Conditions: Nonradiographic Axial Spondylitis, Ankylosing
Keywords: Nonradiographic Axial Spondylitis, Ankylosing Ustekinumab
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 356
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the efficacy and safety of ustekinumab in adult participants with active nonradiographic axial spondyloarthritis (nr-AxSpA) measured by the reduction in signs and symptoms of nonradiographic axial spondyloarthritis (nr-AxSpA).

Detailed description:
This is a phase 3, multicenter, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of ustekinumab in the treatment of participants with active non-radiographic axial spondylo arthritis. Participants will receive either placebo or ustekinumab 45 or 90 milligram (mg). Participants will primarily be assessed for Assessment of Spondylo Arthritis (ASAS) International Society criteria 20 at Week 24. Safety will be monitored throughout the study.

Arms:
arm 1: Participants will receive placebo subcutaneously (SC) at Weeks 0, 4, 16, and 20. At Week 24, all participants (except those who early escaped) will crossover to receive ustekinumab 45 or 90 milligram (mg) SC at Weeks 24 and 28 followed by every 12 weeks up to Week 52. At Week 16, participants in placebo group with \< 10% improvement from baseline in both total back pain and morning stiffness measures at Week 12 and 16 will enter early escape to receive ustekinumab 45 mg or 90 mg at Weeks 16, 20, and 28 followed by every 12 weeks up to Week 52. At Week 52, participants who achieved inactive disease by ASDAS (ESR) \<1.3 at both Week 40 and 52 will be re-randomized to receive placebo or ustekinumab every 12 weeks up to Week 88. At Week 52, participants who did not achieve inactive disease by ASDAS (ESR) \<1.3 at Week 40 or 52 will continue with ustekinumab every 12 weeks up to Week 88. NOTE: Intervention Description should have no more than 800 characters. arm 2: Participants will receive ustekinumab 45 mg subcutaneously at Weeks 0 and 4, followed by every 12 weeks through Week 52. At Weeks 20 and 24, participants will receive placebo subcutaneously to maintain the blind. At Week 52, participants who achieved inactive disease by ASDAS (ESR) \<1.3 at both Week 40 and Week 52 will be re-randomized to receive either placebo or ustekinumab 45 mg every 12 weeks in a blinded fashion. At Week 52, participants who did not achieve inactive disease by ASDAS (ESR) \<1.3 at Week 40 or Week 52 will continue receiving ustekinumab 45 mg every 12 weeks through Week 88. arm 3: Participants will receive ustekinumab 90 mg subcutaneously at Weeks 0 and 4, followed by every four weeks through Week 52. At Weeks 20 and 24, participants will receive placebo subcutaneously to maintain the blind. At Week 52, participants who achieved inactive disease by ASDAS (ESR) \<1.3 at both Week 40 and Week 52 will receive either placebo or ustekinumab 90 mg every 12 weeks in a blinded fashion. At Week 52, participants who did not achieve inactive disease by ASDAS (ESR) \<1.3 at Week 40 or Week 52 will continue receiving ustekinumab 90 mg every 12 weeks through Week 88.

Interventions: intervention 1: Group 1: Placebo intervention 2: Group 2: Ustekinumab 45 mg intervention 3: Group 3: Ustekinumab 90 mg
Intervention descriptions: intervention 1: Participants will receive placebo SC at Weeks 0, 4, 16, and 20. At Week 24, all participants (except those who early escaped) will crossover to receive ustekinumab 45 or 90 mg SC at Weeks 24 and 28 followed by every 12 weeks up to Week 52. At Week 16, participants in placebo group with \< 10% improvement from baseline in both total back pain and morning stiffness measures at Week 12 and 16 will enter early escape to receive ustekinumab 45 mg or 90 mg at Weeks 16, 20, and 28 followed by every 12 weeks up to Week 52. At Week 52, participants who achieved inactive disease by ASDAS (ESR) \<1.3 at both Week 40 and 52 will be re-randomized to receive placebo or ustekinumab every 12 weeks up to Week 88. At Week 52, participants who did not achieve inactive disease by ASDAS (ESR) \<1.3 at Week 40 or 52 will continue with ustekinumab every 12 weeks up to Week 88. intervention 2: Participants will receive ustekinumab 45 mg subcutaneously at Weeks 0 and 4, followed by every 12 weeks through Week 52. At Weeks 20 and 24, participants will receive placebo subcutaneously to maintain the blind. At Week 52, participants who achieved inactive disease by ASDAS (ESR) \<1.3 at both Week 40 and Week 52 will be re-randomized to receive either placebo or ustekinumab 45 mg every 12 weeks in a blinded fashion. At Week 52, participants who did not achieve inactive disease by ASDAS (ESR) \<1.3 at Week 40 or Week 52 will continue receiving ustekinumab 45 mg every 12 weeks through Week 88. intervention 3: Participants will receive ustekinumab 90 mg subcutaneously at Weeks 0 and 4, followed by every four weeks through Week 52. At Weeks 20 and 24, participants will receive placebo subcutaneously to maintain the blind. At Week 52, participants who achieved inactive disease by ASDAS (ESR) \<1.3 at both Week 40 and Week 52 will receive either placebo or ustekinumab 90 mg every 12 weeks in a blinded fashion. At Week 52, participants who did not achieve inactive disease by ASDAS (ESR) \<1.3 at Week 40 or Week 52 will continue receiving ustekinumab 90 mg every 12 weeks through Week 88.

Protocol document:
Prot_000.pdf: 
1
Approved, Date: 09 April 2015
Janssen Research & Development*
Clinical Protocol
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating 
the Efficacy and Safety of Ustekinumab in the Treatment of Subjects With Active 
Nonradiographic Axial Spondyloarthritis
Protocol CNTO1275AKS3003; 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 Infectious Diseases BVBA; 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: 2015-000289-67
Status:
Approved
Date:
09 April 2015
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-ERI-96426907, 2.0
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.
NCT02407223


STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
2
Approved, Date: 09 April 2015
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
SYNOPSIS.................................................................................................................................................... 6
TIME AND EVENTS SCHEDULE .............................................................................................................. 12
ABBREVIATIONS ...................................................................................................................................... 16
1.
INTRODUCTION................................................................................................................................ 18
1.1.
Disease Background...................................................................................................................... 18
1.2.
Overall Rationale for the Study...................................................................................................... 19
1.2.1.
Scientific Rationale for Use of Anti-IL-12/23p40 Therapy in Axial Spondyloarthritis.................. 19
1.2.2.
Rationale for Ustekinumab in Axial Spondyloarthritis................................................................. 20
1.2.3.
CNTO1275PSA3001 and CNTO1275PSA3002 PsA Studies.................................................... 20
1.2.3.1.
Subgroup of Subjects with Spondylitis .................................................................................... 21
1.2.3.2.
Enthesitis Evaluation ............................................................................................................... 22
1.2.4.
Investigator-Initiated Study in AS ............................................................................................... 22
1.3.
Dose Justification........................................................................................................................... 23
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 25
2.1.
Objectives ...................................................................................................................................... 25
2.2.
Hypothesis ..................................................................................................................................... 25
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 25
3.1.
Overview of Study Design.............................................................................................................. 25
3.1.1.
Study Population......................................................................................................................... 28
3.1.2.
Treatment Groups, Dosage, and Dose Administrations Interval................................................ 29
3.1.3.
Study Phases and Duration of Treatment .................................................................................. 30
3.1.4.
Study Control, Randomization, and Blinding.............................................................................. 30
3.2.
Study Design Rationale.................................................................................................................. 30
4.
SUBJECT POPULATION.................................................................................................................. 31
4.1.
Inclusion Criteria ............................................................................................................................ 31
4.2.
Exclusion Criteria ........................................................................................................................... 37
4.3.
Prohibitions and Restrictions ......................................................................................................... 40
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 41
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 43
6.1.
Dosing Regimen and Blinding........................................................................................................ 43
6.2.
Study agent Administration and Timing ......................................................................................... 45
7.
TREATMENT COMPLIANCE............................................................................................................ 45
8.
CONCOMITANT THERAPY.............................................................................................................. 45
8.1.
Methotrexate, Sulfasalazine, or Hydroxychloroquine .................................................................... 45
8.2.
Corticosteroid Therapy................................................................................................................... 46
8.3.
Nonsteroidal Anti-inflammatory Drugs and Other Analgesics........................................................ 46
8.4.
Disease Modifying Antirheumatic Drugs/Systemic Immunosuppressives ..................................... 47
8.5.
Biologic Agents or Investigational Agents...................................................................................... 47
8.6.
Complementary Therapies............................................................................................................. 47
9.
STUDY EVALUATIONS .................................................................................................................... 48
9.1.
Study Procedures........................................................................................................................... 48
NCT02407223


STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
3
Approved, Date: 09 April 2015
9.1.1.
Overview..................................................................................................................................... 48
9.1.2.
Screening Phase ........................................................................................................................ 48
9.1.3.
Treatment Phases ...................................................................................................................... 50
9.1.4.
Posttreatment Phase (Follow-Up) .............................................................................................. 50
9.2.
Efficacy........................................................................................................................................... 51
9.2.1.
Evaluations ................................................................................................................................. 51
9.2.1.1.
Assessment of SpondyloArthritis International Society Response Criteria............................. 51
9.2.1.2.
Bath Ankylosing Spondylitis Disease Activity Index................................................................ 51
9.2.1.3.
Bath Ankylosing Spondylitis Functional Index......................................................................... 52
9.2.1.4.
Patient’s Global Assessment................................................................................................... 52
9.2.1.5.
Total Back Pain ....................................................................................................................... 52
9.2.1.6.
Night Back Pain ....................................................................................................................... 52
9.2.1.7.
Morning Stiffness..................................................................................................................... 52
9.2.1.8.
Musculoskeletal Assessments................................................................................................. 52
9.2.1.8.1.
Bath Ankylosing Spondylitis Metrology Index ...................................................................... 53
9.2.1.8.2.
Chest Expansion .................................................................................................................. 53
9.2.1.8.3.
Enthesitis Index.................................................................................................................... 53
9.2.1.9.
Ankylosing Spondylitis Disease Activity Score........................................................................ 54
9.2.1.10.
Imaging Evaluations ................................................................................................................ 54
9.2.1.10.1.
X-ray of Sacroiliac Joints...................................................................................................... 54
9.2.1.10.2.
Magnetic Resonance Imaging.............................................................................................. 55
9.2.1.11.
36-Item Short-form Health Survey........................................................................................... 55
9.2.1.12.
Medical Outcomes Study Sleep Scale .................................................................................... 56
9.2.1.13.
Ankylosing Spondylitis Quality of Life (ASQoL) Questionnaire............................................... 56
9.2.1.14.
Functional Assessment of Chronic Illness Therapy−Fatigue Questionnaire........................... 56
9.2.1.15.
Euroqol 5 Dimension Questionnaire........................................................................................ 56
9.2.2.
Endpoints.................................................................................................................................... 57
9.3.
Pharmacokinetics and Immunogenicity ......................................................................................... 58
9.3.1.
Serum Collection and Handling .................................................................................................. 58
9.3.2.
Analytical Procedures................................................................................................................. 58
9.3.2.1.
Pharmacokinetics of Ustekinumab .......................................................................................... 58
9.3.2.2.
Immunogenicity (Antibodies to Ustekinumab)......................................................................... 59
9.4.
Pharmacodynamic Evaluations...................................................................................................... 59
9.4.1.
Serum Biomarkers...................................................................................................................... 59
9.4.2.
Microbiome Substudy ................................................................................................................. 59
9.5.
Pharmacogenomic (DNA) Evaluations .......................................................................................... 59
9.6.
Health Economics .......................................................................................................................... 60
9.6.1.
Work Productivity and Activity Impairment Questionnaire.......................................................... 60
9.7.
Safety Evaluations ......................................................................................................................... 60
9.8.
Sample Collection and Handling.................................................................................................... 63
10.
SUBJECT COMPLETION/WITHDRAWAL....................................................................................... 63
10.1.
Completion ..................................................................................................................................... 63
10.2.
Discontinuation of Study Treatment............................................................................................... 63
10.3.
Withdrawal from the Study............................................................................................................. 65
11.
STATISTICAL METHODS................................................................................................................. 66
11.1.
Subject Information ........................................................................................................................ 66
11.2.
Sample Size Determination ........................................................................................................... 66
11.3.
Efficacy Analyses ........................................................................................................................... 67
11.4.
Pharmacokinetic Analyses............................................................................................................. 70
11.5.
Immunogenicity Analyses .............................................................................................................. 70
11.6.
Biomarker and Microbiome Analyses ............................................................................................ 70
11.7.
Pharmacokinetic/Pharmacodynamic Analyses.............................................................................. 70
11.8.
Pharmacogenomic Analyses ......................................................................................................... 70
11.9.
Health Economics Analyses .......................................................................................................... 71
11.10.
Safety Analyses ............................................................................................................................. 71
11.11.
Interim Analysis.............................................................................................................................. 71
NCT02407223


STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
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Approved, Date: 09 April 2015
11.12.
Data Monitoring Committee ........................................................................................................... 72
12.
ADVERSE EVENT REPORTING ...................................................................................................... 72
12.1.
Definitions ...................................................................................................................................... 73
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 73
12.1.2.
Attribution Definitions.................................................................................................................. 74
12.1.3.
Severity Criteria .......................................................................................................................... 74
12.2.
Special Reporting Situations.......................................................................................................... 75
12.3.
Procedures..................................................................................................................................... 75
12.3.1.
All Adverse Events...................................................................................................................... 75
12.3.2.
Serious Adverse Events ............................................................................................................. 76
12.3.3.
Pregnancy................................................................................................................................... 77
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 77
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 77
13.1.
Procedures..................................................................................................................................... 77
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 78
14.
STUDY AGENT INFORMATION....................................................................................................... 78
14.1.
Physical Description of Study agent .............................................................................................. 78
14.2.
Packaging ...................................................................................................................................... 78
14.3.
Labeling.......................................................................................................................................... 78
14.4.
Preparation, Handling, and Storage............................................................................................... 78
14.5.
Drug Accountability ........................................................................................................................ 79
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 79
16.
ETHICAL ASPECTS ......................................................................................................................... 79
16.1.
Study-Specific Design Considerations........................................................................................... 79
16.2.
Regulatory Ethics Compliance....................................................................................................... 80
16.2.1.
Investigator Responsibilities ....................................................................................................... 80
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 80
16.2.3.
Informed Consent ....................................................................................................................... 82
16.2.4.
Privacy of Personal Data ............................................................................................................ 82
16.2.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 83
16.2.6.
Country Selection ....................................................................................................................... 83
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 83
17.1.
Protocol Amendments.................................................................................................................... 83
17.2.
Regulatory Documentation ............................................................................................................ 84
17.2.1.
Regulatory Approval/Notification ................................................................................................ 84
17.2.2.
Required Prestudy Documentation............................................................................................. 84
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 85
17.4.
Source Documentation................................................................................................................... 85
17.5.
Case Report Form Completion ...................................................................................................... 86
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 87
17.7.
Record Retention ........................................................................................................................... 87
17.8.
Monitoring ...................................................................................................................................... 88
17.9.
Study Completion/Termination....................................................................................................... 88
17.9.1.
Study Completion ....................................................................................................................... 88
17.9.2.
Study Termination....................................................................................................................... 88
17.10.
On-Site Audits ................................................................................................................................ 89
17.11.
Use of Information and Publication................................................................................................ 89
REFERENCES............................................................................................................................................ 91
APPENDIX A: QUANTIFERON-TB GOLD TESTING ............................................................................. 94
APPENDIX B: TUBERCULIN SKIN TESTING .......................................................................................... 96
NCT02407223


STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
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Approved, Date: 09 April 2015
APPENDIX C: HBV SCREENING AND MONITORING ............................................................................ 97
INVESTIGATOR AGREEMENT ................................................................................................................. 98
LAST PAGE................................................................................................................................................ 98
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Time and Events from Study Initiation Through Week 100 ...................................................... 12
Table 2:
Scores (S) for the five components of the BASMIlin.................................................................. 53
Table 3:
Power to detect a significant treatment difference in achieving an ASAS 20 Response 
at Week 24................................................................................................................................ 67
FIGURES
Figure 1:
Proportion of subjects with BASDAI 50 responses at Week 24 in CNTO1275PSA3001 
and CNTO1275PSA3002 trials in subjects with active PsA ..................................................... 21
Figure 2:
Summary of Efficacy Results in Investigator Initiated Study in AS (TOPAS)........................... 23
Figure 3:
Schematic Overview of the Study from Screening through Week 52....................................... 27
Figure 4:
Schematic Overview of the Study from Week 52 through Week 100....................................... 28
Figure 5:
Overview of Multiplicity Control................................................................................................. 69
NCT02407223


STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
6
Approved, Date: 09 April 2015
SYNOPSIS
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating the 
Efficacy and Safety of Ustekinumab in the Treatment of Subjects with Active Nonradiographic
Axial Spondyloarthritis
Ustekinumab is a fully human monoclonal antibody that binds to the interleukin (IL)-12/23p40 protein 
subunit of human and primate IL-12 and IL-23 with high affinity and specificity. The binding of 
ustekinumab to the IL-12p40 subunit blocks the binding of IL-12 or IL-23 to the IL-12R1 receptor on 
the surface of NK and CD4+ T cells, inhibiting IL-12- and IL-23-specific intracellular signaling and 
subsequent activation and cytokine production. In this manner, ustekinumab inhibits the biological 
activity of IL-12 and IL-23 in all in vitro assays examined.
Elevated IL-23 levels have been reported in ankylosing spondylitis, and increased numbers of IL-23 
responsive Th17 cells have been demonstrated in peripheral blood mononuclear cells from 
spondyloarthritis (SpA) patients. Ustekinumab has shown preliminary efficacy in the radiographic axial 
spondyloarthritis (AxSpA) population in a small open-label study.
OBJECTIVES AND HYPOTHESIS
Primary Objective
The primary objective of this study is to assess the efficacy of ustekinumab in adult subjects with active 
nonradiographic (nr)-AxSpA measured by the reduction in signs and symptoms of nr-AxSpA.
Secondary Objectives

Efficacy related to improving physical function, range of motion, health-related quality of life, and 
other health outcomes.

Safety.

Pharmacokinetics (PK) and immunogenicity.

