 

The change from maintenance baseline in fecal lactoferrin concentration over time through 
Week 44. 

The change from maintenance baseline in fecal calprotectin concentration over time through 
Week 44.

Normalization of CRP over time through Week 44 among subjects with abnormal CRP at 
induction baseline.  
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
Normalization of fecal lactoferrin over time through Week 44 among subjects with 
abnormal fecal lactoferrin at induction baseline.

Normalization of fecal calprotectin over time through Week 44 among subjects with 
abnormal fecal calprotectin concentration at induction baseline.
In addition, CRP concentration, fecal lactoferrin concentration and fecal calprotectin
concentration through Week 44 will be provided by CRP (≤3 mg/L, > 3 mg/L), fecal lactoferrin 
(≤7.24 ug/g, > 7.24 µg/g) and fecal calprotectin (≤250 mg/kg, > 250 mg/kg) at Week 0 of the
induction study, respectively.
5.4.1.3.
Patient Reported Outcomes
The following endpoints will be summarized and compared between each of the ustekinumab 
treatment groups and the placebo treatment group. 

The change from maintenance baseline in the total IBDQ score and each of the 4 IBDQ 
dimensions through Week 44. 

A >20-point improvement from induction baseline in the IBDQ score at Week 44. 

A ≥16-point improvement from induction baseline in the IBDQ score at Week 44. 

IBDQ remission at Week 44

Maintenance of 20-point improvement in IBDQ through Week 44 among subjects with a
>20-point improvement in IBDQ at the maintenance baseline from the induction baseline.

Maintenance of 16-point improvement in IBDQ through Week 44 among subjects with a 
≥16-point improvement in IBDQ at the maintenance baseline from the induction baseline.

Maintenance of IBDQ remission among subjects with IBDQ remission at the maintenance 
baseline.

The change from maintenance baseline in the SF-36 physical and mental component 
summary scores and the individual scale scores through Week 44.

Maintenance of 5-point improvement in the SF-36 physical component score (PCS) through 
Week 44 among subjects with a ≥5-point improvement in the SF-36 PCS at the maintenance 
baseline from the induction baseline

Maintenance of 5-point improvement in the SF-36 mental component score (MCS) through 
Week 44 among subjects with a ≥5-point improvement in the SF-36 MCS at the
maintenance baseline from the induction baseline

A ≥5-point improvement from induction baseline in the SF-36 PCS through Week 44.

A ≥5-point improvement from induction baseline in the SF-36 MCS through Week 44.

The changes from maintenance baseline in the EQ-5D dimensions, EQ-5D index, and health 
state VAS scores through Week 44. 
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5.4.2.
Definitions
The Mayo/Partial Mayo scores, and global and US-specific definitions of clinical remission are 
defined in Section 5.2.1, Clinical response and endoscopic healing are defined in Section 5.3.1. 
The definitions for other efficacy endpoints not defined previously are as follows:
Clinical Endpoints:

Partial Mayo remission: A partial Mayo score ≤ 2.

Durable partial Mayo remission: Achieving partial Mayo remission at ≥80% of all visits 
(at least 9 out of 11 visits) prior to Week 44 and in partial Mayo remission at last visit 
(Week 44).

Symptomatic remission: A stool frequency subscore of 0 or 1 and a rectal bleeding 
subscore of 0.

Maintenance of symptomatic remission: Achieving symptomatic remission at ≥80% of all 
visits from Week 4 to Week 40 (at least 8 out of 10 visits) and in symptomatic remission at 
last visit (Week 44) among subjects who had achieved symptomatic remission at 
maintenance baseline.

Normal or inactive mucosal disease: Endoscopy subscore = 0.

Histological healing: It is based on the Geboes score (Attachment 2; Geboes et al, 2000)4
and is defined as 0-<5% neutrophils in epithelium and no crypt destruction, erosions, 
ulcerations or granulations.

Mucosal healing: Endoscopic healing (i.e., endoscopy subscore of the Mayo score = 0 or 1) 
and histological healing.

The time to loss of clinical remission/response through Week 44: It is defined as the 
number of days elapsed from the date of the Week 0 study agent administration in this 
maintenance study to the date of first loss of clinical remission/response at or prior to 
Week 44.  Subjects who have missing data or who do not have an event at or prior to 
Week 44 will be censored at Week 44, date of study completion, or early termination, 
whichever happens earlier. Subjects who have a treatment failure (see Section 5.1.1.1) prior 
to Week 44 will be considered to have an event (loss of clinical remission/response) at the 
time of treatment failure.

Average daily prednisone-equivalent corticosteroid dose: For corticosteroid medication
(excluding budesonide and beclomethasone dipropionate) use at a specific time point, the 
average daily prednisone-equivalent corticosteroid dose is calculated using the corticosteroid 
dosage levels from the 6 days prior to the day before the visit. 
CRP and Fecal Biomarkers:

Normalization of CRP concentration: CRP concentration ≤3 mg/L.