Time to flare after randomized withdrawal.
Exploratory Objective
The exploratory objectives are to evaluate the effect of ustekinumab on pharmacodynamics, 
pharmacogenomics, the microbiome, and structural damage progression in subjects with nr-AxSpA.
Hypothesis
The primary hypothesis for this study is that at least 1 of the ustekinumab groups is statistically superior 
to placebo in reducing the signs and symptoms in subjects with active nr-AxSpA, as assessed by the 
proportion of subjects who achieve at least 20% improvement from baseline in the Assessment of 
SpondyloArthritis International Society (ASAS) criteria 20 at Week 24.
OVERVIEW OF STUDY DESIGN
This is a Phase 3 multicenter, randomized, double-blind, placebo-controlled study of the efficacy and 
safety of ustekinumab compared with placebo in adult subjects with active nr-AxSpA with an inadequate 
response or intolerance to nonsteroidal anti-inflammatory drugs (NSAID) and/or exposure to no more 
than 1 anti-tumor necrosis factor alpha (TNFα) agent. Approximately 390 subjects will be randomized at 
approximately 85 investigational sites. The sample size of the study may be increased to approximately 
480 subjects if the number of subjects with an inadequate response to no more than 1 anti-TNFα agent is 
higher than anticipated among the first 200 subjects randomized. Subjects will be randomly assigned to 
NCT02407223


STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
7
Approved, Date: 09 April 2015
receive subcutaneous (SC) ustekinumab 45 mg or 90 mg or placebo administrations at Weeks 0, 4, and 
16. At Week 16, subjects in the placebo group who qualify for early escape (subjects with <10% 
improvement from baseline in both total back pain and morning stiffness measures at both Week 12 and 
Week 16), will begin receiving randomly assigned SC ustekinumab 45 mg or 90 mg administrations at 
Weeks 16, 20, and 28 and every 12 weeks (q12w) thereafter through Week 52. At Week 24, all remaining 
subjects in the placebo group who did not meet early escape criteria will be randomized to receive 
ustekinumab 45 mg or 90 mg at Weeks 24 and 28 followed by q12w therapy through Week 52. Subjects 
in the ustekinumab treatment groups will receive a placebo administration at Weeks 20 and 24 to maintain 
the blind and continue to receive SC ustekinumab 45 mg or 90 mg at Week 28 and q12w thereafter 
through Week 52. At Week 52, all subjects who achieve inactive disease (Ankylosing Spondylitis Disease 
Activity Score [ASDAS] erythrocyte sedimentation rate [ESR] <1.3) at both Week 40 and Week 52 visits 
will undergo rerandomization to either remain on ustekinumab or receive placebo.
Subjects who do not achieve inactive disease (ASDAS [ESR] <1.3) at either the Week 40 or Week 52 
visits will receive their previously assigned ustekinumab dose at their scheduled visits.
All subjects who experience a flare after Week 52 defined as ASDAS (ESR) >2.1 will be given the option 
to discontinue study injections and utilize an alternative therapy per the physicians’ discretion or to 
continue study injections in a blinded fashion. Subjects who elect to continue and were rerandomized to 
placebo at Week 52 will have ustekinumab injections reinstituted at their next scheduled visit. Subjects 
who elect to continue and were rerandomized to ustekinumab at Week 52 will continue with ustekinumab 
dose at their scheduled visits.
Database locks (DBLs) are scheduled for Weeks 24, 52, and 100.
An independent Data Monitoring Committee (DMC) will be commissioned for this study.
SUBJECT POPULATION
The target study population is subjects with active nr-AxSpA, defined as subjects with AxSpA with 
evidence of sacroiliitis on magnetic resonance imaging (MRI) or elevated high sensitivity C-reactive 
protein (hsCRP) ≥0.6 mg/dL at screening, and no radiographic sacroiliitis fulfilling the 1984 modified 
New York Criteria. In addition, all subjects will have active disease, as evidenced by Bath Ankylosing 
Spondylitis Disease Activity Index (BASDAI) score ≥4 and a visual analog scale (VAS) score for total 
back pain of ≥4, each on a scale of 0 to 10.
Study population will include subjects who have active nr-AxSpA disease and have had an inadequate 
response or intolerance to NSAIDs. Subjects who received 1 anti-TNF agent will be allowed into the 
study. Anti-TNFα-experienced subjects include those who have had an inadequate response or intolerance 
to 1 anti-TNFα agent (TNF-IR) or cannot continue anti-TNF therapy due to other reasons.
DOSAGE AND ADMINISTRATION
Before the first study agent administration, subjects will be randomly assigned in a ratio of 1:1:1 to 1 of 3 
treatment groups:
Week 0 to Week 52

Group 1 (placebo): Placebo SC at Weeks 0, 4, 16, and 20. At Week 24, all subjects (with exception 
of subjects who qualified for early escape) will crossover and be rerandomized to receive 
ustekinumab 45 mg or 90 mg SC at Weeks 24 and 28 followed by q12w dosing through Week 52.

Group 2 (ustekinumab 45 mg): Ustekinumab 45 mg SC at Weeks 0 and 4, followed by q12w 
dosing through Week 52. At Weeks 20 and 24, subjects will receive placebo SC to maintain the 
blind.
NCT02407223


STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
8
Approved, Date: 09 April 2015

Group 3 (ustekinumab 90 mg): Ustekinumab 90 mg SC at Weeks 0 and 4, followed by q12w 
dosing through Week 52. At Weeks 20 and 24, subjects will receive placebo SC to maintain the 
blind.
Early Escape
At Week 16, subjects in the placebo group with <10% improvement from baseline in both total back pain 
and morning stiffness measures at both Week 12 and Week 16 will enter early escape in a double-blinded 
fashion. Subjects in the placebo group who qualify for early escape will be rerandomized to receive 
ustekinumab 45 mg or 90 mg at Weeks 16, 20, and 28 followed by q12w dosing through Week 52. 
Subjects in Groups 2 and 3 who meet early escape criteria will continue on their already assigned doses 
through Week 52.
Any subject with <10% improvement from baseline in total back pain and morning stiffness measures 
will be allowed to discontinue study agent at any time and be transferred to alternative therapy.
Week 52 to Week 100

Group 1a (placebo → 45 mg): At Week 52, subjects randomized to placebo at Week 0 who 
received ustekinumab 45 mg after Week 16 (ie, placebo subjects who qualified for early escape at 
Week 16 and then were randomized to ustekinumab 45 mg or placebo subjects who were 
randomized to ustekinumab 45 mg at Week 24) and who achieved inactive disease by ASDAS (ESR) 
<1.3 at both Week 40 and Week 52 will be rerandomized to receive placebo or to continue on 
ustekinumab 45 mg q12w in a blinded fashion.
At Week 52, subjects who did not achieve inactive disease by ASDAS (ESR) <1.3 at Week 40 or 
Week 52 will continue receiving ustekinumab 45 mg q12w through Week 88.

Group 1b (placebo → 90 mg): At Week 52, subjects randomized to placebo at Week 0 who 
received ustekinumab 90 mg after Week 16 (ie, placebo subjects who qualified for early escape at 
Week 16 and then were randomized to ustekinumab 90 mg or placebo subjects who were 
randomized to ustekinumab 90 mg at Week 24) and who achieved inactive disease by ASDAS (ESR) 
<1.3 at both Week 40 and Week 52 will be rerandomized to receive placebo or to continue on 
ustekinumab 90 mg q12w in a blinded fashion.
At Week 52, subjects who did not achieve inactive disease by ASDAS (ESR) <1.3 at Week 40 or 
Week 52 will continue receiving ustekinumab 90 mg q12w through Week 88.

Group 2 (ustekinumab 45 mg): At Week 52, subjects randomized to ustekinumab 45 mg at Week 0 
and who achieved inactive disease by ASDAS (ESR) <1.3 at both Week 40 and Week 52 will be 
rerandomized to receive either placebo or ustekinumab 45 mg q12w in a blinded fashion.
At Week 52, subjects who did not achieve inactive disease by ASDAS (ESR) <1.3 at Week 40 or 
Week 52 will continue receiving ustekinumab 45 mg q12w through Week 88.

Group 3 (ustekinumab 90 mg): At Week 52, subjects randomized to ustekinumab 90 mg at Week 0 
and who achieved inactive disease by ASDAS (ESR) <1.3 at both Week 40 and Week 52 will be 
rerandomized to receive either placebo or ustekinumab 90 mg q12w in a blinded fashion.
At Week 52, subjects who did not achieve inactive disease by ASDAS (ESR) <1.3 at Week 40 or 
Week 52 will continue receiving ustekinumab 90 mg q12w through Week 88.
All subjects who experience a flare after Week 52 defined as ASDAS (ESR) >2.1 will be given the option 
to discontinue study injections and utilize an alternative therapy per the physicians’ discretion or to 
continue study injections in a blinded fashion. Subjects who elect to continue and were rerandomized to 
placebo at Week 52 will have ustekinumab injections reinstituted at their next scheduled visit. Subjects 
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STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
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Approved, Date: 09 April 2015
who elect to continue and were rerandomized to ustekinumab at Week 52 will continue with ustekinumab 
injections at their scheduled visits.
EFFICACY EVALUATIONS/ENDPOINTS
Assessments for nonradiographic axial spondyloarthritis include:

Assessment in Ankylosing Spondylitis Response Criteria

Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)

Bath Ankylosing Spondylitis Functional Index (BASFI)

Patient’s Global Assessment

Total Back Pain

Night Back Pain

Morning Stiffness

Musculoskeletal Assessments

Bath Ankylosing Spondylitis Metrology Index (BASMI)

Chest Expansion

Enthesitis Index

Ankylosing Spondylitis Disease Activity Score

Imaging Evaluations

X-rays of SI joints

Magnetic Resonance Imaging of SI joints

36-Item Short-form Health Survey

Medical Outcomes Study Sleep Scale

Ankylosing Spondylitis Quality of Life (ASQoL) Questionnaire

Functional Assessment of Chronic Illness Therapy−Fatigue (FACIT-F)Questionnaire

Euroqol 5 Dimension (EQ-5D) Questionnaire

Work Productivity and Activity Impairment Questionnaire –Specific Health Problem (WPAI-SHP)
Primary Endpoint
The primary endpoint is the proportion of subjects achieving an ASAS 20 response at Week 24.
Major Secondary Endpoints
The following major secondary analyses will be performed. The major secondary endpoints are listed in 
order of importance as specified below:
1.
The proportion of subjects who achieve an ASAS 40 at Week 24.
2.
The proportion of subjects who achieve at least 50% improvement from baseline in BASDAI at 
Week 24.
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STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
10
Approved, Date: 09 April 2015
3.
The change from baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) at Week 24.
4.
The proportion of subjects who achieve ASDAS (C-reactive protein [CRP]) inactive disease (<1.3) 
at Week 24.
PHARMACOKINETIC AND IMMUNOGENICITY EVALUATIONS
Serum samples will be used to evaluate the PK of ustekinumab, as well as the immunogenicity of 
ustekinumab (antibodies to ustekinumab).
BIOMARKER EVALUATIONS
Serum blood samples will be collected for serum biomarker and RNA gene expression analysis. Stool 
samples will be collected for microbiome analysis. Biomarker, RNA gene expression, and microbiome
samples will be used for research related to ustekinumab and axial spondyloarthritis.
GENETIC (DNA) EVALUATIONS
Whole blood samples will be collected for genetic analyses. Only subjects who sign the consent form to 
participate in the genetic assessment will have whole blood DNA samples collected. DNA samples will 
be used for research related to ustekinumab and axial spondyloarthritis.
SAFETY EVALUATIONS
Safety evaluations include assessments of the following: adverse events (including injection-site reactions 
and allergic reactions), clinical laboratory tests (hematology, chemistry, and pregnancy testing), vital 
signs, physical examinations, concomitant medication review, electrocardiograms, and early detection of 
tuberculosis.
STATISTICAL METHODS
Descriptive statistics will include counts and proportions for categorical data, and median, mean, 
interquartile range, and range for continuous data. Graphical data displays may also be used to summarize 
the data.
Primary Endpoint Analysis
The primary endpoint is the proportion of subjects who achieve an ASAS 20 response at Week 24.
To address the primary objective, the proportion of subjects who achieve an ASAS 20 response at 
Week 24 will be compared between the ustekinumab groups and placebo groups using a Cochran-Mantel-
Haenzel (CMH) test stratified by the combined MRI/hsCRP status and the status of previous exposure to 
anti-TNFα agents at a significance level of 0.05 (2-sided).
To control for multiplicity for the primary endpoint analysis, the proportion of subjects with ASAS 20 
response at Week 24 will be evaluated by comparing between the 90 mg group and the placebo group 
first. To maintain a Type I error rate of 0.05, the comparison between the 45 mg group and placebo group
will be performed at a significance level of 0.05 (2-sided) after the 90 mg group shows a significant 
treatment effect compared with the placebo group at a significance level of 0.05 (2-sided).
In the primary efficacy analysis, data from all randomized subjects who received at least 1 administration 
of study treatment (modified intention-to-treat) will be analyzed according to their assigned treatment 
group regardless of their actual treatment received. In general, subjects with missing data for ASAS at 
Week 24 will be considered nonresponders for ASAS 20 at Week 24. In addition, treatment failure rules 
will be applied.
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STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
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Approved, Date: 09 April 2015
Major Secondary Analyses
To control for multiplicity for the primary endpoint analysis and the major secondary endpoint analyses, 
the 4 major secondary analyses listed below will be performed sequentially contingent upon the success 
of the primary statistical analysis in that treatment group comparison. Otherwise, the p-values for the 
subsequent endpoints will be considered as supportive analyses. The following prespecified order will be 
used to analyze the major secondary endpoints.

The proportion of subjects who achieve an ASAS 40 at Week 24.

The proportion of subjects who achieve at least a 50% improvement from baseline in BASDAI at 
Week 24.

The change from baseline in BASFI at Week 24.

The proportion of subjects who achieve ASDAS (CRP) inactive disease (<1.3) at Week 24.
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STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
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TIME AND EVENTS SCHEDULE
Table 1:
Time and Events from Study Initiation Through Week 100
Phase
Screening
Active Comparator Controlled Phase = Active Treatment 
Controlled Phase
Randomized Withdrawal 
Phase
Final 
Efficacy 
and Safety 
visita,b
Week
-8
0
4
8
12
16
20
24
28
40
52
64
76
88
100
Study Proceduresc
Screening/Administratived
Informed consente
X
Informed consent for 
pharmacogenomics substudy
(optional)
X
Inclusion/exclusion criteria
X
X
Medical history and demographics
X
Study agent Administration
Randomization
X
Xf
Xg
Xh
Study agent administration
X
X
X
X
X
X
X
X
X
X
X
Injection site reaction evaluationi
X
X
X
X
X
X
X
X
X
X
X
Safety Assessments
Physical examination
X
X
ECG
X
HIV, HBV, and HCV
X
QuantiFERON-TB Gold test
X
Tuberculin skin testj
X
TB evaluationk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum pregnancy testl
X
Urine pregnancy test
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
Chest X-raym
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
NCT02407223


STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
13
Approved, Date: 09 April 2015
Table 1:
Time and Events from Study Initiation Through Week 100
Phase
Screening
Active Comparator Controlled Phase = Active Treatment 
Controlled Phase
Randomized Withdrawal 
Phase
Final 
Efficacy 
and Safety 
visita,b
Week
-8
0
4
8
12
16
20
24
28
40
52
64
76
88
100
Study Proceduresc
Efficacy Assessments
BASDAI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BASFI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient’s Global assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Total Back Pain assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Night Back Pain assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BASMI
X
X
X
X
X
Chest expansion
X
X
X
X
X
Enthesitis evaluation
X
X
X
X
X
IWRS for total back pain and 
morning stiffness
X
X
IWRS for ASDAS (ESR)
X
X
IWRS for ASDAS (flare
assessment)
X
X
X
SF-36n
X
X
X
X
X
ASQOLn
X
X
X
X
X
EQ-5Dn
X
X
X
X
X
FACIT-Fn
X
X
X
X
X
MOS-SSn
X
X
X
X
X
WPAI-SHPn
X
X
X
X
X
X-ray (SI joints)
Xo
X
MRI (SI joints)
Xo
X
X
Clinical Laboratory Assessments
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
hsCRP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ESRp
X
X
X
X
X
NCT02407223


STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
14
Approved, Date: 09 April 2015
Table 1:
Time and Events from Study Initiation Through Week 100
Phase
Screening
Active Comparator Controlled Phase = Active Treatment 
Controlled Phase
Randomized Withdrawal 
Phase
Final 
Efficacy 
and Safety 
visita,b
Week
-8
0
4
8
12
16
20
24
28
40
52
64
76
88
100
Study Proceduresc
Pharmacokinetics/Immunogenicity
Serum ustekinumab 
concentrationsq
X
X
X
X
X
X
X
X
X
X
X
X
Antibodies to study agentq
X
X
X
X
X
X
X
X
X
Pharmacogenomics (DNA)
Whole blood DNAr
X
X
X
Biomarkers
HLA-B27 statuss
X
Whole blood for RNA gene 
expression
X
X
X
Serum for biomarker assessment
X
X
X
Microbiome stool samplet
X
X
X
X
X
a.
Subjects who discontinue study agent administrations before the Week 24 visit should return for all visits through Week 24.
b.
Subjects who discontinue study agent after Week 24 and before the Week 88 visit, must return 12 weeks after last study agent administration for a 
final efficacy and safety follow-up visit (Week 100 assessments).  Subjects do not need to repeat the imaging assessments if they discontinue prior to 
Week 76.
c.
All assessments are to be completed prior to study agent injection, except at Weeks 8, 12, and 100 (no study agent injection), unless otherwise 
specified. For subjects who withdraw from study participation, every effort should be made to conduct final efficacy and safety assessments.
d.
X-ray and MRI assessments may be performed after all other screening assessments are performed.
e.
The informed consent to participate in the optional microbiome substudy at selected sites is offered in the main informed consent.
f.
Rerandomization to ustekinumab 45 mg or 90 mg of subjects who qualify for early escape at Week 16.
g.
Rerandomization to ustekinumab 45 mg or 90 mg of subjects who crossover from placebo at Week 24.
h.
Randomized withdrawal of responders.
i.
Subjects should be monitored for the occurrence of injection site reactions for 30 minutes after the injection.
j.
Only required if QuantiFERON®-TB Gold Test is not registered/approved locally or the TST as mandated by local health authorities.
k.
If TB is suspected at any time during the study, a chest x-ray, and QuantiFERON®-TB Gold test should be performed. A TST is additionally required 
if the QuantiFERON®-TB Gold test is not registered/approved locally or the TST as mandated by local health authorities.
l.
In addition to the screening evaluation, the serum pregnancy test may be repeated at any time at the discretion of investigator or subject.
m.
May be taken within 3 months prior to the first administration of study agent.
n.
All visit-specific PRO assessments should be conducted before any tests, procedures, or other consultations for that visit to prevent influencing 
NCT02407223


STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
15
Approved, Date: 09 April 2015
Table 1:
Time and Events from Study Initiation Through Week 100
Phase
Screening
Active Comparator Controlled Phase = Active Treatment 
Controlled Phase
Randomized Withdrawal 
Phase
Final 
Efficacy 
and Safety 
visita,b
Week
-8
0
4
8
12
16
20
24
28
40
52
64
76
88
100
Study Proceduresc
subjects’ perceptions.
Table 1:
Time and Events from Study Initiation Through Week 100
o.
An existing x-ray taken within 6 months or MRI done within 3 months of screening may be sent for central reading in lieu of screening x-ray or MRI.
p.
ESR will be performed at the sites.
q.
The same serum samples will be used for the measurement of ustekinumab concentration and detection of antibodies to ustekinumab. For visits with 
study agent administration, all blood samples for assessing pre-injection ustekinumab concentration and antibodies to ustekinumab MUST be collected 
BEFORE the administration of the study agent.
r.
Participation is optional and subjects must sign a separate pharmacogenomics informed consent.
s.
This test should be performed only if previous results are not available.
t.
Only from approximately 100 subjects who consent and are randomized to participate in the microbiome substudy at selected sites.
NCT02407223


STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
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Approved, Date: 09 April 2015
ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase 
AS
ankylosing spondylitis
ASAS
Assessment of SpondyloArthritis International Society
ASDAS
Ankylosing Spondylitis Disease Activity Score
ASQoL
Ankylosing Spondylitis Quality of Life
AST
aspartate aminotransferase
AxSpA
axial spondyloarthritis
BASDAI
Bath Ankylosing Spondylitis Disease Activity Index
BASFI
Bath Ankylosing Spondylitis Functional Index
BASMI
Bath Ankylosing Spondylitis Metrology Index
BCG
Bacille Calmette-Guérin
BLQ
below the limit of quantification
CL/F
apparent total systemic clearance
CMH
Cochran-Mantel-Haenszel
CRP
C-reactive protein
DBL
database lock
DMARD
disease-modifying anti-rheumatic drug
DMC
Data Monitoring Committee
ECG
electrocardiogram
eCRF
electronic case report form
eDC
electronic data capture
EQ-5D
EuroQol 5 Dimension Questionnaire
ESR
erythrocyte sedimentation rate
FACIT-F
Functional Assessment of Chronic Illness Therapy-Fatigue 
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCQ
hydroxychloroquine
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
hsCRP
high sensitivity C-reactive protein
IB
Investigator's Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IL
interleukin
IM
intramuscular
IRB
Institutional Review Board
IV
intravenous
IWRS
interactive web response system
MA
musculoskeletal assessor
MASES
Maastricht Ankylosing Spondylitis Enthesitis Score
MCS
Mental Component Summary
MOS-SS
Medical Outcomes Study Sleep Scale
MRI
magnetic resonance imaging
MTX
methotrexate
NONMEM
nonlinear mixed effects modeling
nr-AxSpA
nonradiographic axial spondyloarthritis 
NSAID
nonsteroidal anti-inflammatory drug
PCS
Physical Component Summary
PFS
prefilled syringe
PK
pharmacokinetics
PO
orally
PQC
product quality complaint
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STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
17
Approved, Date: 09 April 2015
PRO
patient-reported outcomes
PsA
psoriatic arthritis
q12w
every 12 weeks
RBC
red blood cell
SAE
serious adverse event
SAP
Statistical Analysis Plan
SC
subcutaneous/ subcutaneously
SF-36
36-item short form health survey
SI
sacroiliac
SpA
spondyloarthritis
SSZ
sulfasalazine
SUSAR
suspected unexpected serious adverse reaction
TB
tuberculosis
Th
T-helper
TNFα
tumor necrosis factor alpha
TNF-IR
tumor necrosis factor inadequate response
TOPAS
usTekinumab for the treatment Of Patients with active Ankylosing Spondylitis
TST
tuberculin skin test
V/F
apparent volume of distribution
VAS
visual analog scale
WBC
white blood cell
WPAI - SHP
Work Productivity and Activity Impairment Questionnaire - Specific Health Problem
NCT02407223


STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
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Approved, Date: 09 April 2015
1.
INTRODUCTION
Ustekinumab is a fully human monoclonal antibody (mAb) that binds to the interleukin 
(IL)-12/23p40 protein subunit of human IL-12 and IL-23 with high affinity and specificity. The 
binding of ustekinumab to the IL-12p40 subunit blocks the binding of IL-12 or IL-23 to the 
IL-12R1 receptor on the surface of NK and CD4+ T cells, inhibiting IL-12- and IL-23-specific 
intracellular signaling and subsequent activation and cytokine production. In this manner, 
ustekinumab inhibits the biological activity of IL-12 and IL-23 in all in vitro assays examined.
For the most comprehensive nonclinical and clinical information regarding ustekinumab, refer to 
the latest version of the Investigator's Brochure (IB) and Addenda for ustekinumab.
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.
Disease Background
The spondyloarthritides (ankylosing spondylitis [AS], psoriatic arthritis [PsA], enthesitis-related 
arthritis [a subset of juvenile inflammatory arthritis], the enthesitis/arthritis associated with 
inflammatory bowel disease, and reactive arthritis) are a family of chronic inflammatory 
disorders of unknown etiology characterized by enthesitis (inflammation at the sites where 
tendons or ligaments insert into the bone) and a high association with the human leukocyte 
antigen (HLA)-B27. These syndromes have been more recently distinguished by focusing on the 
peripheral or axial predominance of their inflammatory manifestations. Axial spondyloarthritis 
(AxSpA) is a chronic inflammatory disease of the axial skeleton manifested by back pain and 
progressive stiffness of the spine.
Axial spondyloarthritis is defined using the Assessment of SpondyloArthritis International 
Society (ASAS) 2009 classification criteria as a condition characterized by back pain for at least 
3 months and an age of onset less than 45 years. In addition, evidence of sacroiliitis by 
radiographs or by magnetic resonance imaging (MRI) with at least 1 typical spondyloarthritis
(SpA) feature or the presence of HLA-B27 and at least 2 typical SpA features needs to be 
present. Previously established criteria for AS required radiographic evidence of sacroiliitis.54
With ongoing inflammation, it can take 7 to 10 years for these radiographic damages to become 
evident.36 Axial spondyloarthritis encompasses the continuum of disease presentation, with 10 to 
12% of patients progressing from a nonradiographic state to a radiographic state over 2 years38
and up to approximately 60% progressing to AS over a 4 year period.21 Radiographic AxSpA is 
thus synonymous with established AS with radiographic evidence of sacroiliitis defined by the 
modified New York criteria,54 and therefore radiographic AxSpA and AS terms have been used 
interchangeably throughout the document.
These radiographic changes in the axial skeleton, such as sclerosis, and ankylosis, are not 
necessarily manifestations of active inflammation, but rather reflect the consequences of 
previous inflammation. Nonradiographic axial spondyloarthritis (nr-AxSpA) refers to a 
presentation of AxSpA in subjects who exhibit signs and symptoms of AxSpA, but who do not 
yet have x-ray changes that meet the traditional criteria for diagnosis of AS.
NCT02407223


STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
19
Approved, Date: 09 April 2015
Importantly, patients with nr-AxSpA have similar clinical features and disease activity as those 
with AS. A cohort study of subjects with either AS or nr-AxSpA demonstrated that disease 
activity, fatigue, morning stiffness, and pain at night were comparable in subjects with AS and 
nr-AxSpA.45 Patients with nr-AxSpA typically manifested impairment of function but were not 
yet encumbered by fixed disability from a fused spine that is the hallmark of AS.45
While nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in treating the signs and 
symptoms of nr-AxSpA in many patients, traditional disease-modifying anti-rheumatic drugs 
(DMARDs) are not effective for the axial component, and the use of systemic corticosteroids is 
not supported by evidence. However, anti-tumor necrosis factor alpha (TNFα) therapies have 
been approved for use in AS for several years.
While anti-TNFα agents show efficacy in patients with nr-AxSpA, there are reasons to study the 
effectiveness of new agents targeting different mechanisms of action. For example, there is a 
large subset of the patient population who do not achieve a clinical response, as defined by at 
least 20% improvement from baseline in ASAS measures. Furthermore, an even smaller 
proportion of patients achieve a higher level of ASAS response (40% improvement) following 
treatment with current TNFα therapies, and these products, while efficacious, also have 
significant potential risks. Current ASAS treatment guidelines note that after primary or 
secondary non-response, switching to a different anti-TNFα agent may be successful;7 however 
this is in part because no other effective therapies (other than TNF inhibitors) have been 
approved for use in these patients.
Therefore, for patients with nr-AxSpA, there is an unmet need for new therapies targeting 
pathways other than TNFα, especially those with an improved benefit/risk profile.
1.2.
Overall Rationale for the Study
1.2.1.
Scientific Rationale for Use of Anti-IL-12/23p40 Therapy in Axial 
Spondyloarthritis
Ankylosing spondylitis is thought to be triggered by a combination of both environmental and 
genetic factors. Ankylosing spondylitis is most strongly associated with the HLA-B27 gene, a 
major histocompatibility complex Class I molecule expressed ubiquitously across cell types. 
Misfolding and accumulation of HLA-B27 proteins can activate cellular stress responses that are 
linked to cytokine dysregulation, including upregulation of IL-23 production and induction of the 
T-helper (Th)17 axis.13 The IL-23/Th-17 axis is emerging as an important inflammatory 
pathway, with strong genetic associations with IL-23R polymorphisms having been shown in 
AS,8,14,42 suggesting that IL-23 may be involved in AxSpA disease pathogenesis.24 Interestingly, 
protection from AS, as well as other SpA-associated features like Crohn’s disease and psoriasis, 
is conferred by an IL23R variant due to reductions in responsiveness to IL-23 and downstream 
factors, including Th17.16 Genetic as well as clinical correlations with the IL-23/Th17 pathway 
are also evident in another spondyloarthropathy, PsA.5,25,35,39,40
In terms of cytokine overexpression, elevated IL-23 levels have been reported in AS,47 and 
increased numbers of IL-23 responsive Th17 cells have been demonstrated in peripheral blood 
NCT02407223


STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
20
Approved, Date: 09 April 2015
mononuclear cells from SpA patients.46 Interleukin-23 levels in blood and synovial fluid can be 
higher than normal in SpA patients;33,44 however, serum IL-23 levels have not been shown to 
correlate with disease activity in SpA.34 Cells expressing IL-12 and IL-23 have been detected in 
the subchondral bone marrow and fibrous tissue replacing bone marrow in the facet joints of 
patients with AS.3 Subclinical bowel inflammation is commonly associated with 70% of 
spondyloarthropathy patients, and IL-23 expression is upregulated in the ileum of patients with 
AS.12 Clinical studies of the anti-IL-17 agent, secukinumab, have shown that blocking the Th17 
axis in AS can be an effective approach.4,15,49
Structural damage in AxSpA is characterized by 2 distinct features: erosive bone damage and 
pathological new bone formation. Chronic inflammation in the spine and pelvis stimulates bone 
erosion followed by osteoproliferation and formation of bony spurs that create the ankylosis 
characteristic of the structural damage observed in radiographic AxSpA. In the preclinical 
setting, a pivotal study48 showed that over-expression of IL-23 in a mouse spondylitis model 
leads to axial and peripheral enthesitis and new bone formation by stimulating a population of 
inflammatory CD4−, CD8− resident T cells in the entheses.48 While IL-23 and other cytokines, 
including TNF, IL-1, and IL-6, have been shown to mediate inflammatory processes responsible 
for bone resorption,1,11,24 the link between chronic inflammation and new bone formation are not 
fully understood. Interferon gamma and cytokines downstream of IL-23, including IL-17 and 
IL-22, have been shown to play a role in new bone formation.18,29,48 Therefore, by blocking 
IL-23 and its downstream mediators, ustekinumab may theoretically lead to improvement in 
structural damage over time.
1.2.2.
Rationale for Ustekinumab in Axial Spondyloarthritis
Ustekinumab has shown preliminary efficacy in the radiographic AxSpA population in a small 
open-label study (Section. 1.2.4). The benefits of ustekinumab demonstrated in the PsA 
population26,31,43 are summarized in Section 1.2.3, including improvements in symptoms in the 
subgroups of PsA subjects with spondylitis.
1.2.3.
CNTO1275PSA3001 and CNTO1275PSA3002 PsA Studies
The Sponsor has conducted 2 Phase 3 placebo-controlled studies with ustekinumab in over 
900 subjects 
with 
active 
PsA, 
CNTO1275PSA3001
and 
CNTO1275PSA3002. 
Study CNTO1275PSA3001 included biologic naïve subjects and in study CNTO1275PSA3002, 
approximately 60% of subjects were exposed to anti-TNFα agents prior to study entry. 26,31,43 The 
24-week data from these studies formed the basis for the approval of ustekinumab for the 
treatment of subjects with active PsA. These 2 studies clearly demonstrated improvements in 
peripheral arthritis, physical function, dermatologic manifestation, soft tissue disease (dactylitis 
and enthesitis), and improvements in health-related quality of life in subjects with active PsA.
Approximately 30% of subjects in study CNTO1275PSA3001 and 22% in study 
CNTO1275PSA3002 in addition to peripheral joint involvement, had evidence of spondylitis 
(axial inflammation) at baseline as judged by investigator.  Over 70% of subjects in both trials 
had also evidence of enthesitis based on investigators’ assessment.
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Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
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Approved, Date: 09 April 2015
1.2.3.1.
Subgroup of Subjects with Spondylitis
Efficacy analyses in the spondylitis subset showed improvement for both ustekinumab 45 mg 
and 90 mg in the signs and symptoms of PsA as measured by American College of 
Rheumatology (ACR) 20 at Week 24 which focuses on peripheral manifestations of the disease. 
Results were comparable with other subtypes of PsA.
The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) questionnaire (a validated 
tool for the assessment of spinal disease in subjects with AS) was used as an exploratory analysis 
in the ustekinumab PsA studies for the purpose of providing data on axial manifestations of PsA.
The number of subjects in each study included in the BASDAI analyses was 186 subjects in 
CNTO1275PSA3001 and 70 subjects in CNTO1275PSA3002. In both studies, a significantly 
higher proportion of subjects achieved a BASDAI 50 response at Week 24 in the ustekinumab 
90 mg group compared with placebo (31.7% vs 13.1% [p=0.014] in CNTO1275PSA3001 and 
(38.1% vs 5.6% [p=0.019] in CNTO1275PSA3002) (Figure 1). Numerically higher proportions 
of subjects achieved a BASDAI 50 response in the ustekinumab 45 mg group compared with 
placebo (23.5% vs 13.1% in CNTO1275PSA3001 and 28.0% vs 5.6% in CNTO1275PSA3002; 
(Figure 1).
Figure 1:
Proportion of subjects with BASDAI 50 responses at Week 24 in CNTO1275PSA3001 and 
CNTO1275PSA3002 trials in subjects with active PsA
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STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
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1.2.3.2.
Enthesitis Evaluation
In both Phase 3 studies, a dose response was observed in the percent improvement in enthesitis 
from baseline at Week 24 based on the Maastricht Ankylosing Spondylitis Enthesitis Score 
(MASES). Statistical significance was reached for both dose groups as compared with placebo in 
CNTO1275PSA3001 (median percent change in MASES was -50.00 vs 0.00 for 90 mg vs 
placebo [p<0.001] and -42.86 vs 0.00 for 45 mg vs placebo [p=0.002]), while significance was 
only reached for 90 mg as compared with placebo in CNTO1275PSA3002 (median percent 
change in MASES was -48.33 vs 0.00 for 90 mg vs placebo [p=0.008] and -33.33 vs 0.00 for 
45 mg vs placebo [p=0.098]).
1.2.4.
Investigator-Initiated Study in AS
Ustekinumab was evaluated for the treatment of subjects with active AS in an open-label, 
proof-of-concept investigator-initiated study TOPAS.37
In this study, 20 subjects with active AS (defined as meeting the modified New York criteria and 
having active disease defined as a BASDAI score ≥4 despite concomitant treatment with an 
NSAID) received ustekinumab 90 mg at Weeks 0, 4, and 16, and were followed through 
Week 28. One (5%) of the subjects had previously received anti-TNFα therapy. Subjects who 
had a history of lack of efficacy to an anti-TNFα agent were excluded, but otherwise previous 
exposure to anti-TNFα agents was allowed.
The proportion of subjects who achieved the primary endpoint, ASAS 40 response at Week 24, 
was 65% (Figure 2). Key secondary endpoints also showed clinically meaningful improvement:
75% of subjects achieved an ASAS 20 response at Week 24 and 55% achieved a BASDAI 50 
response at Week 24 (Figure 2). Significant mean improvement from baseline to Week 24 was 
observed for the MRI imaging parameters (sacroiliac [SI] joint osteitis score and spine osteitis 
score).37
Ustekinumab was well tolerated in this study. There was 1 serious adverse event (SAE) of 
hospitalization for back pain due to an uncomplicated flare of AS. No new safety signals were 
detected.
Although this was a small, uncontrolled open label study, the efficacy and safety data showed 
promising results for ustekinumab use in the AS population.
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Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
23
Approved, Date: 09 April 2015
Figure 2:
Summary of Efficacy Results in Investigator Initiated Study in AS (TOPAS)
ASAS=Assessment of SpondyloArthritis international Society; ASAS PR=Assessment of SpondyloArthritis 
international Society-Partial remission; BASDAI=Bath Ankylosing Spondylitis Disease Activity Index; ASDAS 
CII=Ankylosing Spondylitis Disease Activity Score-Clinically Important Improvement; ASDAS MI =Ankylosing 
Spondylitis Disease Activity Score-Major Improvement; PASS=Patient Acceptable Symptom State; 
PhASS=Physician Acceptable Symptom State.
1.3.
Dose Justification
The proposed dose regimen for the CNTO1275AKS3003 study is selected primarily based on the
dosing regimen used in the Phase 3 CNTO1275PSA3001 and CNTO1275PSA3002 studies in 
PsA, supplemented with data from the TOPAS study. Ustekinumab 45 mg and 90 mg (for 
patients weighing >100 kg) at Weeks 0 and 4 followed by every 12 weeks (q12w) maintenance 
therapy are the approved doses for the treatment of patients with active PsA.
The proposed dosing regimens for this Phase 3 study in nr-AxSpA are ustekinumab 45 mg and 
90 mg administered subcutaneously (SC) at Weeks 0 and 4, then q12w. The rationale for the 
45 mg and 90 mg q12w dose regimens is as follows:

In studies CNTO1275PSA3001 and CNTO1275PSA3002 in PsA, improvement in the joint, 
soft tissue, and skin manifestations of active PsA improved through the 24-week 
placebo-controlled observation period and over time for subjects treated with both 
ustekinumab 45 mg and 90 mg.
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STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
24
Approved, Date: 09 April 2015

Most relevant to the proposed study, CNTO1275PSA3001 and CNTO1275PSA3002 
included a subset of total 255 (27.5%) subjects with spondylitis (in addition to peripheral 
arthritis; see Section 1.2.3.1 and Figure 1). These subjects were included in the BASDAI 
analyses. In both studies, and although not powered to show a difference, a significantly 
higher proportion of subjects achieved a BASDAI 50 response at Week 24 in the 
ustekinumab 90 mg group compared with placebo, and there were numerical improvements 
in subjects receiving 45 mg ustekinumab compared with placebo (Section 1.2.3.1)

In both ustekinumab Phase 3 studies in PsA, over 70% of the subjects randomized in each of 
the studies were diagnosed with enthesitis using modified MASES. In both Phase 3 studies, 
a dose response was observed in the percent improvement from baseline in MASES at 
Week 24. Statistical significance was reached for both ustekinumab 45 mg and 90 mg dose 
groups as compared with placebo in CNTO1275PSA3001 while significance was only 
reached for 90 mg as compared with placebo in CNTO1275PSA3002 (Section 1.2.3.2).