Normalization of fecal lactoferrin concentration: Fecal lactoferrin concentration 
≤7.24 μg/g.

Normalization of fecal calprotectin concentration: Fecal calprotectin concentration 
≤250 mg/kg.
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Patient Reported Outcomes:

Inflammatory Bowel Disease Questionnaire (IBDQ): The IBDQ is a 32-item 
questionnaire for subjects with IBD that will be used to evaluate the disease-specific health-
related quality of life across 4 dimensional scores:  bowel (loose stools, abdominal pain), 
systemic (fatigue, altered sleep pattern), social (work attendance, need to cancel social 
events), and emotional (anger, depression, irritability). The range of the IBDQ score is 32 to 
224. Higher scores indicate better quality of life. Each of the individual IBDQ dimensions 
will be calculated when no more than 1 item is missing in the dimension. The missing item 
will be estimated using the average value across the nonmissing items. If any one of the 
dimensions within the IBDQ cannot be calculated, then the total IBDQ score cannot be 
calculated.

SF-36: The SF-36, a generic measure of health status, evaluates eight individual subscales 
(physical functioning[PF], role
physical[RP], bodily pain[BP], general health[GH], 
vitality[VT], social functioning[SF], roleemotional[RE], and mental health[MH]) and the 
physical component summary (PCS, calculated from the subscales PF, RP, BP and GH) and 
the mental component summary (MCS, calculated from the subscales VT, SF, RE and MH) 
scores. 
Each of the SF-36 subscales and two summary scores are derived and are scaled to scores 
with a mean of 50 and standard deviations of 10, based upon general US population norms 
of year 2009. Maximum Data Recovery option will be used to estimate scores with missing 
items. Based on the user’s guide from the developer, the software applies a value to a scale 
item rendered missing if at least one of the items in that scale has valid data. A scale 
receives a “missing” score (“.”) only if all the items in that scale are missing. PCS and MCS 
are calculated when at least seven of the eight profile scales have valid data, either actual or 
estimated. However, to calculate PCS, the PF scale must be one of the seven scales having 
valid data. Also, to calculate MCS, the MH scale must be one of the seven scales having 
valid data.

IBDQ remission: IBDQ≥170 (Irvine et al, 1994; Higgins et al, 2005)5,6

Maintenance of 20-point improvement in IBDQ through Week 44: Among subjects with 
a >20-point improvement in IBDQ at the maintenance baseline from the induction baseline, 
a >20-point improvement in IBDQ at both Week 20 and Week 44 from Week 0 of the
induction study.

Maintenance of 16-point improvement in IBDQ through Week 44: Among subjects with 
a ≥16-point improvement in IBDQ at the maintenance baseline from the induction baseline, 
a ≥16-point improvement in IBDQ at both Week 20 and Week 44 from Week 0 of the
induction study.

Maintenance of IBDQ remission: in IBDQ remission at both Week 20 and Week 44 among 
subjects with IBDQ remission at the maintenance baseline.

Maintenance of 5-point improvement in the SF-36 PCS through Week 44: A ≥5-point 
improvement in the SF-36 PCS at both Week 20 and Week 44 from Week 0 of an induction 
study.
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
Maintenance of 5-point improvement in the SF-36 MCS through Week 44: A ≥5-point 
improvement in the SF-36 MCS at both Week 20 and Week 44 from Week 0 of an induction 
study.