Ustekinumab 90 mg was the only dose evaluated for the treatment of patients with active AS 
in an open-label, proof-of-concept investigator-initiated study (TOPAS; Section 1.2.4). 
Although this was a small, uncontrolled study in 20 patients, the efficacy data showed 
promising results for the AS population treated with the 90 mg dose. In addition to the 
primary endpoint (Section 1.2.4), key secondary endpoints (ASAS 20 and BASDAI 50 at 
Week 24) also showed clinically meaningful improvement. The 90 mg dose was well 
tolerated with no safety signals identified. These data at the 90 mg dose were generally 
comparable to other open-label studies of TNFα blockers in AS.27,45

In the global psoriasis and PsA studies, ustekinumab at doses 45 mg and 90 mg was 
generally well tolerated with no clear impact of ustekinumab on the targeted events 
including death, malignancy, serious infections, or major adverse cardiovascular events. The 
cumulative global exposure through 31 December 2014
has been estimated as 
379,596 person-years.
In summary, both the ustekinumab 45 mg and 90 mg doses were demonstrated to be efficacious 
in the treatment of PsA. Improvements in enthesitis in PsA subjects were observed with both 
doses; however the 90 mg dose was associated with somewhat greater improvements that were 
consistently statistically significant across the 2 randomized controlled trials. Reductions in the 
signs and symptoms of spondylitis in patients with PsA in large randomized controlled trials 
were statistically significantly greater in those treated with ustekinumab 90 mg as compared to 
placebo, and numerically greater with 45 mg as compared to placebo. Treatment with 
ustekinumab 90 mg was associated with good efficacy responses in patients with active AS in an 
open-label, proof-of concept study. Overall, the data suggests efficacy in reducing spondylitis 
and enthesitis signs and symptoms may be more robust with the 90 mg dose versus the 45 mg 
dose, supporting a dose-response relationship.
Based on these considerations, it is reasonable to study ustekinumab both 45 mg and 90 mg dose
regimens in the nr-AxSpA Phase 3 study as studied in the Phase 3 PsA and psoriasis clinical 
programs.
In addition to nr-AxSpA study, the ustekinumab AxSpA development program will include 
2 trials in the AS population which will evaluate 45 mg and 90 mg ustekinumab doses in subjects 
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STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
25
Approved, Date: 09 April 2015
with active AS who are anti-TNFα-naïve (CNTO1275AKS3001) and who are inadequate 
responders to anti-TNFα agents (CNTO1275AKS3002).
2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives
Primary Objective
The primary objective of this study is to assess the efficacy of ustekinumab in adult subjects with 
active nr-AxSpA, measured by the reduction in signs and symptoms of nr-AxSpA.
Secondary Objectives
The secondary objectives are:

Efficacy related to improving physical function, range of motion, health-related quality of 
life, and other health outcomes.

Safety.

Pharmacokinetics (PK) and immunogenicity.

Time to flare after the randomized withdrawal.
Exploratory Objective
The exploratory objectives are to evaluate the effect of ustekinumab on pharmacodynamics, 
pharmacogenomics, the microbiome, and structural damage progression in subjects with nr-
AxSpA.
2.2.
Hypothesis
The primary hypothesis for this study is that at least 1 of the ustekinumab groups is statistically 
superior to placebo in reducing the signs and symptoms in subjects with active nr-AxSpA, as 
assessed by the proportion of subjects who achieve at least 20% improvement from baseline in 
the ASAS criteria (ASAS 20) at Week 24.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a Phase 3 multicenter, randomized, double-blind, placebo-controlled study of the efficacy 
and safety of ustekinumab compared with placebo in adult subjects with active nr-AxSpA with 
an inadequate response or intolerance to NSAIDs and/or exposure to no more than 1 anti-TNFα 
agent. Approximately 390 subjects will be randomized at approximately 85 investigational sites. 
The sample size of the study may be increased to approximately 480 subjects if the number of 
subjects with an inadequate response to no more than 1 anti-TNFα agent is higher than 
anticipated among the first 200 subjects randomized (See Section 11.2 for details). Subjects will 
be randomly assigned to receive SC ustekinumab 45 mg or 90 mg or placebo administrations at 
Weeks 0, 4, and 16. At Week 16, subjects in the placebo group who qualify for early escape 
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STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
26
Approved, Date: 09 April 2015
(subjects with <10% improvement from baseline in both total back pain and morning stiffness 
measures at both Week 12 and Week 16), will begin receiving randomly assigned SC 
ustekinumab 45 mg or 90 mg administrations at Weeks 16, 20, and 28 and q12w thereafter 
through Week 52. At Week 24, all remaining subjects in the placebo group who did not meet 
early escape criteria will be rerandomized to receive ustekinumab 45 mg or 90 mg at Weeks 24 
and 28 followed by q12w therapy through Week 52. Subjects in the ustekinumab treatment 
groups will receive a placebo administration at Weeks 20 and 24 to maintain the blind and 
continue to receive SC ustekinumab 45 mg or 90 mg at Week 28 and q12w thereafter through 
Week 52. At Week 52, all subjects who achieve inactive disease (Ankylosing Spondylitis 
Disease Activity Score [ASDAS] erythrocyte sedimentation rate [ESR] <1.3) at both Week 40 
and Week 52 visits will undergo rerandomization to either remain on ustekinumab or receive 
placebo.
Subjects who do not achieve inactive disease (ASDAS [ESR] <1.3) at either the Week 40 or 
Week 52 visit will receive their previously assigned ustekinumab dose at their scheduled visits.
All subjects who experience a flare after Week 52 defined as ASDAS (ESR) >2.1 will be given 
the option to discontinue study injections and utilize an alternative therapy per the physicians’ 
discretion or to continue study injections in a blinded fashion. Subjects who elect to continue and 
were rerandomized to placebo at Week 52 will have ustekinumab injections reinstituted at their 
next scheduled visit. Subjects who elect to continue and were rerandomized to ustekinumab at 
Week 52 will continue with ustekinumab dose at their scheduled visits.
Database locks (DBL) are scheduled for Weeks 24, 52, and 100.
An independent Data Monitoring Committee (DMC) will be commissioned for this study. For 
details, refer to Section 11.12, Data Monitoring Committee.
A pharmacogenomic blood sample will be collected from subjects who consent separately to this 
component of the study
where local regulations permit.
Subject participation in 
pharmacogenomics research is optional.
Subjects will be followed for adverse events (AEs) and SAEs at least 12 weeks following the last 
study treatment administration. The end of study is defined as the time the last subject completes 
the Week 100 visit.
A diagram of the study design is provided below in Figure 3.
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STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
27
Approved, Date: 09 April 2015
Figure 3:
Schematic Overview of the Study from Screening through Week 52
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Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
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Approved, Date: 09 April 2015
Figure 4:
Schematic Overview of the Study from Week 52 through Week 100
3.1.1.
Study Population
The target study population is subjects with active nr-AxSpA, defined as subjects with AxSpA 
with evidence of sacroiliitis on MRI or elevated high sensitivity C-reactive protein (hsCRP)
≥0.6 mg/dL at screening, and no radiographic sacroiliitis fulfilling the 1984 modified New York 
Criteria. In addition, all subjects will have active disease, as evidenced by BASDAI score ≥4 and 
a visual analog scale (VAS) score for total back pain of ≥4, each on a scale of 0 to 10.
Study population will include adult subjects who have active nr-AxSpA disease and have had an 
inadequate response or intolerance to NSAIDs. Subjects who received 1 anti-TNF agent will be 
allowed into the study. Anti-TNFα-exposed subjects include those who have had an inadequate 
response or intolerance to 1 anti-tumor necrosis factor alpha (TNFα) agent (TNF-IR) or cannot 
continue anti-TNF therapy due to other reasons.
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Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
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Approved, Date: 09 April 2015
3.1.2.
Treatment Groups, Dosage, and Dose Administrations Interval
At Week 0, approximately 390 nr-AxSpA subjects (n = 130 per arm) who satisfy all inclusion 
and exclusion criteria will be randomly assigned in a 1:1:1 ratio to placebo, ustekinumab 45 mg 
or 90 mg. Block randomization will be used. Randomization will be stratified by MRI/hsCRP 
status (MRI+/hsCRP+; MRI+/hsCRP-; MRI-/hsCRP+) and by the status of previous exposure to 
anti-TNFα therapy (naïve, TNF-IR, or other).
At Week 16, placebo subjects meeting early escape criteria (<10% improvement from baseline in 
both total back pain and morning stiffness measures at both Week 12 and Week 16) will be 
randomly assigned via the interactive web response system (IWRS) to begin receiving either 
ustekinumab 45 mg or 90 mg in a blinded fashion. Subjects in ustekinumab treatment groups 
who meet early escape criteria will continue their assigned randomization treatment. At 
Week 24, all remaining placebo subjects who did not meet early escape criteria will be 
randomized to receive ustekinumab 45 mg or 90 mg at Weeks 24 and 28 followed by q12w 
therapy through Week 52.
At Week 52, all subjects who have achieved inactive disease (ASDAS [ESR] <1.3) at both 
Week 40 and Week 52 visits will be rerandomized using IWRS to either stay on ustekinumab 
therapy (45 mg or 90 mg q12w) or to receive placebo in a blinded fashion through Week 88. 
Subjects will be assigned to treatment groups using permuted block randomization.
At Week 52, subjects who have not achieved inactive disease at either Week 40 or Week 52 will 
continue their assigned treatment regimen through Week 88.
All subjects will be assessed for flare after Week 52. Assessments for flare will occur at each 
study visit after Week 52 or on demand. On demand assessment may be done during an 
unscheduled visit. Subjects who experience a flare after Week 52 defined as ASDAS (ESR) >2.1
at a scheduled or unscheduled visit will be given the option to discontinue study injections and 
utilize an alternative therapy per the physicians’ discretion or to continue study injections in a 
blinded fashion. (In either case, adjustments in permitted concomitant therapy will be allowed 
upon flare [See Section 6.1 for details]).  Subjects electing to continue on study injections will be 
dosed at their next scheduled visit, and subjects receiving placebo injections who elect to 
continue study injections will have ustekinumab reinstated at the next scheduled visit. Upon 
decision to treat flare, site personnel and subjects will remain blinded to the study treatment 
received prior to flare. Subjects with flares who elect to continue study treatment will be 
followed until Week 100. Subjects who choose alternative therapy and do not continue study 
injections will have safety and efficacy assessments performed 12 weeks (Week 100 
assessments) after last injection.
Subjects who do not meet the definition of flare will continue on assigned therapy through 
Week 88 in blinded fashion.
The study will end when the last subject completes the last scheduled visit (Week 100 visit).
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Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
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3.1.3.
Study Phases and Duration of Treatment
There will be 4 phases in this study:  Screening, placebo-controlled and active treatment, 
randomized withdrawal, and efficacy/safety follow-up. The screening phase of up to 8 weeks 
will allow for sufficient time to perform screening study evaluations and determine study 
eligibility.  The second phase of the study will be the placebo-controlled and active treatment 
from Week 0 to Week 52. The third phase of the study will be the randomized withdrawal period
from Week 52 through Week 88. The fourth phase of the study will be the efficacy and safety 
follow-up phase for 12 weeks from the last administration of study agent. Initial treatment 
assignment for each subject will be blinded to sites and subjects throughout the 100 weeks of the 
study.
3.1.4.
Study Control, Randomization, and Blinding
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. Block randomization will be used in this 
study. In addition, randomization will be stratified by MRI/hsCRP status (MRI+/hsCRP+; 
MRI+/hsCRP-; MRI-/hsCRP+) and by status of previous exposure to anti-TNFα therapy (naïve, 
TNF-IR, or other).
Individual subjects and investigators will remain blinded for the duration of the study, until the 
Week 100 DBL has occurred. Blinded treatment will be used to reduce potential bias during data 
collection and evaluation of clinical endpoints. Three DBLs are planned for the study at 
Week 24, Week 52 and Week 100. Limited Sponsor personnel will be unblinded to subject-level 
data at the Week 24 and Week 52 DBLs for data analyses and data review. Identification of 
Sponsor personnel who will have access to the unblinded subject-level data for the Week 24 
DBL will be documented prior to unblinding.
3.2.
Study Design Rationale
As described in Section 1.2.1, there is substantial scientific evidence supporting the critical role 
of IL-23 in the pathogenesis of nr-AxSpA. Specifically, the clinical response to ustekinumab 
observed in Phase 3 PsA trials, especially for the spondylitis/enthesitis subset of subjects, and the 
fact that there is a close genetic/pathophysiologic connection between PsA and AxSpA as well as
the response noted in the open label ‘TOPAS’ trial supports a direct to Phase 3 approach. The 
dose justification for this study is described in Section 1.3.
Study Population Rationale
The target study population includes adult subjects fulfilling 2009 ASAS criteria with no 
evidence of radiographic sacroiliitis. In order to address the concern of treating subjects with a 
self-limiting condition or with mechanical back pain, and to better define distinct populations of 
interest, the Sponsor will require that subjects have objective signs of inflammation, ie, 
sacroiliitis on MRI for those meeting the imaging arm criteria and hsCRP >0.6 mg/dL for those
meeting the clinical arm criteria. In addition, all eligible subjects will be required to have active 
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Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
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Approved, Date: 09 April 2015
disease based on symptoms (defined as BASDAI and total back pain ≥4) which should further 
assure selection of subjects being the most appropriate candidates for a treatment with a biologic. 
Therefore, the Sponsor’s criteria for enrollment in the study should reliably exclude subjects with 
non-inflammatory mechanical back pain.
Blinding, Control, Study Phase/Periods, Treatment Groups
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 primary endpoint is evaluated at 
Week 24, which is the time point used in the ustekinumab PsA Phase 3 studies.26,31,43
Ustekinumab is expected to achieve maximal efficacy by Week 20 to Week 28 of treatment 
based on the findings in the ustekinumab Phase 3 studies in subjects with PsA. The 100-week 
study duration is preferred over a shorter study (eg, 24 or 28 weeks) to ensure that ustekinumab 
reaches steady-state exposures and to allow sufficient time to evaluate the durability of the effect 
(eg, time to flare after treatment withdrawal) and safety of ustekinumab in subjects with active 
nr-AxSpA over a prolonged period of time. Subjects in all treatment groups will always have the 
option to withdraw from the study at any time for any reason, including inadequate response.
Biomarker Collection
Biomarker samples will be collected to evaluate the mechanism of action of ustekinumab or help 
to explain inter-individual variability in clinical outcomes or may lead to identification of 
population subgroups that respond differently to this study agent. The goal of the biomarker 
analyses is to evaluate the pharmacodynamics effects of ustekinumab and aid in evaluating the 
drug-clinical response relationship.
Biomarker samples may be used to help address emerging issues, better understand the natural 
history or nr-AxSpA and to enable the development of safer, more effective, and ultimately 
individualized therapies for patients with nr-AxSpA.
4.
SUBJECT POPULATION
Screening for eligible subjects will be performed within 8 weeks before administration of the 
study agent.
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator should consult with the appropriate Sponsor representative before enrolling a subject 
in the study.
4.1.
Inclusion Criteria
Each potential nr-AxSpA subject must satisfy all of the following criteria to be enrolled in the 
study. 
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Clinical Protocol CNTO1275AKS3003
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1.
Subjects must be between 18 (or the age of consent for the country if older than 
18 years) and 50 years of age, inclusive.
2.
Subjects must be classified as having nr-AxSpA based on 2009 ASAS criteria:

Have back pain ≥3 months and age at onset ≤45 years, and

Active (acute) inflammation on MRI highly suggestive of sacroiliitis associated 
with spondyloarthritis, AND at least 1 of the following SpA features:

Inflammatory back pain

Arthritis

Enthesitis in the heel

Uveitis

Dactylitis

Psoriasis

Crohn’s disease/colitis

Good response to NSAIDs

Family history for SpA

HLA-B27 positive

Elevated CRP
OR

HLA-B27 positive
AND, at least 2 of these SpA features:

Inflammatory back pain

Arthritis

Enthesitis of the heel

Uveitis

Dactylitis

Psoriasis

Crohn’s disease/colitis

Good response to NSAIDs

Family history for SpA

Elevated CRP.
3.
Subjects must have nr-AxSpA diagnosis per 2009 ASAS criteria for ≤5 years.
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Clinical Protocol CNTO1275AKS3003
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4.
Subjects must have an age at nr-AxSpA onset of ≤45 years.
5.
Subjects must have at screening or within 3 months of screening, active inflammation 
on MRI highly suggestive of sacroiliitis associated with spondyloarthritis (as evidenced 
by the central readers) and no radiographic sacroiliitis that fulfills the 1984 modified 
New York Criteria (as confirmed by x-ray assessed by central readers).
Types of findings required for definition of sacroiliitis by MRI according to 2009 ASAS 
criteria will include:

Bone marrow edema (Short Tau Inversion Recovery) highly suggestive of SpA 
must be clearly present and located in the typical anatomical areas (subchondral or 
periarticular bone marrow).

If there is only 1 signal (lesion) per MRI slice suggesting active inflammation, the 
lesion should be present on at least 2 consecutive slices. If there is more than 
1 signal (lesion) on a single slice, 1 slice may be sufficient.
OR,
Subjects must have an elevated hsCRP level of ≥0.6 mg/dL at screening and no 
radiographic sacroiliitis that fulfills the 1984 modified New York Criteria (as confirmed 
by x-ray assessed by central readers).
NOTE: A one-time repeat assessment of hsCRP level is allowed during the 8-week 
screening period and the Investigator may consider the subject eligible if the test result 
is within protocol acceptable range on repeat testing in the central laboratory.
6.
Subjects must have symptoms of active disease at screening and at baseline, as 
evidenced by both a BASDAI score of 4 and a VAS score for total back pain of 4, 
each on a scale of 0 to 10.
7.
Subjects must either have an inadequate response to at least 2 NSAIDs over a 4-week 
period in total with maximal recommended doses of NSAID(s), or is unable to receive a 
full 4 weeks of maximal NSAID therapy because of intolerance, toxicity, or 
contraindications to NSAIDs.
8.
Subjects previously treated with a biologic anti-TNFagent, must:
a.
Be a primary or secondary non-responder to no more than 1 anti-TNFagent, 
or
b.
Have a documented intolerance to no more than 1 anti-TNFtherapy (eg, 
infusion/injection site reaction, or other AE(s) that precludes continuation of 
anti-TNFagent) or
c.
Discontinued no more than 1 anti-TNFagent for a non-efficacy/non-safety 
reason.
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Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
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9.
If using NSAIDs or other analgesics for nr-AxSpA, subjects must be on a stable dose 
for at least 2 weeks prior to the first administration of study agent. If currently not using 
NSAIDs or other analgesics for nr-AxSpA, must not have received NSAIDs or other 
analgesics for nr-AxSpA for at least 2 weeks prior to the first administration of the study 
agent.
10.
If using oral corticosteroids, subjects must be on a stable dose equivalent to 10 mg of 
prednisone/day for at least 2 weeks prior to the first administration of study agent. If 
currently not using corticosteroids, must have not received oral corticosteroids for at 
least 2 weeks prior to the first administration of the study agent.
11.
If using methotrexate (MTX), sulfasalazine (SSZ), or hydroxychloroquine (HCQ), 
subjects should have started treatment at least 3 months prior to the first administration 
of study agent and should have no serious toxic side effects attributable to those 
DMARDs. MTX routes of administration and doses (not to exceed 25 mg/week) should 
be stable for at least 4 weeks prior to the first administration of the study agent. If using 
SSZ or HCQ, must also be on a stable dose for at least 4 weeks prior to the first 
administration of study agent. If currently not using MTX, SSZ, or HCQ, must have not 
received these DMARDs for at least 4 weeks prior to the first administration of the 
study agent.
12.
Before randomization, a woman must be either:

Not of childbearing potential: premenarchal; postmenopausal (>45 years of age 
with amenorrhea for at least 12 months); permanently sterilized (eg, tubal 
occlusion, hysterectomy, bilateral salpingectomy); or otherwise be incapable of 
pregnancy,