EuroQoL-5D Health Questionnaire: The EQ-5D is designed for self-completion by 
subjects and consists of 2 pages - the EQ-5D descriptive system and the EQ visual analog 
scale (EQ VAS).  The EQ-5D descriptive system comprises the following 5 dimensions:  
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.  Each 
dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, 
and extreme problems.  The EQ VAS records the respondent’s self-rated health on a 
vertical, visual analog scale where the endpoints are labeled ‘Best imaginable health state’ 
(score of 100) and ‘Worst imaginable health state’ (score of 0).  The EQ-5D descriptive 
system can be converted into a single summary EQ-5D Index. EQ-5D index scores in this 
analysis will be derived with the algorithm and software provided by the developer based on 
the UK model.2
5.4.3.
Analysis Methods for Other Efficacy Endpoints
The analyses in this section will be based on the Primary Efficacy Analysis Set. A 2-sided 
significance level of 0.05 will be used for all tests.  The treatment failure rules and missing data 
rules described in Section 5.1.1 will be applied to each of the above endpoints unless otherwise 
specified. For endpoints involving friability, subjects with missing friability or a friability that 
cannot be determined will be considered not to have friability.
Dichotomous endpoints will be summarized and compared between each of the ustekinumab 
treatment groups and the placebo treatment group using a CMH chi-square test, stratified by 
clinical remission status at maintenance baseline and induction treatment. In cases of rare events, 
Fisher’s exact test will be used for treatment comparisons.
The change from maintenance baseline in the Mayo, partial Mayo score, modified Mayo score,
and the average daily prednisone-equivalent corticosteroid dose will be analyzed using analysis 
of covariance (ANCOVA) with the respective baseline value, clinical remission status at 
maintenance baseline, induction treatment, and maintenance treatment group as covariates. 
The normality assumption of the other continuous endpoints (i.e., the change from maintenance 
baseline in CRP, Fecal Lactoferrin, Fecal Calprotectin, total IBDQ, IBDQ dimensions, SF-36 
PCS and MCS, EQ-5D index, and health state VAS score etc.) is in question based on results 
from previous studies, therefore for them,  the comparison between each ustekinumab treatment 
group and the placebo group will be made  using an ANCOVA on the van der Waerden normal 
scores with the respective baseline value, clinical remission status at maintenance baseline, 
induction treatment, and maintenance treatment group as covariates. 
For the change from baseline in EQ-5D dimensions scores, comparisons between each of the 
ustekinumab treatment groups and placebo will be made using a CMH chi-square (Row Mean 
Scores) test stratified by clinical remission status at maintenance baseline and induction 
treatment.
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Time to event endpoints will be compared between each of the ustekinumab treatment groups
and the placebo treatment group using the stratified log-rank test with clinical remission status at 
maintenance baseline and induction treatment as the stratification factors.  The Kaplan-Meier 
curve by treatment group will be provided. 
5.5.
Efficacy Endpoints in Other Populations
The following endpoints will be summarized based on the Non-randomized Analysis Set.
Treatment failure and missing data rules will be applied.

Clinical remission (for both global and US-specific definitions) at Week 44

Maintenance of clinical response through Week 44

Endoscopic healing at Week 44

Partial Mayo remission over time through Week 44

Corticosteroid-free clinical remission at Week 44

Mucosal healing at Week 44
5.6.
Exploratory Endpoints
The following exploratory endpoints will be summarized and compared between each of the 
ustekinumab treatment groups and the placebo treatment group. The analyses will be based on 
the Primary Efficacy Analysis Set.  
5.6.1.
Clinical Endpoints

Modified Mayo score response (i.e., response based on the Mayo score without the PGA 
subscore) at Week 44 by two definitions as defined in Section 5.2.1.1. 

The change from baseline in Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score 
at Week 44.

UCEIS score ≤4 at Week 44.

The UCEIS score at Week 0 and at Week 44 of the maintenance study by the level of the 
Mayo endoscopy subscore at the corresponding visit.
5.6.2.
Definitions
Modified Mayo score response definition 1: decrease in the modified Mayo score of ≥2 points 
and ≥35% and either a decrease in the rectal bleeding subscore of ≥ 1 or a rectal bleeding 
subscore of 0 or 1. 
Modified Mayo score response definition 2: decrease in the modified Mayo score of ≥2 points 
and ≥30% and either a decrease in rectal bleeding of ≥ 1 or a rectal bleeding score of 0 or 1.
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Ulcerative Colitis Endoscopic Index of Severity (UCEIS):9 The UCEIS (Attachment 3) is an 
index that provides an overall assessment of endoscopic severity of UC and is the summation of 
the scores from the following three components:

Mucosal vascular pattern (1=Normal; 2=Patchy obliteration; 3=Obliterated)

Bleeding (1=None; 2=Mucosal; 3=Luminal mild; 4=Luminal moderate or severe)

Ulceration (1=None; 2=Erosions; 3=Superficial ulcer; 4=Deep ulcer)
The UCEIS score ranges from 3 to 11 with a higher score indicating more severe disease by 
endoscopy. The UCEIS score will be assessed only by the central video readers for all 
endoscopies.
The treatment failure rules and missing data rules described in Section 5.1.1 will be applied to 
these endpoints, except for the UCEIS score by the level of Mayo endoscopy subscore.  For the 
UCEIS score by the level of Mayo endoscopy subscore, no treatment failure and missing data 
rules will be applied.
5.6.3.
Analysis Methods
The endpoints in Section 5.6.1 will not be controlled for multiplicity. Statements of significance 
will be based on nominal p-values.
For dichotomous endpoints, the comparison between each ustekinumab treatment group and the 
placebo group will be conducted using a CMH chi-square test, stratified by clinical remission
status at maintenance baseline and induction treatment.
The change from baseline in the UCEIS score at Week 44 will be analyzed using an ANCOVA 
with the respective baseline value, clinical remission status at maintenance baseline, induction 
treatment, and maintenance treatment group as covariates.
The UCEIS score at Week 0 and at Week 44 of the maintenance study will be summarized by the 
level of Mayo endoscopy subscore at the corresponding visit to assess the association between 
the UCEIS score and the Mayo endoscopy subscore.  The endoscopy subscores assigned by the 
central reader will be used. 
6.
SAFETY
Safety will be assessed by summarizing the frequency and type of AEs and by summarizing
laboratory parameters (hematology and chemistry) and vital signs parameters.
Unless otherwise mentioned, safety summaries will be provided for subjects in the Safety 
Analysis Set, overall and by randomization status.  In general, subjects will be analyzed 
according to their assigned treatment.
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6.1.
Adverse Events
Treatment-emergent AEs through Week 44 will be summarized by treatment group and Medical 
Dictionary for Regulatory Affairs (MedDRA) system organ class and preferred term.  A 
treatment-emergent AE is any AE that occurs at or after the initial administration of study agent 
of this maintenance study.  
The following treatment-emergent summary tables will be provided:
1.
Any AEs.
2.
SAEs.
3.
Reasonably related AEs.
4.
AEs leading to discontinuation of study agent.
5.
Infections, including infections requiring with an oral or parenteral antibiotic treatment.
6.
Serious infections.
7.
Injection-site reactions. 
These summary tables will provide counts and percentages of subjects with 1 or more of the 
specified AEs by treatment group.  In addition to the summary tables, listings of subjects with 
SAEs, and AEs leading to discontinuation of study agent will be provided.  Any deaths, possible 
anaphylactic or serum-sickness like reactions, malignancies, or major cardiovascular events will 
either be presented in a listing or described in the clinical study report.
The number of adverse events per hundred subject-years of follow-up through Week 44 will also 
be provided.
AEs, SAEs, and serious infections will also be summarized by treatment group and induction 
baseline body weight (≤ median body weight or > median body weight).
A reasonably related AE is defined as any event with a relationship to study agent of ‘Very 
Likely’, ‘Probable’, or ‘Possible’ on the AE eCRF page or if the relationship to study agent is 
missing.
An infection is defined as any AE that was recorded as an infection by the investigator on the 
eCRF.
A study agent injection-site reaction is any adverse reaction at an SC study agent injection site. 
The injection sites will be evaluated for reactions and any injection site reaction will be recorded 
as an AE (and an injection-site reaction) by the investigator on the eCRF.
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Since safety should be assessed relative to exposure and follow-up, all AE summary tables will 
summarize the average weeks of follow-up and number of administrations for each treatment 
group.
If any subject receives ustekinumab outside of this study protocol (i.e commercially available 
Stelara), AE data after the receipt of ustekinumab will be excluded from the AE analyses to 
preserve the integrity and accuracy of the randomized treatment groups.  
6.2.
Clinical Laboratory Tests
Routine laboratory data for hematology and clinical chemistry will be collected at study visits 
from Week 0 through Week 44 according to the Time and Events schedule in the Protocol. The 
following laboratory assessments will be collected:  
1.
Hematology: hemoglobin, hematocrit, platelet count, total and differential WBC count. 
2.
Chemistry: total and direct bilirubin, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase, albumin, total protein, calcium, phosphate, 
sodium, potassium, chloride, blood urea nitrogen (BUN), and creatinine.
The following summaries of clinical laboratory tests will be provided for subjects in the Safety 
Analysis Set:
1. Line plots of the observed values and changes from maintenance baseline over time through 
Week 44.
2. Summary of maximum National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI-CTCAE) toxicity grade for postbaseline laboratory values through Week 44.
3. Shift tables for selected laboratory parameters (hematology: hemoglobin, platelets, total 
WBC, absolute lymphocytes, and absolute neutrophils; chemistry: ALT, AST, and Alkaline 
phosphatase) from baseline to corresponding postbaseline laboratory values through 
Week 44.
4. Summary of maximum postbaseline measurement through Week 44 for ALT, AST, alkaline 
phosphatase and total bilirubin relative to ULN.  
In addition, summaries for #’s 2 and 4 (above) will be provided by randomization status.  
Listings of subjects with any abnormal postbaseline laboratory values of CTCAE grade ≥2 will 
also be provided.
The baseline value for a subject is the value closest to, but prior to, the first dose of study agent 
of the maintenance study unless specified otherwise. Change from maintenance baseline is 
defined to be the assessment at the postbaseline visit minus the assessment at maintenance 