Of childbearing potential and 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 associated with inhibition of 
ovulation; placement of an intrauterine device or intrauterine system; 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 childbearing potential changes after start of the study (eg, woman who 
is not heterosexually active becomes active, premenarchal woman experiences 
menarche) a woman must begin a highly effective method of birth control, as 
described above.
13.
A woman of childbearing potential must have a negative serum (-human chorionic 
gonadotropin at screening and a negative urine pregnancy test at Week 0 before 
randomization.
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Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
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Approved, Date: 09 April 2015
14.
A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during the study and for 5 months after receiving the last dose of study 
agent.
15.
A man who is sexually active with a woman of childbearing potential and 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, and all men 
must also not donate sperm during the study and for 5 months after receiving the last 
dose of study agent.
16.
Subjects are considered eligible according to the following tuberculosis (TB) screening 
criteria:
a.
Have no history of latent or active TB prior to 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 prior to first 
administration of study agent, or have documentation of having completed 
appropriate treatment for latent TB within 5 years prior to 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.
Have no signs or symptoms suggestive of active TB upon medical history 
and/or physical examination.
c.
Have 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 prior to the first administration of study agent.
d.
Within 8 weeks prior to the first administration of study agent, have a negative 
QuantiFERON®-TB Gold test result, or have a newly identified positive 
QuantiFERON®-TB Gold test result (Appendix A) in which active TB has 
been ruled out and for which appropriate treatment for latent TB has been 
initiated prior to the first administration of study agent.  Within 8 weeks prior 
to the first administration of study agent, a negative tuberculin skin test (TST)
(Appendix B), or a newly identified positive TST in which active TB has been 
ruled out and for which appropriate treatment for latent TB (Section 9.1.2) has 
been initiated prior to the first administration of study agent, is additionally 
required if the QuantiFERON®-TB Gold test is not approved/registered in that 
country or the TST is mandated by local health authorities.
e.
Subjects with persistently indeterminate QuantiFERON®-TB Gold test results 
may be enrolled 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.
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Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
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Approved, Date: 09 April 2015
f.
The QuantiFERON®-TB Gold test and the TST 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.
g.
Have a chest radiograph (posterior-anterior and lateral views, or per country 
regulations where applicable) taken within 3 months prior to the first 
administration of study agent and read by a qualified radiologist, with no 
evidence of current, active TB or old, inactive TB.
17.
Subjects must have screening laboratory test results within the following parameters: 
a.
Hemoglobin
8.5 g/dL
(SI:  85 g/L) 
b. White blood cells  3.5 x 103/L
(SI:  3.5 GI/L)
c.
Neutrophils
1.5 x 103/L
(SI:  1.5 GI/L)
d. Platelets 100 x 103/L
(SI:  100 GI/L)
e.
Serum creatinine 1.5 mg/dL
(SI:  129 mol/L)
f.
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline 
phosphatase levels must be within 1.5 times the upper limit of normal range for 
the laboratory conducting the test.
NOTE: A one-time repeat of these screening laboratory tests is allowed during the 
8-week screening period and the Investigator may consider the subject eligible if the 
previously abnormal laboratory test result is within acceptable range on repeat testing in 
the central laboratory (Section 9.1.2).
18.
Subject must be willing and able to adhere to the prohibitions and restrictions specified 
in this protocol.
19.
Be able to read, write, understand and complete study questionnaires.
20.
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 are willing to 
participate in the study. 
21.
Each subject must sign a separate ICF if he or she agrees to provide an optional DNA 
sample for research (where local regulations permit). Refusal to give consent for the 
optional DNA research sample does not exclude a subject from participation in the 
study.
22.
Subjects must be willing to refrain from the use of complementary therapies including 
ayurvedic medicine, traditional Chinese medication(s), and acupuncture within 2 weeks 
prior to the first study agent administration and throughout the duration of the study.
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Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
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Approved, Date: 09 April 2015
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study. 
1.
Have radiographic sacroiliitis fulfilling the 1984 modified New York Criteria (as 
confirmed by x-ray assessed by central readers).
2.
Have other inflammatory diseases that might confound the evaluations of benefit from 
the ustekinumab therapy, including but not limited to: rheumatoid arthritis, systemic 
lupus erythematosus, or Lyme disease.
3.
Are pregnant, nursing, or planning a pregnancy or fathering a child while enrolled in the 
study or within 5 months after receiving the last administration of study agent.
4.
Have received any systemic immunosuppressives or DMARDs other than MTX, SSZ, 
or HCQ within 4 weeks prior to first administration of study agent. Medications in these 
categories include, but are not limited to chloroquine, azathioprine, cyclosporine, 
tacrolimus, mycophenolate mofetil, gold, and penicillamine. Corticosteroids are not 
included in this criterion; see other eligibility criteria regarding corticosteroids.
5.
Have received leflunomide within 3 months prior to the first administration of study 
agent (irrespective of undergoing a drug elimination procedure), or have received 
leflunomide within 12 months prior to the first administration of study agent and have 
not undergone a drug elimination procedure.
6.
Have received epidural, intra-articular, intramuscular (IM), or intravenous (IV)
corticosteroids, including adrenocorticotropic hormone during the 4 weeks prior to first 
administration of study agent.
7.
Have ever received ustekinumab or any other agent that targets IL-23.
8.
Have received more than 1 prior anti-TNFα agent.
9.

Have received infliximab or infliximab biosimilar, within 12 weeks of the first study 
agent administration.

Have received adalimumab, adalimumab biosimilar, golimumab, or certolizumab 
pegol within 6 weeks of the first study agent administration.

Have received etanercept, etanercept biosimilar, or yisaipu within 6 weeks of the 
first study agent administration.
Anti-TNFtherapy
Last Treatment prior to first study agent 
administration
Infliximab, infliximab biosimilar
12 weeks
Adalimumab, adalimumab biosimilar, 
golimumab, or certolizumab pegol
6 weeks
Etanercept, etanercept biosimilar or yisaipu
6 weeks
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STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
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Approved, Date: 09 April 2015
10. Have received prior biologic therapy other than anti-TNFα agents, before the planned 
first dose of study agent, including but not limited to tocilizumab, alefacept, efalizumab, 
natalizumab, abatacept, anakinra, ustekinumab, brodalumab, secukinumab, ixekizumab, 
and B-cell depleting therapies.
11. Have ever received tofacitinib or any other Janus kinase inhibitor.
12. Have a known hypersensitivity to human immunoglobulin proteins.
13. Have used cytotoxic drugs, including chlorambucil, cyclophosphamide, nitrogen 
mustard, or other alkylating agents.
14. Have a history of active granulomatous infection, including histoplasmosis, or 
coccidioidomycosis, prior to screening. Refer to Inclusion Criteria #16 for information 
regarding eligibility with a history of latent TB.
15. Have had a Bacille Calmette-Guérin (BCG) vaccination within 12 months of screening.
16. Have a chest radiograph within 3 months prior to the first administration of study agent
that shows an abnormality suggestive of a malignancy or current active infection, 
including TB. 
17. Have had a nontuberculous mycobacterial infection or opportunistic infection 
(eg, cytomegalovirus, pneumocystosis, aspergillosis).
18. Have received, or are expected to receive, any live virus or bacterial vaccination within 
3 months before the first administration of study agent, during the study, or within 
3 months after the last administration of study agent. For BCG vaccination criterion, 
refer to Exclusion Criterion #15.
19. Have a history of an infected joint prosthesis, or have received antibiotics for a 
suspected infection of a joint prosthesis, if that prosthesis has not been removed or 
replaced.
20. Have had a serious infection (including but not limited to, hepatitis, pneumonia, sepsis, 
or pyelonephritis), or have been hospitalized for an infection, or have been treated with 
IV antibiotics for an infection within 2 months prior to 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.
21. Have 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), an open, draining, or 
infected skin wound, or an ulcer.
22. Subject has a history of human immunodeficiency virus (HIV) antibody positive, or 
tests positive for HIV at screening.
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STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
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Approved, Date: 09 April 2015
23. Has a hepatitis B infection. Subjects must undergo screening for hepatitis B virus 
(HBV). At a minimum, this includes testing for hepatitis B surface antigen (HBsAg;
HBV surface antigen), anti-HBs (HBV surface antibody), and anti-HBc total (HBV core 
antibody total).
24. Subjects who are seropositive for antibodies to hepatitis C virus (HCV), unless they 
have 2 negative HCV RNA test results 6 months apart prior to screening and have a 
third negative HCV RNA test result at screening.
25. Have current signs or symptoms of severe, progressive, or uncontrolled renal, hepatic, 
hematological, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, cerebral, or 
psychiatric disease.
26. Have a known history of lymphoproliferative disease, including lymphoma, or signs and 
symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy 
of unusual size or location, clinically significant splenomegaly, or history of monoclonal 
gammopathy of undetermined significance.
27. Subject has a history of malignancy within 5 years before screening (exceptions are 
squamous and basal cell carcinomas of the skin that has been treated with no evidence 
of recurrence for at least 3 months before the first study agent administration and 
carcinoma in situ of the cervix that has been surgically cured).
28. Subject has known allergies, hypersensitivity, or intolerance to ustekinumab or its 
excipients (refer to the ustekinumab IB).
29. Are currently receiving venom immunotherapy (honeybee, wasp, yellow jacket, hornet, 
or fire ant).
30. Subject has received an investigational drug (including investigational vaccines) within 
5 half-lives or 3 months, whichever is longer, or used an invasive investigational 
medical device within 3 months before the planned first dose of study agent or is 
currently enrolled in an investigational study.
31. Subject 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.
32. Subject has had major surgery, (eg, requiring general anesthesia) within 1 month before 
screening, or will not have fully recovered from surgery, or has surgery planned during 
the time the subject is expected to participate in the study or within 1 month after the 
last dose of study agent administration.
Note: subjects with planned surgical procedures to be conducted under local anesthesia 
may participate.
33. Have a transplanted organ (with the exception of a corneal transplant performed 
>3 months prior to first administration of study agent).
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STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
40
Approved, Date: 09 April 2015
34. Have or have had a substance abuse (drug or alcohol) problem within the previous 3 
years.
35. Are unwilling or unable to undergo multiple venipunctures because of poor tolerability 
or lack of easy access.
36. Subject is an employee 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 he or she no longer 
meets all eligibility criteria, then the subject should be excluded from participation in the study. 
Section 17.4, Source Documentation, describes the required documentation to support meeting 
the 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.
Both heterosexually active women of childbearing potential and men capable of fathering a 
child must consent to use a highly effective method of contraception and continue to use 
contraception for the duration of the study and for 5 months after the last administration of 
study agent.
2.
A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during the study and for 5 months after receiving the last dose of study agent.
3.
All men must also not donate sperm during the study and for 5 months after receiving the 
last dose of study agent.
4.
Must agree not to receive an investigational medical device for the duration of this study.
5.
The use of the following drugs is not permitted concomitantly with study agent
administration and within 12 weeks after the :last study agent administration:

Systemic immunosuppressives or DMARDs (other than MTX, SSZ, and HCQ) 
including chloroquine, azathioprine, oral cyclosporine A, tacrolimus, mycophenolate 
mofetil, leflunomide, oral or parenteral gold. Systemic immunosuppressives do not 
refer to corticosteroids; see Section 8.2 regarding corticosteroid restrictions.

Biologic agents targeted at reducing TNF(including but not limited to infliximab
[Remicade®, Remsima®, Inflectra®, Infimab®], golimumab, certolizumab pegol, 
etanercept [Yisaipu, Etanar®] and adalimumab [Humira®, Exemptia®].

Biologic agents targeting IL-1ra (anakinra).
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STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
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Approved, Date: 09 April 2015

Tocilizumab or any other biologic targeting IL-6 or IL-6 receptor.

Tofacitinib or any other Janus kinase inhibitor.

B-cell depleting agents (eg, rituximab).

Alefacept or efalizumab.

Cytotoxic drugs such as cyclophosphamide, chlorambucil, nitrogen mustard, or other 
alkylating agents.

Abatacept.

Anti-IL-17 agents (eg, brodalumab, secukinumab, and ixekizumab). 

Any anti-integrin therapy (eg, natalizumab or vedolizumab).

Investigational drugs.
6.
Subjects must not receive a live virus or bacterial vaccination during the study and for 
3 months after the last administration of study agent.
7.
Subjects must not receive a BCG vaccination during the study and for 12 months after the 
last administration of study agent.
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. The IWRS will assign a unique 
treatment code, which will dictate the treatment assignment for the subject. The requestor must 
use his or her own user identification and personal identification number when contacting the 
IWRS, and will then give the relevant subject details to uniquely identify the subject.
At Week 0, eligible subjects will be randomly assigned to receive ustekinumab 45 mg or 90 mg 
or placebo based on a computer-generated randomization schedule prepared before the study 
under the supervision of the Sponsor. Subject allocation to a treatment group will be done using 
a stratified block randomization method in a 1:1:1 ratio to 1 of 3 treatment groups. 
Randomization will be stratified by MRI/hsCRP status (MRI+/hsCRP+; MRI+/hsCRP-; 
MRI-/hsCRP+) and by the status of previous exposure to anti-TNFα (naïve, TNF-IR, or other).
At Week 16, subjects in the placebo group who meet early escape criteria: <10% improvement 
from baseline in both total back pain and morning stiffness measures at both Week 12 and 
Week 16, will be randomly assigned using IWRS to begin receiving either ustekinumab 45 mg or 
90 mg in a blinded fashion. At Week 24, all remaining placebo subjects not meeting early escape 
criteria will crossover to ustekinumab 45 mg or 90 mg randomly at Weeks 24 and 28 followed 
by q12w therapy through Week 52.
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STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
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Approved, Date: 09 April 2015
At Week 52, subjects who achieve inactive disease defined by ASDAS (ESR) <1.3 at both 
Week 40 and Week 52 will be rerandomized using permuted block method by the IWRS to 
either stay on therapy or withdraw from therapy (ie, receiving placebo treatment).
Blinding
To maintain the study blind, the study agent container will have a multipart label containing the 
study name, study agent number, and reference number, and other information on each part. 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. 
However, if it is necessary for a subject's safety, the study blind may be broken and the identity 
of the study agent ascertained. The study agent number will be entered in the case report form 
when the study agent is administered. The study agents will be identical in appearance and will 
be packaged in identical containers.
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, and treatment allocation) 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 time of DBL and 
unblinding.
Under normal circumstances, the blind should not be broken until all subjects have completed 
the study and the database is 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 the blind is broken, the Sponsor must be informed as soon as possible. The date of 
unblinding must be documented by the IWRS, in the appropriate section of the electronic case 
report form (eCRF), and in the source document; the reason for unblinding must be documented 
in the appropriate section of the eCRF 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.
Subjects who have had their treatment assignment unblinded should continue to return for 
scheduled evaluations. The decision to continue or discontinue study treatment for these subjects 
will be based upon consultation of the investigator with the study responsible physician.
The study responsible physician will remain blinded throughout the study to subject level 
treatment assignment and dosing regimen. At the Week 24 DBL, the data will be unblinded for 
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STELARA® (ustekinumab)
Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
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Approved, Date: 09 April 2015
analysis while subjects are still participating in the study. Identification of Sponsor personnel 
who will have access to the unblinded subject level data will be documented prior to unblinding.
6.
DOSAGE AND ADMINISTRATION
6.1.
Dosing Regimen and Blinding
Before the first study agent administration, subjects will be randomly assigned in a ratio of 1:1:1 
to 1 of 3 treatment groups:
Week 0 to Week 52 (Placebo-Controlled and Active Treatment Phase)

Group 1 (placebo): Placebo SC at Weeks 0, 4, 16, and 20. At Week 24 all subjects (with 
exception of subjects who qualified for early escape) will crossover and be rerandomized to 
receive ustekinumab 45 mg or 90 mg SC at Weeks 24 and 28 followed by q12w dosing 
through Week 52.

Group 2 (ustekinumab 45 mg): Ustekinumab 45 mg SC at Weeks 0 and 4, followed by 
q12w dosing through Week 52. At Weeks 20 and 24, subjects will receive placebo SC to 
maintain the blind.

Group 3 (ustekinumab 90 mg): Ustekinumab 90 mg SC at Weeks 0 and 4, followed by 
q12w dosing through Week 52. At Weeks 20 and 24, subjects will receive placebo SC to 
maintain the blind.
Early Escape
At Week 16, subjects in the placebo group with <10% improvement from baseline in both total 
back pain and morning stiffness measures at both Week 12 and Week 16 will enter early escape 
in a double-blinded fashion. Subjects in the placebo group who qualify for early escape will be 
rerandomized to receive ustekinumab 45 mg or 90 mg at Weeks 16, 20, and 28 followed by 
q12w dosing through Week 52. Subjects in Groups 2 and 3 who meet early escape criteria will 
continue on their already assigned doses through Week 52.
Any subject with <10% improvement from baseline in total back pain and morning stiffness 
measures will be allowed to discontinue study agent at any time and be transferred to alternative 
therapy.
Week 52 to Week 88 (Randomized Withdrawal)

Group 1a (placebo → 45 mg): At Week 52, subjects randomized to placebo at Week 0 who 
received ustekinumab 45 mg after Week 16 (ie, placebo subjects who qualified for early 
escape at Week 16 and then were randomized to ustekinumab 45 mg or placebo subjects 
who were randomized to ustekinumab 45 mg at Week 24) and who achieved inactive 
disease by ASDAS (ESR) <1.3 at both Week 40 and Week 52 will be rerandomized to 
receive placebo or to continue on ustekinumab 45 mg q12w in a blinded fashion.
At Week 52, subjects who did not achieve inactive disease by ASDAS (ESR) <1.3 at 
Week 40 or Week 52 will continue receiving ustekinumab 45 mg q12w through Week 88.
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Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
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Approved, Date: 09 April 2015

Group 1b (placebo → 90 mg): At Week 52, subjects randomized to placebo at Week 0 
who received ustekinumab 90 mg after Week 16 (ie, placebo subjects who qualified for 
early escape at Week 16 and then were randomized to ustekinumab 90 mg or placebo 
subjects who were randomized to ustekinumab 90 mg at Week 24) and who achieved 
inactive disease by ASDAS (ESR) <1.3 at both Week 40 and Week 52 will be rerandomized 
to receive placebo or to continue on ustekinumab 90 mg q12w in a blinded fashion.
At Week 52, subjects who did not achieve inactive disease by ASDAS (ESR) <1.3 at 
Week 40 or Week 52 will continue receiving ustekinumab 90 mg q12w through Week 88.

Group 2 (ustekinumab 45 mg): At Week 52, subjects randomized at Week 0 to 
ustekinumab 45 mg and who achieved inactive disease by ASDAS (ESR) <1.3 at both 
Week 40 and Week 52 will be rerandomized to receive either placebo or ustekinumab 45 mg 
q12w in a blinded fashion.
At Week 52, subjects who did not achieve inactive disease by ASDAS (ESR) <1.3 at 
Week 40 or Week 52 will continue receiving ustekinumab 45 mg q12w through Week 88.