baseline. Summaries of laboratory data will be completed using all the available laboratory data 
at the time point of interest without imputing missing data. Shift tables will summarize the 
number of subjects with low, normal, and high values (determined by the laboratory normal 
ranges) at the post baseline visits for each of the classifications of low, normal, and high at 
baseline of the maintenance study. 
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Clinical laboratory test values are to be graded based on CTCAE version 4.03 (Table 4). The 
laboratory tests not included in Table 4 will not be presented in the corresponding tables or 
listings.
Table 4:
Grading Criteria for Clinical Laboratory Tests [CTCAE Version 4.03]
Hematology Tests
Criteria
Test
Direction
1
2
3
4
Hemoglobin (g/L)
Decrease
≥100 - <LLN
≥80 - <100.0
≥65 - <80
<65
Leukocytes (WBC) 
(109/L)
Decrease
≥3.0 - <LLN
≥2.0 - <3.0
≥1.0 - <2.0
<1.0
Lymphocytes (109/L)
Decrease
≥0.8 - <LLN
≥0.5 - <0.8
≥0.2 - <0.5
<0.2
Neutrophils (109/L)
Decrease
≥1.5 - <LLN
≥1.0 - <1.5
≥0.5 - <1.0
<0.5
Platelets (109/L)
Decrease
≥75.0 - <LLN
≥50.0 - <75.0
≥25.0 - <50.0
<25.0
Chemistry Tests
Criteria
Test
Direction
1
2
3
4
ALT
Increase
>ULN - ≤3.0 
xULN
>3.0 xULN -
≤5.0 xULN
>5.0 xULN -
≤20.0 xULN
>20.0 xULN
Albumin (g/L)
Decrease
≥30 - <LLN
≥20 - <30
<20
Alkaline Phosphatase
Increase
>ULN - ≤2.5 
xULN
>2.5 xULN -
≤5.0 xULN
>5.0 xULN -
≤20.0 xULN
>20.0 xULN
AST
Increase
>ULN - ≤3.0 
xULN
>3.0 xULN -
≤5.0 xULN
>5.0 xULN -
≤20.0 xULN
>20.0 xULN
Bicarbonate (mmol/L)
Decrease
≥16 - <LLN
≥11 – <16
≥8 – <11
<8
Bilirubin
Increase
>ULN - ≤1.5 
xULN
>1.5 xULN -
≤3.0 xULN
>3.0 xULN -
≤10.0 xULN
>10.0 xULN
Calcium (mmol/L)
Increase
>ULN - ≤2.9
>2.9 - ≤3.1
>3.1 - ≤3.4
>3.4
Calcium (mmol/L)
Decrease
[Albumin ≥40 
g/L or missing 
and calcium ≥2.0 
- <LLN]; or
[Albumin < 40 
g/L and (calcium 
– 0.8 x (albumin 
– 40)) ≥2.0 -
<LLN]
[Albumin ≥40 
g/L or missing 
and calcium 
≥1.75 - <2.0]; 
or
[Albumin < 40 
g/L and 
(calcium – 0.8 
x (albumin –
40)) ≥1.75 -
<2.0]
[Albumin ≥40 
g/L or missing 
and calcium 
≥1.5 - <1.75]; 
or
[Albumin < 40 
g/L and 
(calcium – 0.8 
x (albumin –
40)) ≥1.5 -
<1.75]
[Albumin ≥40 
g/L or missing 
and calcium 
<1.5]; or
[Albumin < 40 
g/L and 
(calcium – 0.8 
x (albumin –
40)) <1.5]
Creatinine
Increase
>ULN - ≤1.5 
xULN
>1.5 xULN -
≤3.0 xULN
>3.0 xULN -
≤6.0 xULN
>6.0 xULN
Phosphate (mmol/L)
Decrease
≥0.8 - <LLN
≥0.6 - <0.8
≥0.3 - <0.6
<0.3
Potassium (mmol/L)
Increase
>ULN - ≤5.5
>5.5 - ≤6.0
>6.0 - ≤7.0
>7.0
Potassium (mmol/L)
Decrease
≥3.0 - <LLN
≥2.5 - <3.0
<2.5
Sodium (mmol/L)
Increase
>ULN - ≤150
>150 - ≤155
>155 - ≤160
>160
Sodium (mmol/L)
Decrease
≥130 - <LLN
≥120 - <130
<120
6.3.
Vital Signs 
Vital signs will be measured at each study visit.  The measurements of the vital signs and the 
changes from maintenance baseline will be summarized by visit and treatment group.  
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7.
PHARMACOKINETICS/PHARMACODYNAMICS
In general, subjects will be analyzed according to their assigned treatment for PK analyses. 
7.1.
Pharmacokinetics
Blood samples for determining the serum ustekinumab concentrations will be drawn from all 
subjects according to the Time and Events Schedule in the Protocol. Unless otherwise 
mentioned, serum ustekinumab concentration summaries will be provided based on the PK 
Analysis Set and Randomized PK Analysis Set. These summaries will be based on observed 
data (i.e., no data imputation). Serum ustekinumab concentrations through Week 44 will be 
summarized. In addition, serum ustekinumab concentrations through Week 44 will be 
summarized by induction baseline body weight quartiles for subjects in the Randomized PK 
Analysis Set. The proportion of subjects with concentrations below the lowest quantifiable 
concentration at each visit through Week 44 will also be summarized. Subjects with 
concentrations below the lowest quantifiable concentration will be treated as 0 in the summary 
statistics and labeled as 0 in any listings that contain serum concentration data. 
All serum ustekinumab concentration summaries will exclude, from the time of occurrence, data 
collected for subjects who 1) discontinue study agent, 2) skip an injection, 3) receive an 
incomplete injection, 4) receive an incorrect injection, 5) receive an additional injection, and/or 
6) receive commercial ustekinumab.  In addition, PK samples taken outside the scheduled visit 
window (±10 days of each scheduled visit) will be excluded from the summaries.
The relationship between ustekinumab serum concentrations (at Week 24 and at Week 44) and 
change in Mayo score, clinical remission (for both global and US-specific definitions), clinical 
response, endoscopic healing and CRP concentration at Week 44 will be explored based on the 
Randomized PK Analysis Set. Subject data will be summarized according to their assigned 
treatment.
A population PK analysis will be performed to characterize the PK of ustekinumab. The 
influence of important covariates on the population PK parameter estimates may be evaluated.  
The plan for the population PK analyses will be in a separate document and results will be 
presented in a separate technical report.
7.2.
Immune Response
Blood samples will be collected to determine immune response to ustekinumab at Week 0, and at 
Weeks 4, 12, 24, 36 and 44 using a drug tolerant assay. The antibody to ustekinumab status 
(positive at any time, negative) and titer through Week 44 will be summarized by treatment 
group for subjects who received a dose of ustekinumab either in the induction study or in this 
study and have appropriate samples for detection of antibodies to ustekinumab (i.e., subjects with 
at least 1 sample obtained after their first dose of ustekinumab). In addition, the Neutralizing 
Antibody (NAB) Status will be summarized by treatment group through Week 44 weeks.
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An evaluation of antibody to ustekinumab status versus change in Mayo score, clinical remission 
(for both global and US-specific definitions), clinical response, and endoscopic healing at 
Week 44 will be performed based on the Randomized PK Analysis Set to determine the 
influence of antibodies to ustekinumab on the efficacy of ustekinumab, if the number of subjects 
with positive antibody status permits.
The relationship between antibody to ustekinumab status and safety will be assessed based on the 
Randomized PK Analysis Set with a summary of injection-site reactions through Week 44 by 
antibody to ustekinumab status throughWeek 44, if the number of subjects with positive antibody 
status permits.
Median serum concentrations over time through Week 44 by antibody to ustekinumab status 
through Week 44 will also be summarized by treatment group based on the Randomized PK 
Analysis Set, if the number of subjects with positive antibody status permits.
A listing of subjects who are positive for antibodies to ustekinumab will be provided. This listing 
will provide information regarding dose administered, injection-site reactions/AEs within 1 hour 
of infusion, concomitant medications, partial Mayo score/Mayo Score, ustekinumab serum 
concentration, and antibody status.
7.3.
Pharmacodynamics
Blood samples for serum-based biomarker analyses, and fecal and mucosal biopsy samples will 
be collected at visits indicated in Time and Events schedule of the protocol. Changes in the 
concentration of individual serum markers from baseline to the selected post treatment time 
points will be summarized. RNA analyses and microbiome analysis will be performed. 
Biomarker analyses are considered exploratory and will be summarized in separate technical 
reports.
Whole blood samples will be collected for genetic and epigenetic analyses as specified in the 
Time and Events Schedules of the protocol. Genetic and epigenetic (DNA) analyses will be 
conducted only in subjects who sign the consent form to participate in the genetic and epigenetic 
assessments. These analyses are considered exploratory and will be summarized in a separate 
technical report. 
C-reactive protein, fecal lactoferrin, fecal calprotectin and histology assessments are included in 
the efficacy analysis section.
8.
HEALTH ECONOMICS
The health economics analyses described in this section will be based on the Primary Efficacy 
Analysis Set. The data for each subject will be analyzed according to the assigned treatment 
regardless of the actual treatment received.
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Medical resource utilization, including UC-related hospitalizations and UC-related surgeries, 
will be collected. Other heath economics data including Work Productivity and Activity 
Impairment Questionnaire-General Health (WPAI-GH) and the productivity visual analog scale 
(VAS) will be collected.
The productivity VAS will measure the impact of disease on subjects' daily productivity using a 
VAS (0=no impact at all to 10=impact productivity very much).
The Work Productivity and Activity Impairment Questionnaire-General Health (WPAI-GH) is a 
validated instrument created as a patient-reported quantitative assessment of the amount of 
absenteeism, presenteeism, and daily activity impairment attributable to general health. The 
WPAI-GH consists of 6 questions to determine employment status, hours missed from work due 
to UC, hours missed from work for other reasons, hours actually worked, the degree to which 
general health affected work productivity while at work, and the degree to which general health 
affected activities outside of work. Four impairment percentages (Percent work time missed due 
to health, Percent impairment while working due to health, Percent overall work impairment due 
to health and Percent activity impairment due to health) can be derived based on WPAI, each 
ranging from 0 to 100, with higher numbers indicating greater impairment and less productivity, 
i.e., worse outcomes.
No imputation will be performed for missing health economics values. The treatment failure 
rules only apply to WPAI-GH and productivity VAS endpoints. These endpoints are not adjusted
for multiplicity; nominal p-values will be reported.
1.
The proportion of subjects with a UC-related hospitalization through Week 44 will be 
summarized and compared between treatment groups using a CMH chi-square test, stratified 
by clinical remission status at maintenance baseline and induction treatment.
2.
The time to the first UC-related hospitalization through Week 44 will be compared using the 
stratified log-rank test with clinical remission status at maintenance baseline and induction 
treatment as the stratification factors.  The Kaplan-Meier curve by treatment group will be 
provided. The time to the first UC-related hospitalization is defined as the number of days 
elapsed from the date of the Week 0 study agent administration in this maintenance study to 
the date of the first hospitalization prior to or at Week 44. Subjects who are not hospitalized 
prior to Week 44 will be censored at Week 44, date of study completion, or early 
termination, whichever happens earlier. 
3.
The proportion of subjects with a UC-related surgery through Week 44 will be summarized 
and compared between treatment groups using a CMH chi-square test, stratified by clinical 
remission status at baseline and induction treatment. 
4.
The time to first colectomy (partial or full) through Week 44 will be compared between 
treatment groups using the stratified log-rank test with clinical remission status at baseline 
and induction treatment as the stratification factors. This analysis takes into account all 
reported colectomies that occurred prior to 44 weeks following the first maintenance study 
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agent administration.  The time to the first colectomy is defined as the number of days 
elapsed from the date of Week 0 study agent administration in this maintenance study to the 
date of colectomy prior to or at Week 44.  Subjects who do not have an event prior to 
Week 44 following the first maintenance study agent administration will be censored at
Week 44, date of study completion, or early termination, whichever happens earlier.
5.
The proportion of subjects with a UC-related hospitalization or surgery through Week 44 
will be summarized and compared between treatment groups using a CMH chi-square test, 
stratified by clinical remission status at maintenance baseline and induction treatment.
6.
The time to the first UC-related hospitalization or surgery through Week 44 will be 