Group 3 (ustekinumab 90 mg): At Week 52, subjects randomized at Week 0 to 
ustekinumab 90 mg and who achieved inactive disease by ASDAS (ESR) <1.3 at both 
Week 40 and Week 52 will be rerandomized to receive either placebo or ustekinumab 90 mg 
q12w in a blinded fashion.
At Week 52, subjects who did not achieve inactive disease by ASDAS (ESR) <1.3 at 
Week 40 or Week 52 will continue receiving ustekinumab 90 mg q12w through Week 88.
Flares
All subjects who experience a flare after Week 52 defined as ASDAS (ESR) >2.1 will be given 
the option to discontinue study administrations and utilize an alternative therapy per the 
physicians’ discretion or to continue study agent in a blinded fashion. At the time of flare, 
concomitant medication, including NSAIDs, oral corticosteroids, analgesics, and non-biologic 
DMARDs (MTX, SSZ, HCQ) can be adjusted per investigator’s discretion. Subjects who elect to 
continue and were rerandomized to placebo at Week 52 will have ustekinumab administrations 
reinstituted at their next scheduled visit (Figure 4).
Flares will be assessed at each visit after Week 52 or on demand. On demand assessment will be 
done during unscheduled visit upon subject request.
After the last study agent injection at Week 88, the subjects will be followed for safety and 
efficacy at Week 100.
To maintain the blind, all randomized subjects will receive each administration of study agent as 
2 SC injections in 2 different locations as follows:

Ustekinumab 45 mg: 0.5 mL ustekinumab 45 mg injection and 1.0 mL placebo injection;

Ustekinumab 90 mg: 1.0 mL ustekinumab 90 mg injection and 0.5 mL placebo injection;

Placebo: 0.5 mL placebo injection and 1.0 mL placebo injection.
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Nonradiographic-Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3003
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6.2.
Study agent Administration and Timing
All postbaseline visits through Week 24 may occur at the indicated week ±4 days. After 
Week 24 and throughout the study, visits may occur at the indicated week ±7 days. In case it is 
not possible to administer the missed injection in time, site personnel should discuss the issue 
with the medical monitor.
7.
TREATMENT COMPLIANCE
Study agent will be administered SC by a qualified individual who administers study agent at the 
study sites throughout the study. Study personnel will maintain a log of all study agent 
administrations. Study personnel will inventory and account for study agent supplies for each 
subject. All ongoing therapies administered at the time of screening must be recorded.
It is understood that treatment may be interrupted for health-related or safety reasons, but 
compliance with the treatment schedule is strongly encouraged.
8.
CONCOMITANT THERAPY
Every effort should be made to keep subjects’ concomitant medications stable through Week 24 
or as specified in the following sections. The concomitant medication dose may be reduced or 
the medication temporarily discontinued because of abnormal laboratory values, side effects,
concurrent illness, or the performance of a surgical procedure, but the change and reason for the 
change should be clearly documented in the subject’s medical record.
Concomitant medication review will occur at study visits identified in the Time and Events 
Schedule.
8.1.
Methotrexate, Sulfasalazine, or Hydroxychloroquine
Subjects are permitted to enter the study on stable doses of MTX, SSZ, or HCQ.
If subjects are using MTX, SSZ, or HCQ, treatment should have started at least 3 months prior to 
the first administration of study agent. MTX routes of administration and doses ≤25 mg/week 
should be stable for at least 4 weeks prior to the first administration of the study agent. It is 
recommended that all subjects taking MTX in this study receive at least 5 mg oral folate or 5 mg 
folinic acid weekly. If using SSZ or HCQ, subjects must also be on a stable dose for at least 
4 weeks prior to the first administration of study agent. Every effort should be made to maintain 
stable doses and routes of administration of MTX, SSZ, and HCQ through Week 24 of the study 
in subjects receiving this medication. After Week 24 and through the end of the study, dose 
adjustment in MTX, SSZ, and HCQ is allowed, except the dose should not be increased above 
the study entry level dose. Upon flare occurring after Week 52, dose increases can be done as 
needed.
Subjects not on treatment with MTX, SSZ, or HCQ must have discontinued the treatment for at 
least 4 weeks prior to the first administration of study agent, and must not receive MTX, SSZ, or 
HCQ through Week 52. After Week 52 and upon flare, these medications can be introduced and 
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adjusted as needed. Guidelines for dose adjustment in the event of MTX toxicity are included in 
the Trial Center File.
8.2.
Corticosteroid Therapy
Subjects treated with oral corticosteroids for AxSpA should receive a stable dose equivalent to 
≤10 mg prednisone per day for at least 2 weeks prior to first administration of study agent and 
continue to receive this dose through Week 24; the dose and type of oral corticosteroid may be 
changed at the discretion of the investigator only if the subject develops unacceptable side 
effects. After Week 24 and through Week 52, dose adjustment in oral corticosteroids is allowed, 
except the dose should not be increased above the study entry level dose. After Week 52 and 
upon flare, the dose of oral corticosteroids can be adjusted as needed.
Subjects not treated with oral corticosteroids at baseline must have discontinued oral 
corticosteroids at least 2 weeks prior to the first administration of study agent, and they must not 
receive oral corticosteroids for AxSpA through Week 52. After Week 52 and upon flare, oral 
corticosteroids can be introduced and adjusted as needed.
Intravenous, IM, or epidural administration of corticosteroids for the treatment of nr-AxSpA is 
not allowed through Week 52.
Short-term (≤2 weeks) oral, IV, IM, or epidural corticosteroid used for indications other than 
AxSpA should be limited to situations where, in the opinion of the treating physician, there are 
no adequate alternatives. Long-term (>2 weeks) oral or IV corticosteroids use for indications 
other than AxSpA are not allowed throughout the course of the study. 
Inhaled, otic, ophthalmic, intranasal, and other routes of mucosal delivery of corticosteroids are 
allowed throughout the course of the study.
Attempts should be made to avoid intra-articular corticosteroid injections especially during the 
first 24 weeks of the study. However if necessary, subjects may receive up to 2 intra-articular, 
tendon sheath, or bursal corticosteroid injections in no more than 2 affected sites during the 
52 weeks of the study. In the case of severe tenderness or swelling in a single joint, it is 
suggested that the subject be evaluated for infection prior to receiving an intra-articular 
corticosteroid injection.
8.3.
Nonsteroidal Anti-inflammatory Drugs and Other Analgesics
The use of stable doses of NSAIDs and other analgesics is allowed.
Subjects treated with NSAIDs, including aspirin and selective cyclooxygenase-2 inhibitors, and 
other analgesics should receive the usual marketed doses approved in the country in which the 
study is being conducted, and should have been on a stable dose at least 2 weeks prior to the first 
administration of the study agent. Through Week 24, the dose and type of NSAIDs and other 
analgesics may be changed only if the subject develops unacceptable side effects. After 
Week 24, dose adjustment is allowed.
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The use of topical analgesics including capsaicin and diclofenac is allowed. The dose of topical 
analgesics may be adjusted, except for analgesic patches. For transdermal analgesic patches, the 
dose should be stable through Week 24 and may be changed only if the subject develops 
unacceptable side effects. After Week 24, dose adjustment in analgesic patches is allowed; in this 
study.
Subjects not treated with NSAIDs or other analgesics at baseline must not have received 
NSAIDs and other analgesics at least 2 weeks prior to the first administration of study agent, and 
they must not receive NSAIDs and other analgesics for AxSpA through Week 24. After 
Week 24, NSAIDs and other analgesics can be introduced and adjusted as needed.
Aspirin is considered an NSAID, except for low-dose aspirin prescribed for cardiovascular or 
cerebrovascular disease.
8.4.
Disease Modifying Antirheumatic Drugs/Systemic Immunosuppressives
Disease modifying antirheumatic drugs/systemic immunosuppressive agents, with the exception 
of MTX, SSZ, and HCQ must be discontinued at least 4 weeks prior to the first administration of 
study agent and are prohibited throughout the study. These DMARDs include, but are not limited 
to, chloroquine, gold preparations, penicillamine, and leflunomide. If a subject received 
leflunomide within 12 months prior to the first administration of study agent, the subject must 
have undergone a drug elimination procedure. Prohibited systemic immunosuppressive drugs 
throughout the study (ie, up to 12 weeks post last study agent dose), include, but are not limited 
to, cyclosporine, tacrolimus, mycophenolate mofetil, and azathioprine (see Section 4.3). 
Systemic immunosuppressives do not refer to corticosteroids; see Section 8.2 for restrictions 
regarding the use of corticosteroids.
8.5.
Biologic Agents or Investigational Agents
The use of biologic agents (eg, golimumab, anakinra, etanercept, adalimumab, infliximab, 
tocilizumab, alefacept, efalizumab, rituximab, natalizumab, abatacept, commercial ustekinumab, 
brodalumab, secukinumab, ixekizumab), cytotoxic agents (eg, chlorambucil, cyclophosphamide,
nitrogen mustard, other alkylating agents), or investigational drugs is not allowed throughout the 
study (ie, up to 12 weeks post last study agent dose). If any of these medications are used, the 
subject will be discontinued from further study agent injections.
8.6.
Complementary Therapies
The use of complementary therapies including, but not limited to, ayurvedic medicine, traditional 
Chinese medications or non-medicinal therapy such as acupuncture is not allowed throughout the 
study.
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9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule summarizes the frequency and timing of efficacy, PK,
immunogenicity, biomarker, pharmacogenomic, medical resource utilization, health economic,
and safety measurements applicable to this study.
All visit-specific patient-reported outcomes (PRO) assessments should be conducted/completed
before any tests, procedures, or other consultations for that visit to prevent influencing subject 
perceptions. For additional details, refer to the PRO user manual.
For women of childbearing potential only, 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 study.
Also additional TB tests may be performed as determined necessary by the investigator or 
required by local regulation.
Health economics data will be collected. For details see Section 9.6.
Every effort should be made to perform all other assessments as specified in the Time and Events 
Schedule unless logistically not feasible, and if possible, the same individual(s) should perform 
the assessments at each visit.
Serum for the analysis of biomarkers and whole blood (for gene expression analysis) will be 
collected from all subjects. At Weeks 0, 24, and 52, a single whole blood sample for DNA 
analysis will be collected only from subjects who have consented to participate in the optional 
pharmacogenomics (DNA) component of the study. Blood samples for DNA analyses will only 
be collected if permitted by local regulations. Refer to the Laboratory Reference Manual for the 
Pharmacogenomics Sample Collection and Shipment Procedures for details on collecting and 
handling blood samples for pharmacogenomics research. In the event of DNA extraction failure, 
a replacement pharmacogenomics blood sample may be requested from the subject. Signed 
informed consent will be required to obtain a replacement sample.
The total blood volume to be collected from each subject will be approximately 250 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
9.1.2.
Screening Phase
Screening procedures will be performed as indicated in Table 1.
After written informed consent has been obtained and within a period of 8 weeks before 
randomization, all screening evaluations will be performed.  The screening visit may be divided 
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into no more than 2 visits.  For example, after obtaining informed consent, the investigator will 
complete all laboratory tests at the first visit.  The subject will then return for the remainder of 
the screening procedures only if the subject is eligible for the study as determined by the central 
laboratory test results. Subjects who meet all of the inclusion and none of the exclusion criteria 
will be enrolled in the study. Every effort should be made to adhere to the study Time and Events 
Schedule for each subject. Subjects must complete a separate written pharmacogenomics 
informed consent to participate in the optional pharmacogenomics research component of the 
study.
Women of childbearing potential must have a negative serum pregnancy test at screening and a 
negative urine pregnancy test before randomization. Women of childbearing potential and men 
capable of fathering a child must agree to use a highly effective method of contraception and 
continue to use contraception for the duration of the study and for 5 months after.  The method(s) 
of contraception used by each subject must be documented. For details, see Section 4.1.
A 12-lead electrocardiogram (ECG) will be performed locally at screening to ensure that if a 
subject should require an ECG during the study for any reason, an ECG prior to first study agent
administration is available for comparison to detect changes.
A chest radiograph will be performed at screening to ensure that the subject does not have any 
abnormality suggestive of a malignancy or current active infection, including TB. Chest x-rays 
taken up to 3 months prior to the first administration of study agent may be used.
Subjects must undergo testing for TB (Appendix A and Appendix B) 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 TST result in 
countries in which the QuantiFERON®-TB Gold test is not approved/registered or the TST is 
mandated by local health authorities) are eligible to continue with prerandomization procedures.  
Subjects with a newly identified positive QuantiFERON®-TB Gold test (or TST) result must 
undergo an evaluation to rule out active TB and initiate appropriate treatment for latent TB prior 
to the administration of the first dose of study agent. An exception is made for subjects currently 
receiving treatment for latent TB with no evidence of active TB, or who have a history of latent 
TB and documentation of having completed appropriate treatment for latent TB within 5 years 
prior to the first administration of study agent.  These subjects do not need to be retested with the 
QuantiFERON®-TB Gold test (or TST) during screening. 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 must be excluded from the study. It is the responsibility of the investigator to verify 
the adequacy of previous anti-TB treatment and provide appropriate documentation.
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, 
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the subject may be enrolled 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.
Retesting
The re-testing of abnormal screening laboratory blood tests and hsCRP levels that lead to 
exclusion is allowed only once using an unscheduled visit during the screening period (to 
reassess eligibility).
If a subject has signed the ICF and failed to meet at least 1 entry requirement, the site may retest 
lab values or repeat a study entry procedure once during the screening period. This is inclusive of 
only 1 additional blood draw to be completed for retesting, regardless of whether an additional 
lab value is found to be out of range. The goal of the retest procedure is to assess if the subject is 
eligible for randomization within the screening window or should be considered a screen failure.
Subjects that have lab values that do not meet entry criteria following the retest are to be deemed 
a screen failure. An exception to this is a positive QuantiFERON®-TB Gold test which may not 
be repeated to meet eligibility criteria.
Rescreening
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 one 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 restart a new screening phase.
9.1.3.
Treatment Phases
Treatment phases include the placebo-controlled and active treatment, and randomized 
withdrawal phases. At Week 0, eligible subjects will be randomly assigned to receive 1 of 
3 treatments: placebo, ustekinumab 45 mg, or ustekinumab 90 mg. For additional details, see 
Section 6.1.
9.1.4.
Posttreatment Phase (Follow-Up)
Subjects will be instructed that study agent will not be made available to them after they have 
completed/discontinued study agent and that they should return to their primary physician to 
determine standard of care.
All subjects who complete the Week 88 visit assessments will be asked to return for a final 
safety and efficacy visit at Week 100.
If a subject discontinues study agent at any time before the Week 24 visit, the subject should 
return for all visits through Week 24. If a subject discontinues study agent after Week 24 and
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before the Week 88 visit, all assessments performed at the Week 100 visit (Table 1) should be
performed 12 weeks after the last study agent administration.
No procedures and evaluations should be conducted after a subject withdraws consent.
9.2.
Efficacy
9.2.1.
Evaluations
9.2.1.1.
Assessment of SpondyloArthritis International Society Response 
Criteria
A 20% improvement in response according to the criteria of the ASAS (ASAS 20)2,50,53 is 
defined as:
1.
An improvement of ≥20% from baseline and absolute improvement from baseline of at least 
1 on a 0 to 10 scale in at least 3 of the following 4 domains:
i. Patient global
ii. Total back pain
iii. Function (Bath Ankylosing Spondylitis Functional Index [BASFI])
iv. Inflammation (average of the last 2 questions of the BASDAI concerning 
morning stiffness)
2.
Absence of deterioration from baseline (≥20% and worsening of at least 1 on a 0 to 10 scale) 
in the potential remaining domain.
ASAS 40 is defined as a ≥40% improvement in 3 of 4 domains, with an absolute improvement of 
at least 2 on a 0 to 10 scale, and no deterioration at all in the remaining domain.
ASAS 5/6 is defined as a ≥20% improvement in any 5 of the 6 domains of pain (VAS 0 to 10), 
patient global (VAS 0 to 10), function (BASFI score), morning stiffness (from BASDAI), 
hsCRP, and spine mobility (lumbar side flexion).
ASAS partial remission is defined as a value below 2 on a scale of 0 to 10 in each of the 4 ASAS 
domains described above.
9.2.1.2.
Bath Ankylosing Spondylitis Disease Activity Index
The BASDAI20 is defined below:
Subject self-assessment using a VAS (0 to 10) on the following criteria:
A.
Fatigue
B.
Spinal pain
C.
Joint pain
D.
Enthesitis
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E.
Qualitative morning stiffness
F.
Quantitative morning stiffness
The BASDAI = 0.2 (A + B + C + D + 0.5[E + F]).
9.2.1.3.
Bath Ankylosing Spondylitis Functional Index
The BASFI is a subject’s self-assessment represented as a mean (VAS; 0 to 10) of 10 questions, 
8 of which relate to the subject’s functional anatomy and 2 of which relate to a subject’s ability 
to cope with everyday life.9 An increase along the scale indicates a worsening condition.
9.2.1.4.
Patient’s Global Assessment
Patient’s global assessment of disease activity will be recorded on a VAS (0 to 10; 0 = very well, 
10 = very poor).
9.2.1.5.
Total Back Pain
Subjects will be asked to assess their average total back pain over the past week on a VAS (0 to 
10; 0 = no pain, 10 = most severe pain).
9.2.1.6.
Night Back Pain
Subjects will be asked to assess their nighttime back pain during the past week on a VAS (0 to 
10; 0 = no pain, 10 = most severe pain).
9.2.1.7.
Morning Stiffness
Measured by the average of the responses to the last 2 questions of the BASDAI.
9.2.1.8.
Musculoskeletal Assessments
The musculoskeletal assessments will include each component of the BASMI (Section 9.2.1.8.1), 
chest expansion (Section 9.2.1.8.2), and enthesitis index (Section 9.2.1.8.3).
A MA with adequate training and experience in performing musculoskeletal assessments will be 
designated at each study site to perform all musculoskeletal assessments. The MA should 
preferably be a rheumatologist but if a rheumatologist is not available, should be a health care 
provider with at least 1 year of experience in performing musculoskeletal assessments (for 
additional details, see the Investigative Site File). Health care providers with less than 1 year of 
experience may serve as an MA based upon the discretion and approval of the Sponsor. It is 
recommended that the designated MA identifies an appropriate back-up MA for coverage in the 
event of absences of the designated MA. It is strongly recommended that the same MA who 
performs the baseline musculoskeletal assessments for a subject should also perform the 
musculoskeletal assessments for that subject at every subsequent visit through Week 100.
The Sponsor will provide training for each site’s designated MA prior to the screening of the first 
subject at each site. A back-up MA must complete training before performing a musculoskeletal 
assessment for a subject’s study visit. Training documentation of each MA should be maintained 
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at the study site. However it is recommended that the MA should not be changed during the 
study.
If an MA was trained by the Sponsor in a previous clinical study within the last 3 years and there 
is documentation of this training (certification), that training will be considered adequate for this 
study; however, repeat training prior to start of the trial is encouraged.
All MAs performing the musculoskeletal evaluation at a site must be listed on the Delegation 
Log at the study site and should be documented in the source documents at each visit.
9.2.1.8.1.
Bath Ankylosing Spondylitis Metrology Index
The Bath Ankylosing Spondylitis Metrology Index (BASMI) is represented as an aggregate 
score of 5 components (ranging from 0 to 10) and will be calculated using the van der Heijde 
calculation51 as shown in Table 2. A musculoskeletal assessor (MA; Section 9.2.1.8) will perform 
all BASMI assessments.
Table 2:
Scores (S) for the five components of the BASMIlin
S = 0 if:
Between 0 and 10:
S = 10 if:
Lateral lumbar flexion* (cm)
A 21.1
S = (21.1-A)/2.1
A 0.1
Tragus-to-wall distance* (cm)
A 8
S = (A-8)/3
A 38
Lumbar flexion (modified Schober) (cm)
A 7.4
S = (7.4-A)/0.7
A 0.4
Intermalleolar distance (cm)
A 124.5
S = (124.5-A)/10
A 24.5
Cervical rotation angle* ()
A 89.3
S = (89.3-A)/8.5
A 4.3
*
For lateral lumbar flexion, tragus-to-wall distance, and cervical rotation the average of right and left should be 
taken.  If a score lies beyond the range 0–10, the values 0 or 10 have to be used, respectively.

The BASMIlin is the mean of the five S scores.

The assessments (A) of the 5 components will be collected at the sites when analysis is 
performed and the scores (S) will be calculated programmatically.
9.2.1.8.2.
Chest Expansion
Chest expansion is the difference, in cm, between the circumference of the chest in maximal 
inspiration and maximal expiration. It is measured at the level of the fourth intercostal space in 
males, and just below the breasts in females.  The MA will perform all chest expansion 
assessments.
9.2.1.8.3.
Enthesitis Index
Enthesitis will be assessed using the MASES index.23 The MASES index was developed to 
assess enthesitis in subjects with ankylosing spondylitis, and evaluates the presence or absence of 
pain by applying local pressure to the following entheses:
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
1st costochondral joint, left and right;

7th costochondral joint, left and right;

posterior superior iliac spine, left and right;

anterior superior iliac spine, left and right;

iliac crest, left and right;

5th lumbar spinous process;

proximal insertion of Achilles tendon, left and right.
The range of MASES is 0 to 13.
The MA will perform all enthesitis assessments.  The Sponsor will provide enthesitis assessment 
training.  Documentation of this training will be maintained in the study site’s training files.
9.2.1.9.
Ankylosing Spondylitis Disease Activity Score
The ASAS has developed a disease activity score for use in AS, the ASDAS.30,52 For this study, 
the following formulae will be used to calculate the ASDAS score:
ASDAS (C-reactive protein [CRP]) = 0.121 x Total back pain + 0.058 x Duration of morning 
stiffness + 0.110 x Patient global assessment + 0.073 x Peripheral pain/ swelling + 0.579 x Ln 
(hsCRP (mg/L) +1).
ASDAS (ESR) = 0.08 × Back Pain + 0.07 × Duration of Morning Stiffness + 0.11 × Patient 
global assessment + 0.09 × Peripheral Pain/Swelling + 0.29 × √(ESR)
Major improvement in ASDAS is defined as a decrease ≥2.0. Inactive disease is defined as an 
ASDAS score <1.3.
Clinically important improvement in ASDAS is defined as a decrease ≥1.1 (www.asas-
group.org).
9.2.1.10.
Imaging Evaluations
9.2.1.10.1.
X-ray of Sacroiliac Joints
All subjects will have x-rays of SI joints at screening and at Week 100. An existing x-ray done 
within 3 months of screening may be sent for central reading in lieu of screening x-ray. Detailed 
information on the acquisition of the x-rays will be provided in an Imaging Manual.
Sacroiliac joints will be scored for the presence of sacroiliitis by the central readers using the 
following Sacroiliitis scoring system for x-rays.54

Grade 0: normal

Grade 1: suspicious changes
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
Grade 2: minimum abnormality (small localized areas with erosion or sclerosis, without 
alteration in the joint width)

Grade 3: unequivocal abnormality (moderate or advanced sacroiliitis with erosions, evidence 
of sclerosis widening, narrowing, or partial ankylosis)

Grade 4: severe abnormality (total ankylosis)
9.2.1.10.2.
Magnetic Resonance Imaging
Magnetic resonance imaging is a powerful tool for detecting bone and soft tissue structural 
changes within the spine, is superior to plain radiograph for thoracic spine imaging in nr-AxSpA, 
and has greater sensitivity compared to plain radiographs for measuring changes occurring over 
shorter time intervals.6 MRI-based markers potentially could predict sites of eventual 
radiographic structural progression years later.
MRI of the SI joints will be performed at screening, Week 24, and Week 100.
The MRIs will be read centrally by experienced MRI reviewers. Detailed information on the 
acquisition of the MRI scans will be provided in an Imaging Manual.
9.2.1.11.
36-Item Short-form Health Survey
The 36-item short form health survey (SF-36) questionnaire 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);

general health perception. 
These 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). These summary scores are also scaled 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.55 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.56
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9.2.1.12.
Medical Outcomes Study Sleep Scale
The extent of sleep problems will be assessed using the Medical Outcomes Study Sleep Scale 
(MOS-SS).22 Medical Outcomes Study Sleep Scale measures six dimensions of sleep, including 
initiation, maintenance (eg, staying asleep), quantity, adequacy, somnolence (eg, drowsiness), 
and respiratory impairments (eg, shortness of breath, snoring). The MOS-SS is a generic health 
measure, assessing a health-related quality of life concept-sleep that is relevant to everyone’s
health status and wellbeing and known to be directly affected by disease and treatment. As such, 
the MOS-SS is not specific to any age, disease, or treatment group. The reliability and validity of 
the MOS-SS have been evaluated in a number of disease areas, including neuropathic pain and 
rheumatoid arthritis.
9.2.1.13.
Ankylosing Spondylitis Quality of Life (ASQoL) Questionnaire
Ankylosing Spondylitis Quality of Life questionnaire is a self-administered PRO instrument.17 It 
consists of 18 items requesting a Yes or No response to questions related to the impact of pain on 
sleep, mood, motivation, ability to cope, activities of daily living, independence, relationships, 
and social life. A score of 1 is given to a response of ‘YES” on each item and all item scores are 
summed to a total score with a range of 0 to 18. Higher scores indicate worse health related 
quality of life. Subjects can complete the instrument in less than four minutes.
9.2.1.14.
Functional Assessment of Chronic Illness Therapy−Fatigue 
Questionnaire
The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire 
consists of 13 questions that assess a subject’s level of fatigue and tiredness over the last 7 days.  
Each question is graded on a 5-point scale (0 = not at all; 1 = a little bit; 2 = somewhat; 3 = quite 
a bit; 4 = very much), then scored 0 to 4; accordingly, total scores can range from 0 to 52. Lower 
score reflects more severe fatigue. Although not developed for nr-AxSpA, FACIT-F has 
demonstrated strong internal consistency and test-test reliability. It distinguishes between healthy 
and PsA patients and is correlated with swollen joint count and actively inflamed joint count. In
rheumatology, a change of 4 points is considered meaningful10 and has been used in the PsA 
population.32
9.2.1.15.
Euroqol 5 Dimension Questionnaire
The Euroqol 5 Dimension Questionnaire (EQ-5D) is a standardized measure of health status 
developed by the EuroQoL Group to provide a simple, generic measure of health for clinical and 
economic appraisal.19 The EQ-5D is applicable to a wide range of health conditions and 
treatments. EQ-5D essentially consists of 2 elements: The EQ-5D descriptive system and the EQ 
visual analogue 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 respondent is asked to indicate his/her health state by ticking (or placing 
a cross) in the box against the most appropriate statement in each of the 5 dimensions. This 
decision results in a 1-digit number expressing the level selected for that dimension.  The digits 
for 5 dimensions can be combined in a 5-digit number describing the respondent’s health state 
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which can be converted into a single summary index (EQ-5D index) by applying a formula that 
attaches values (also called weights) to each of the levels in each dimension. The EQ VAS 
records the respondent’s self-rated health on a vertical line, VAS where the endpoints are labeled 
‘Best imaginable health state’ and ‘worst imaginable health state’. The EQ VAS can be used as a 
quantitative measure of health outcome as judged by the individual respondents.
9.2.2.
Endpoints
Primary Endpoint
The primary endpoint is the proportion of subjects achieving an ASAS 20 response at Week 24.
Major Secondary Endpoint(s)
The following major secondary analyses will be performed. The major secondary endpoints are 
listed in order of importance as specified below:
1.
The proportion of subjects who achieve an ASAS 40 at Week 24.
2.
The proportion of subjects who achieve at least 50% improvement from baseline in 
BASDAI at Week 24.
3.
The change from baseline in BASFI at Week 24.
4.
The proportion of subjects who achieve ASDAS (CRP) inactive disease (<1.3) at Week 24.
Other Secondary Endpoints

The proportion of subjects who achieve ASAS partial remission.

The proportion of subjects who achieve ASAS 20.

The proportion of subjects who achieve ASAS 40.

The proportion of subjects who achieve an ASAS 5/6 response.

The proportion of subjects who achieve a ≥20%, ≥50%, ≥70%, ≥90% improvement from 
baseline in BASDAI.

The change from baseline in hsCRP.

The change from baseline in chest expansion.

The change from baseline in ASDAS (CRP).

The proportion of subjects who achieve ASDAS (CRP) inactive disease (<1.3).

The proportion of subjects who achieve ASDAS (CRP) major improvement (decrease ≥2.0).

The proportion of subjects who achieve ASDAS (CRP) clinically important improvement 
(decrease ≥1.1).

The change from baseline in the enthesitis scores in subjects with enthesitis at baseline.

The change from baseline in MRI inflammation scores of the SI joints.

The change from baseline in inflammation (average of the last 2 questions of the BASDAI 
concerning morning stiffness).
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
The change from baseline in total back pain.

The proportion of subjects with radiographic sacroilitis at Week 100.

The change from baseline in patient global assessment.

The change from baseline in SF-36 subscales.

The change from baseline in the PCS scores of SF-36.

The change from baseline in the MCS scores of SF-36.

The change from baseline in domain scores of MOS-SS.

The change from baseline in ASQoL scores.

The change from baseline in Euroqol 5 Dimension (EQ-5D) VAS and in EQ-5D index.

The change from baseline in BASMI.

The change from baseline in FACIT-Fatigue.

The time from Week 52 to flare through Week 100.
9.3.
Pharmacokinetics and Immunogenicity
Serum samples will be used to evaluate the PK of ustekinumab, as well as the immunogenicity of 
ustekinumab (antibodies to ustekinumab). Serum collected for PK and immunogenicity analyses 
may additionally be used to evaluate safety or efficacy aspects that address concerns arising 
during or after the study period. Genetic analyses will not be performed on these serum samples. 
Subject confidentiality will be maintained.
9.3.1.
Serum Collection and Handling
Venous blood samples will be collected at the time points shown in the Time and Events 
Schedule (Table 1) for the determination of serum ustekinumab concentrations and antibodies to 
ustekinumab. Serum samples will also be collected at the final visit from subjects who terminate 
study participation early. At visits where PK and immunogenicity will be evaluated, 1 blood 
draw of sufficient volume can be used. Each sample will be split into 3 aliquots (1 aliquot for 
serum ustekinumab concentration, 1 aliquot for antibodies to study agent, and 1 aliquot as a 
back-up). Samples must be collected before study agent administration at visits when a study 
agent administration is scheduled. The exact dates and times of blood sample collection must be 
recorded in the laboratory requisition form.
Additional information about the collection, handling, and shipment of biological samples can be 
found in the Laboratory Manual.
9.3.2.
Analytical Procedures
9.3.2.1.
Pharmacokinetics of Ustekinumab
Serum samples will be analyzed to determine serum ustekinumab concentrations using a 
validated, specific, and sensitive immunoassay method by Sponsor’s bioanalytical facility or 
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under the supervision of the Sponsor. The Sponsor, or its designee, under conditions in which the 
subjects’ identity remains blinded, will assay these samples.
9.3.2.2.
Immunogenicity (Antibodies to Ustekinumab)
Antibodies to ustekinumab will be detected using a validated immunoassay method in serum 
samples collected from all subjects. Serum samples that test positive for antibodies to 
ustekinumab will be further characterized to determine if antibodies to ustekinumab could 
neutralize the biological effects of ustekinumab in vitro (ie, neutralizing antibodies [NAbs] to 
ustekinumab). All samples will be tested by the Sponsor or Sponsor's designee.
9.4.
Pharmacodynamic Evaluations
9.4.1.
Serum Biomarkers
Samples for the analysis of pharmacodynamic markers will be collected at Weeks 0, 24, and 52. 
The samples will be used to better understand the biology of nr-AxSpA, to provide a biological 
assessment of the response of patients to treatment with ustekinumab, to analyze differences 
between responders and non-responders, and to determine if the markers can be used to classify 
patients as potential responders prior to treatment. Serum samples will be used to analyze 
inflammation and spondyloarthropathy related proteins. Markers related to the biology of 
nr-AxSpA, including (but not limited to) Th17, IL12/23, and bone homeostasis pathways will 
also be measured. RNA from whole blood samples will be used for gene expression analysis to 
determine the molecular profile of nr-AxSpA and assess changes in gene expression post 
ustekinumab treatment.
9.4.2.
Microbiome Substudy
This study will include a fecal microbiome substudy. Approximately 100 subjects will be asked 
to provide stool samples. The objective of the fecal biomarker study is to assess whether 
bacterial species, products of bacterial species, and products of host:bacterial interactions are 
associated with nr-AxSpA or response to ustekinumab. Samples will be collected at baseline, 
Week 4, Week 24, Week 52, and Week 100 in both anti-TNFα naïve and anti-TNFα experienced
subjects.
Participation in this portion of the study is optional and subjects must consent to participate in 
the microbiome substudy in the ICF. Note that genetic analyses of the subject's DNA or RNA 
will not be performed on these samples. Further, a subject may withdraw such consent at any 
time without affecting their participation in other aspects of the study, or their future 
participation in the study.
9.5.
Pharmacogenomic (DNA) Evaluations
In addition to HLA-B27 genotyping, complete genomic testing and/or targeted sequencing will 
be performed to search for links of specific genes to disease or response to drug. DNA 
methylation testing will also be performed to evaluate epigenetics. Only DNA research related to 
ustekinumab or to the diseases for which this drug is developed will be performed. Genome wide 
pharmacogenetics testing as well as methylation testing will be undertaken in this study in
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consenting subjects only. Participation in this portion of the study is optional and subjects must 
sign a separate pharmacogenetics informed consent. Further, a subject may withdraw such 
consent at any time without affecting their participation in other aspects of the study, or their 
future participation in the study.
9.6.
Health Economics
9.6.1.
Work Productivity and Activity Impairment Questionnaire
The Work Productivity and Activity Impairment Questionnaire - Specific Health Problem 
(WPAI-SHP) is a validated instrument that has been used to study the impact of various diseases 
on patients’ ability to work and perform daily activities.41 The WPAI:SpA assesses the impact of 
AS on work and other daily activities during the past 7 days. The WPAI:SpA consists of six 
questions to determine employment status, hours missed from work due to AS, hours missed 
from work for other reasons, hours actually worked, the degree to which AS affected work 
productivity while at work and the degree to which AS affected activities outside of work. Four 
scores are derived: percentage of absenteeism, percentage of presenteeism (reduced productivity 
while at work), an overall work impairment score that combines absenteeism and presenteeism 
and percentage of impairment in activities performed outside of work. Greater scores indicate 
greater impairment.
9.7.
Safety Evaluations
Details regarding the independent DMC are provided in Section 11.12.
Any clinically relevant changes occurring during the study must be recorded on the Adverse 
Event section of the CRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will 
be followed by the investigator until resolution or until a clinically stable endpoint is reached.
Safety and tolerability will be assessed by collecting information on AEs, clinical laboratory 
tests, vital signs, physical examinations, concomitant medication review, injection evaluations, 
allergic reactions, and early detection of TB.
Hematology assessments will include but are not limited to the following: hemoglobin, 
hematocrit, platelet count, total and differential white blood cell count.
Blood chemistry assessments will include but are not limited to the following: chemistry panel 
(total and direct bilirubin, ALT, AST, alkaline phosphatase, albumin, total protein, calcium, 
phosphate, sodium, potassium, chloride, blood urea nitrogen/urea, and creatinine).
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Time and Events Schedule:
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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 study. Adverse events 
will be followed by the investigator as specified in Section 12, Adverse Event Reporting.
Clinical Laboratory Tests 
Blood samples for serum chemistry and hematology will be collected. The investigator must 
review the laboratory report, document this review, and record any clinically relevant changes 
occurring during the study in the AE section of the eCRF.
Tests being performed by the central laboratory include, but are not limited to, the following:

Hematology Panel 
-hemoglobin
-WBC (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils [%, absolute])
-hematocrit
-platelet count
-red blood cell (RBC)
-mean corpuscular volume
-mean corpuscular hemoglobin 
-mean corpuscular hemoglobin concentration 
-RBC morphology
-WBC morphology (if present)

Serum Chemistry Panel
-sodium
-total bilirubin
-potassium
-bilirubin (direct and indirect)
-urea nitrogen 
-calcium
-creatinine
-phosphorous
-albumin
-AST
-total protein
-ALT
-alkaline phosphatase
-chloride
-bicarbonate
-nonfasting glucose

Serum pregnancy testing for women of childbearing potential only will be conducted at 
screening. 

Urine pregnancy testing for women of childbearing potential.
During the study, all abnormal laboratory values will require further explanation from the 
investigator. Clinically significant abnormal laboratory values should be repeated until they 
return to normal or are otherwise explained by the investigator.
Vital Signs
Pulse and blood pressure will be collected.
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Height and Weight
Height and weight will be measured as specified in the Time and Events Schedule.
Electrocardiogram
A 12-lead ECG will be performed at screening.
Concomitant Medication Review
Concomitant medications will be reviewed at each visit.
Injection-site Reactions
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. All subjects should be carefully monitored for the occurrence of injection-site 
reactions for 30 minutes after the injection.
Allergic Reactions
Through Week 88, all subjects must be observed carefully for symptoms of an allergic reaction 
(eg, urticaria, itching, hives) for at least 30 minutes after the injection. If mild or moderate 
allergic reaction is observed, acetaminophen 650 mg orally (PO)
or NSAIDs
and 
diphenhydramine 25 mg PO or IV may be administered.
Subjects with reactions following an injection resulting in bronchospasm with wheezing 
and/or dyspnea requiring ventilator support, or symptomatic hypotension with a decrease 
in systolic blood pressure greater than 40 mm mercury (Hg) will not be permitted to 
receive any additional study agent injections. In the case of such reactions, appropriate 
medical treatment should be administered.
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 the 
Time and Events Schedule) 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.)
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If the evaluation raises suspicion that a subject may have TB reactivation or new TB infection, 
study agent administration should be interrupted and 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.
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 
TST in countries in which the QuantiFERON®-TB Gold test is not approved/registered or TST 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. 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 according to the protocol.
9.8.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the laboratory requisition 
form.
Refer to the Time and Events Schedule (Table 1) for the timing and frequency of all sample 
collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples 
must be under the specified, and where applicable, controlled temperature conditions as indicated 
in the laboratory manual.
10.
SUBJECT COMPLETION/WITHDRAWAL
10.1.
Completion
A subject will be considered to have completed the study if he or she has completed assessments 
at Week 100 of the study. Subjects who prematurely discontinue study treatment for any reason 
before completion of the double-blind phase will not be considered to have completed the study.
10.2.
Discontinuation of Study Treatment 
If a subject's study treatment must be discontinued before the end of the treatment regimen, this 
will not result in automatic withdrawal of the subject from the study. 
If a subject discontinues study agent administrations at or before Week 88, he/she must return for 
specific efficacy and final safety visits (see Section 9.1.4).
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Study agent administrations must be permanently discontinued if any of the following occur:

Pregnancy or pregnancy planned within the study period or within 5 months after the last 
study agent administration.

Reaction resulting in bronchospasm with wheezing and/or dyspnea requiring ventilator 
support, or symptomatic hypotension that occurs following a study agent administration.