compared using the stratified log-rank test with clinical remission status at maintenance 
baseline and induction treatment as the stratification factors.  The Kaplan-Meier curve by 
treatment group will be provided. The time to the first UC-related hospitalization or surgery 
is defined as the number of days elapsed from the date of the Week 0 study agent 
administration in this maintenance study to the date of the first hospitalization or surgery 
prior to or at Week 44. Subjects who are not hospitalized nor had a surgery prior to Week 44 
will be censored at Week 44, date of study completion, or early termination, whichever 
happens earlier. 
7.
The change from maintenance baseline in productivity VAS at Week 44 will be summarized 
and compared between treatment groups using ANCOVA on the van der Waerden normal 
scores with the respective baseline value, clinical remission status at maintenance baseline, 
induction treatment, and maintenance treatment group as covariates. 
8.
The change from maintenance baseline in each of four impairment percentages derived from 
WPAI-GH at Week 44 will be summarized and compared between treatment groups using 
ANCOVA on the van der Waerden normal scores with the respective baseline value, clinical 
remission status at maintenance baseline, induction treatment, and maintenance treatment 
group as covariates.  
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REFERENCES
1.
Baron JH, Connell AM, Lennard-Jones JE. Variation between observers in describing mucosal appearances in 
proctocolitis. Brit Med J. 1964; 1:89-92.
2.
Devlin N, Shah K, Feng Y, Mulhern B, Hout B V. Valuing Health-Related Quality of Life: An EQ-5D-5L 
Value Set for England. Office of Health Economics, Research Paper 16/01.
3.
Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative 
colitis. N Engl J Med. 2013; 369:699-710.
4.
Geboes K , Riddell R , Ost A et al. A reproducible grading scale for histological assessment of inflammation in 
ulcerative colitis. Gut 2000; 47: 404 – 409.
5.
Higgins PDR, Schwartz M, Mapili J, Krokos I, Leung J, Zimmermann EM. Patient defined dichotomous 
endpoints for remission and clinical improvement in ulcerative colitis. Gut. 2005;54(6):782-788.
6.
Irvine EJ, Feagan B, Rochon J, et al. Quality of life: a valid and reliable measure of therapeutic efficacy in the
treatment of inflammatory bowel disease. Canadian Crohn’s Relapse Prevention Trial Study Group.
Gastroenterology. 1994;106(2):287-296.
7.
Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golimumab maintains clinical response in patients 
with moderate-to-severe ulcerative colitis. Gastroenterology. 2014; 146:96-109.
8.
Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately 
active ulcerative colitis. A randomized study. N Engl J Med. 1987; 317(26):1625-1629.
9.
Travis SP, Schnell D, Krzeski P, et al. Developing an instrument to assess the endoscopic severity of ulcerative 
colitis: the Ulcerative Colitis Endoscopic Index of Severity (UCEIS). Gut. 2012; 61:535-542.
10.
Truelove SC, Witts LJ. Cortisone in ulcerative colitis: final report on a therapeutic trial. Brit Med J. 
1955;2:1041-1048.
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ATTACHMENTS
ATTACHMENT 1: MAYO SCORE
Mayo scoring system for assessment of ulcerative colitis activity
Stool frequencya
0 = Normal number of stools for this patient
1 = 1-2 stools more than normal
2 = 3-4 stools more than normal
3 = 5 or more stools more than normal
Rectal bleedingb
0 = No blood seen
1 = Streaks of blood with stool less than half the time
2 = Obvious blood with stool most of the time
3 = Blood alone passed
Findings of endoscopy
0 = Normal or inactive disease
1 = Mild disease (erythema, decreased vascular pattern, mild friability)
2 = Moderate disease (marked erythema, absent vascular pattern, friability, erosions)
3 = Severe disease (spontaneous bleeding, ulceration)
Physician’s global assessmentc
0 = Normal
1 = Mild disease
2 = Moderate disease
3 = Severe disease
a At the screening visit, each person indicates the number of stools he/she passed in a 24-hour period when in 
remission or before his/her UC diagnosis, thereby serving as his/her own control to establish the degree of 
abnormality of stool frequency.
b The daily bleeding score represents the most severe bleeding of the day.
c The physician’s global assessment acknowledges the 3 other criteria, the patient’s recall of abdominal 
discomfort and general sense of well-being, and other observations, such as physical findings and the 
patient’s performance status.
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ATTACHMENT 2: GRADING CRITERIA FOR THE HISTOLOGICAL EVALUATION 
OF DISEASE ACTIVITY IN ULCERATIVE COLITIS
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ATTACHMENT 3: UCEIS
The UCEIS is an index that provides an overall assessment of endoscopic severity of UC based 
upon mucosal vascular pattern, bleeding, and ulceration. The score ranges from 3 to 11. The
UCEIS score will be assessed only by the central readers for all endoscopies received.
UCEIS descriptors and definitions:
Descriptor (score most 
severe lesions)
Likert scale anchor points 
Definition
Vascular pattern
Normal (1)
Normal vascular pattern with
arborisation of capillaries clearly defined, 
or with blurring or patchy loss of capillary 
margins
Patchy obliteration (2)
Patchy obliteration of vascular
Pattern
Obliterated (3)
Complete obliteration of vascular pattern
Bleeding
None (1)
No visible blood
Mucosal (2)
Some spots or streaks of
coagulated blood on the surface of the 
mucosa ahead of the scope, which can be 
washed away
Luminal mild (3)
Some free liquid blood in the
Lumen 
Luminal moderate or severe (4)
Frank blood in the lumen ahead of 
endoscope or visible oozing from mucosa 
after washing intraluminal blood, or visible 
oozing from a haemorrhagic mucosa
Erosions and ulcers
None (1) 
Normal mucosa, no visible
erosions or ulcers
Erosions (2) 
Tiny (# 5mm) defects in the
mucosa, of a white or yellow color with a 
flat edge
Superficial ulcer (3) 
Larger (>5 mm) defects in the
mucosa, which are discrete fibrincovered 
ulcers in comparison with erosions, but 
remain superficial
Deep ulcer (4)
Deeper excavated defects in the mucosa, 
with a slightly raised edge
NCT02407236


CNTO1275  (Ustekinumab)
Statistical Analysis Plan CNTO1275UCO3001: Maintenance Amendment 1
55
Approved, Date: 25 July 2018
ATTACHMENT 4: LIST OF PRIMARY AND MAJOR SECONDARY ENDPOINTS IN 
THE ORDER OF THE US-SPECIFIC TESTING
The following list details the order of the testing that will be performed at the 0.05 level of
significance:

Clinical remission at Week 44 in the ustekinumab high dose group (90 mg SC q8w)

Maintenance of Clinical response through Week 44 in the ustekinumab high dose group 
(90 mg SC q8w)

Endoscopic healing at Week 44 in the ustekinumab high dose group (90 mg SC q8w)

Clinical remission and not receiving concomitant corticosteroids (corticosteroid-free clinical 
remission) at Week 44 in the ustekinumab high dose group (90 mg SC q8w)

Clinical remission at Week 44 in the ustekinumab low dose group (90 mg SC q12w)

Maintenance of Clinical response through Week 44 in the ustekinumab low dose group 
(90 mg SC q12w)

Maintenance of clinical remission through Week 44 among the subjects who had achieved 
clinical remission at maintenance baseline in the ustekinumab high dose group (90 mg SC 
q8w)

Endoscopic healing at Week 44 in the ustekinumab low dose group (90 mg SC q12w)

Clinical remission and not receiving concomitant corticosteroids (corticosteroid-free clinical 
remission) at Week 44 in the ustekinumab low dose group (90 mg SC q12w)

Maintenance of clinical remission through Week 44 among the subjects who had achieved 
clinical remission at maintenance baseline in the ustekinumab low dose group (90 mg SC 
q12w)
NCT02407236