Reaction resulting in myalgia and/or arthralgia with fever and/or rash (suggestive of serum 
sickness and not representative of signs and symptoms of other recognized clinical 
syndromes) occurring 1 to 14 days after an injection of study agent. These may be 
accompanied by other events including pruritus, facial, hand, or lip edema, dysphagia, 
urticaria, sore throat, and/or headache.

Opportunistic infection.

Malignancy, excluding nonmelanoma skin cancer.

Subject is deemed ineligible according to the following TB screening criteria:

A diagnosis of active TB is made.

A subject receiving treatment for latent TB discontinues this treatment prematurely or is 
noncompliant with the therapy.

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 continued evaluation has a chest radiograph with evidence of 
current active TB and/or a positive QuantiFERON-TB Gold test result (and/or a 
positive TST result in countries in which the QuantiFERON-TB Gold test is not 
approved/registered or the TST is mandated by local health authorities), unless active 
TB can be ruled out and appropriate treatment for latent TB can be initiated prior to the 
next administration of study agent and continued to completion.  Indeterminate 
QuantiFERON®-TB Gold test results should be handled as 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.

The initiation of protocol-prohibited medications (see Section 4.3).

Investigator or Sponsor’s medical monitor believes that for safety reasons it is in the 
subject’s best interest.
Discontinuation of study agent administration must be considered for subjects who develop a 
serious infection.
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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
If a subject is 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 eCRF 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. If a 
subject withdraws from the study before the end of the treatment, posttreatment assessments 
should be obtained (Section 9.1.4).
A subject who withdraws from the study will have the following options regarding the optional 
research samples (DNA and microbiome stool samples):

The collected samples 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 samples, in which case the samples 
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 
samples have been destroyed.
Withdrawal of Participation in the Collection of 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 samples 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.
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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 Statistical Analysis Plan (SAP).
Descriptive statistics will include counts and proportions for categorical data, and median, mean, 
interquartile range, and range for continuous data. Graphical data displays may also be used to 
summarize the data.
Unless otherwise specified, the Cochran-Mantel-Haenszel (CMH) chi-square test stratified by 
combined MRI/hsCRP status and by the status of previous exposure to anti-TNFα agents will be 
used to compare categorical variables such as the proportion of subjects responding to treatment. 
In general, continuous response parameters will be compared using an analysis of variance 
model, with the status of combined MRI/hsCRP and the status of previous exposure to 
anti-TNFα agents as covariates if appropriate. Survival analysis techniques based on 
Kaplan-Meier estimation will be used for endpoints such as time to flare. All statistical testing 
will be performed 2-sided.
Subject baseline data, demographic and baseline clinical disease characteristics will be 
summarized. The baseline measurement is defined as the closest measurement taken at or before 
the time of the Week 0 administration.
Efficacy analyses and summaries of subject information will be based on the modified 
intent-to-treat population (ie, all randomized subjects who received at least 1 administration of 
study treatment). Subjects included in the efficacy analyses will be summarized according to 
their assigned treatment group regardless of whether or not they receive the assigned treatment.
Safety and PK analyses will include all subjects who received at least 1 administration of study 
treatment.
11.1.
Subject Information
Subjects’ demographics data (eg, age, race, sex, height, weight) and baseline disease 
characteristics (eg, duration of disease, total back pain, and hsCRP) will be summarized by 
treatment group.
11.2.
Sample Size Determination
The sample size of 390 was chosen to achieve 90% power to detect a treatment difference
between ustekinumab and placebo for the primary endpoint at a significance level of 0.05
(2-sided).
The assumptions for the sample size and power calculations were based on Week 24 data from 
the ustekinumab investigator-initiated study in AS and the certolizumab pegol AxSpA study28
(Table 3).
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Table 3:
Power to detect a significant treatment difference in achieving an ASAS 20 Response at 
Week 24
Percent of 
anti-TNFα 
IR
Treatment 
group
ASAS 20 response
Sample size
Anti-TNFα-
IR
Not Anti-
TNFα-IR
Power
1
5%
placebo
ustekinumab
130
130
35%
50%
40%
60%
0.9018
2
10%
placebo
ustekinumab
130
130
35%
50%
40%
60%
0.8949
3
20%
placebo
ustekinumab
130
130
35%
50%
40%
60%
0.8750
4
40%
placebo
ustekinumab
130
130
35%
50%
40%
60%
0.8386
5
40%
placebo
ustekinumab
160
160
35%
50%
40%
60%
0.8993
Anti-TNFα-IR subjects have had an inadequate efficacy response or intolerance to 1 anti-TNFα-agent.
To ensure the power of the study (Table 3), the total sample size of the study will be increased to 
approximately 480 if there are 25% or more subjects are anti-TNFα-IRs among the first 
200 subjects randomized.
11.3.
Efficacy Analyses
Primary Endpoint
The primary endpoint is the proportion of subjects who achieve an ASAS 20 response at 
Week 24.
To address the primary objective, the proportion of subjects who achieve an ASAS 20 response 
at Week 24 will be compared between the ustekinumab groups and placebo groups using a CMH 
test stratified by the combined MRI/hsCRP status and the status of previous exposure to 
anti-TNFα agents at a significance level of 0.05 (2-sided).
To control for multiplicity for the primary endpoint analysis, the proportion of subjects with 
ASAS 20 response at Week 24 will be evaluated by comparing between the 90 mg group and the 
placebo group first. To maintain a Type I error rate of 0.05, the comparison between the 45 mg 
group and placebo group will be performed at a significance level of 0.05 (2-sided) after the 
90 mg group shows a significant treatment effect compared with the placebo group at a 
significance level of 0.05 (2-sided).
In the primary efficacy analysis, data from all randomized subjects who received at least 
1 administration of study treatment (modified intention-to-treat) will be analyzed according to 
their assigned treatment group regardless of their actual treatment received. In general, subjects 
with missing data for ASAS at Week 24 will be considered nonresponders for ASAS 20 at 
Week 24. In addition, treatment failure rules will be applied. Details of the treatment failure rules 
will be provided in the SAP.
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Sensitivity analyses with modified analysis sets and different rules may be conducted, and will 
be documented in detail in the SAP.
In addition, subgroup analysis will be performed to evaluate consistency in the primary efficacy 
endpoint by demographic characteristics, baseline disease characteristics, and baseline 
medications. Interaction test between the subgroups and treatment group will also be provided if 
appropriate.
Major Secondary Endpoints
To control for multiplicity for the primary endpoint analysis and the major secondary endpoint 
analyses, the 4 major secondary analyses listed below will be performed sequentially contingent 
upon the success of the primary statistical analysis in that treatment group comparison 
(Figure 5). Otherwise, the p-values for the subsequent endpoints will be considered as supportive 
analyses. The following prespecified order will be used to analyze the major secondary 
endpoints.
1.
The proportion of subjects who achieve an ASAS 40 at Week 24.
2.
The proportion of subjects who achieve at least a 50% improvement from baseline in 
BASDAI at Week 24.
3.
The change from baseline in BASFI at Week 24.
4.
The proportion of subjects who achieve ASDAS (CRP) inactive disease (<1.3) at Week 24.
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Figure 5:
Overview of Multiplicity Control
Other Secondary Endpoints
In addition to the primary and major secondary analyses, statistical comparisons will be 
performed at visits prior to or at Week 24 for selected endpoints (eg, ASAS 20 at Week 16, the 
change from baseline in BASMI at Week 24). All endpoints described in Section 9.2.1.15 will be 
summarized over time by treatment groups.
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In subjects who participate in randomized withdrawal at Week 52, the probability of subjects 
free of flares through Week 100 and the median time free of flares, if appropriate, will be 
estimated by treatment groups (ustekinumab 45 mg vs. placebo and ustekinumab 90 mg vs. 
placebo; Week 52 to Week 100) based on the Kaplan-Meier method.
In addition, selected analyses will be performed for the subgroups defined by combined 
MRI/CRP status and by status of previous exposure to an anti-TNFα agent.
11.4.
Pharmacokinetic Analyses
All concentrations below the limit of quantification (BLQ) of the assay or missing data will be 
labeled as such in the concentration data listing or SAS dataset. Concentrations below the BLQ
of the assay will be treated as zero in the summary statistics. All subjects and samples excluded 
from the analysis will be clearly documented.
Descriptive statistics, including arithmetic mean, SD, median, interquartile range, minimum, and 
maximum will be calculated at each sampling timepoint.
Serum ustekinumab concentrations will be summarized for each treatment group over time. If 
feasible, a population PK analysis using NONMEM will be used to characterize the disposition 
characteristics of ustekinumab in the current study. The apparent total systemic clearance (CL/F) 
and apparent volume of distribution (V/F) will be estimated. The influence of important variables 
(such as body weight, positive for antibodies to ustekinumab, and the use of MTX, etc) on the 
population PK parameter estimates may be evaluated. Details will be given in a population PK 
analysis plan, and results of the population PK analysis will be presented in a separate technical 
report.
11.5.
Immunogenicity Analyses
The incidence and titers of antibodies to ustekinumab will be summarized by treatment group 
over time. The impact of antibodies to ustekinumab on PK, efficacy, and safety will be assessed.
11.6.
Biomarker and Microbiome Analyses
Changes in serum biomarkers, RNA, fecal biomarker profiles, and/or other biomarkers over time 
will be summarized by treatment group. Associations between baseline levels and changes from 
baseline in select markers and clinical response will be explored.
Results will be presented in a separate report.
11.7.
Pharmacokinetic/Pharmacodynamic Analyses
If data permit, the relationships between serum ustekinumab concentration and efficacy may be 
analyzed graphically.
11.8.
Pharmacogenomic Analyses
Pharmacogenomic and epigenetics analyses are considered exploratory and results will be 
summarized in a separate technical report.
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11.9.
Health Economics Analyses
The change from baseline in impact of disease on work productivity and daily activity via 
WPAI-SHP will be descriptively summarized by treatment group over time and compared
between treatment groups at Week 24.
11.10. Safety Analyses
Adverse Events
The verbatim terms used in the CRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). All reported AEs with onset during the 
treatment phase (ie, treatment-emergent AEs and AEs that have worsened since baseline) will be 
included in the analysis. For each AE, the percentage of subjects who experience at least 
1 occurrence of the given event will be summarized by treatment group.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue treatment due to an AE, or who experience a severe or an
SAE.
The occurrences of selected AEs of interest including malignancies, infections including TB, and 
opportunistic infections (ie, infection by an organism that normally is not pathogenic or does not 
cause invasive infection in immunocompetent hosts) will be assessed.
Clinical Laboratory Tests
Routine safety evaluations will be performed. AEs, SAEs, reasonably-related AEs, and AEs by 
severity will be summarized by treatment group. The laboratory parameters and change from 
baseline in selected laboratory parameters (hematology and chemistry), and the number of 
subjects with abnormal laboratory parameters (hematology and chemistry) based on National 
Cancer Institute-Common Terminology Criteria for Adverse Events toxicity grading will be 
summarized treatment group. Listings of SAEs will also be provided. All safety analyses will be 
based on the population of subjects who received at least 1 injection of study agent; subjects will 
be summarized by the treatment they actually received in placebo controlled period. Additional 
analyses will be conducted by ustekinumab dose groups for the entire study period.
11.11. Interim Analysis
No formal interim analysis will be conducted. However, an DMC may recommend stopping the 
trial upon the review of the results of the interim futility analysis conducted in the 
CNTO1275AKS3001 study, along with unblinded efficacy and safety data available in 
CNTO1275AKS3003 at the time of the futility analysis in CNTO1275AKS3001.
Details of the plan for the interim analysis of CNTO1275AKS3001 and futility decision rules 
will be specified in the interim analysis plan before the start of the study.
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11.12. Data Monitoring Committee
An independent DMC will be established to monitor data on an ongoing basis to ensure the 
continuing safety of the subjects enrolled in this study and to review unblinded efficacy data at 
the time of interim futility analysis of CNTO1275AKS3001. The committee will meet 
periodically to review interim data. After the review, the DMC will make recommendations 
regarding the continuation of the study. Any safety concerns will be communicated to the 
Sponsor.
The DMC will be independent of the Sponsor. None of the members will be participating in the 
current study. The DMC will consist of at least 2 medical experts in a relevant therapeutic area 
and 1 statistician. The members of the committee will be specified prior to study initiation. The 
major function of this committee will be to monitor the safety of the study agent and to provide 
recommendations for placing the study on hold or stopping the study in the event that any 
unanticipated serious events occur. In addition, the committee will review the interim unblinded 
efficacy results of CNTO1275AKS3001, CNTO1275AKS3002, and CNTO1275AKS3003, and 
recommend the continuation or stopping of the trial according to the specification of each 
protocol.
Periodic safety reviews will occur every 4 months. The DMC may change the frequency or 
number of reviews based on interim safety findings. The safety reviews will focus on particular 
AEs, SAEs, and mortality.
Serious adverse events reports will be provided to the DMC members on an ongoing basis. The 
DMC will have access to unblinded data and review tabulated safety summaries (if appropriate) 
and any additional data that the DMC may request. No formal statistical hypothesis testing is 
planned. In addition, during the study, the Sponsor's study responsible physician (or designee) 
will regularly review blinded safety data from the sites and notify the DMC and appropriate 
Sponsor personnel of any issues.
The content of the efficacy and safety summaries, the DMC role and responsibilities and the 
general procedures (including communications) and their recommendations on the study conduct 
will be defined and documented in the DMC charter prior to the first DMC review.
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.
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12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
(investigational or non-investigational) product. An AE does not necessarily have a causal 
relationship with the treatment. An AE 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 AEs starting with the signing of the ICF (refer to Section 12.3.1, All 
Adverse Events, for time of last AE recording).
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 AE is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For ustekinumab, the expectedness of an AE will be 
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determined by whether or not it is listed in the IB with a marketing authorization, the 
expectedness of an AE will be determined by whether or not it is listed in the package 
insert/summary of product characteristics.
Adverse Event Associated With the Use of the Drug
An AE is considered associated with the use of the drug if the attribution is possible by the 
definitions listed in Section 12.1.2.
12.1.2.
Attribution Definitions
Not Related
An AE that is not related to the use of the drug.
Doubtful
An AE 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.
Possible
An AE 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 AE 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 AE 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.
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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

Unexpected therapeutic or clinical benefit from use of 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 a serious SAE should be recorded on the SAE page of the CRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All AEs and special reporting situations, whether serious or non-serious, 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). Serious adverse events, including 
those spontaneously reported to the investigator within 12 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.
All AEs, 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 
AE to study therapy. All measures required for AE management must be recorded in the source 
document and reported according to Sponsor instructions.
The Sponsor assumes responsibility for appropriate reporting of AEs to the regulatory 
authorities. The Sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). The 
investigator (or Sponsor where required) must report SUSARs to the appropriate Independent 
Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless 
otherwise required and documented by the IEC/IRB.
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The subject must be provided with a "wallet (study) card" and instructed to carry this card with 
them for the duration of the study indicating the following:

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)

Site number

Subject number

Any other information that is required to do an emergency breaking of the blind
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.
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). Serious adverse events related to the disease under study will be collected per 
protocol but will not be unblinded and expedited if they fall into the following categories: 
exacerbation of spondylitis or worsening of pain related to AxSpA.
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 AE (eg, social reasons such as 
pending placement in long-term care facility)
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
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 AE that results in a prolongation of the originally planned 
hospitalization is to be reported as a new SAE.

For convenience the investigator may choose to hospitalize the subject for the duration of 
the treatment period.
The cause of death of a subject in a study within 20 weeks of the last dose of study agent, 
whether or not the event is expected or associated with the study agent, is considered an SAE.
12.3.3.
Pregnancy
Any subject who becomes pregnant during the study must be promptly withdrawn from the study
and 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 will 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.
12.4.
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 
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Events). A sample of the suspected product should be maintained for further investigation if 
requested by the Sponsor.
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
Ustekinumab for this study will be supplied as a sterile solution in a single use prefilled syringe
(PFS) at a volume of either 0.5 ml (45 mg dose) or 1 ml (90 mg dose) as follows:

Ustekinumab 45 mg, L-histidine, L-histidine monohydrochloride monohydrate, sucrose, and 
polysorbate 80 at pH 6.0 in 0.5 mL nominal volume.

Ustekinumab 90 mg, L-histidine, L-histidine monohydrochloride monohydrate, sucrose, and 
polysorbate 80 at pH 6.0 in 1.0 mL nominal volume.
No preservatives are present.
The needle cover on the PFS contains dry natural rubber (a derivative of latex), which may 
cause allergic reactions in individuals sensitive to latex.
Liquid placebo will be supplied in a 0.5 mL and a 1 mL PFS.
14.2.
Packaging
The investigational supplies will be uniquely packaged to assure that they are appropriately 
managed throughout the supply chain process.
14.3.
Labeling
Study agent labels will contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage 
Study agent must be stored at controlled temperatures ranging from 36°F to 46°F (2°C to 8°C). 
The ustekinumab product should not be frozen and should be protected from light. Vigorous 
shaking of the ustekinumab product should be avoided. The formulation does not contain 
preservatives. Prior to administration, the drug 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.
Refer to the Site Investigational Product Procedures Manual for additional guidance on the 
preparation and handling of ustekinumab.
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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 to the Sponsor of unused study 
agent will be documented on the drug return form. When the study site is an authorized 
destruction unit and study agent supplies are destroyed on-site, this must also be documented on 
the drug return form.
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. 
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. 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:

IB

Site Investigational Product Procedures Manual

Laboratory Manual and laboratory supplies

Electronic PRO device and user manual

IWRS user guide and worksheets

Electronic data capture (eDC) Manual

Sample ICF

Imaging Manual
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 
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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 AEs of the study, and provide their consent voluntarily will be enrolled.
The total blood volume to be collected in this study from each subject will be approximately 
250 mL, which is less than the typical blood donation of 500 mL.
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 
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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. 
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 AEs 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.
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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 are 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.
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 disease. 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, including permission to obtain 
information about his or her survival status, 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, and subsequent disease-related treatments or to obtain information about his or her 
survival status.
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.
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 
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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.
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.
Exploratory DNA, pharmacodynamics, and biomarker 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 the mechanism of 
action of ustekinumab, to understand nr-AxSpA, to understand responses to treatment in subjects 
with nr-AxSpA, differential drug responders, and to develop tests/assays related to ustekinumab
and nr-AxSpA. 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 
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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
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)
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
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)

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 AEs and follow-up of AEs; 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 
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before the study and will be described in the monitoring guidelines (or other equivalent 
document).
The following subject- and investigator-completed scales and assessments designated by the 
Sponsor will be recorded directly into an electronic device and will be considered source data:  
SF-36, MOS Sleep Scale, ASQoL, FACIT-F, EQ-5D, WPAI-SHP, nr-AxSpA response 
evaluations (BASDAI, BASFI, PGA, Total back pain, Night back pain, ASDAS), and 
musculoskeletal assessments (BASMI, enthesitis index, chest expansion).
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
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 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.
All subjective measurements (eg, pain scale information or other questionnaires) will be 
completed by the same individual who made the initial baseline determinations whenever 
possible. 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.
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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, and periodic monitoring visits by the Sponsor, and direct 
transmission of clinical laboratory data from a central laboratory, IWRS, and PRO data 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.
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 
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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 data entered into the CRFs with the hospital or clinic records (source 
documents); a sample may be reviewed. 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.
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.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during 
these remote contacts, study-site personnel will be available to provide an update on the progress 
of the study at the site.
Central monitoring will take place for data identified by the Sponsor as requiring central review.
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 
study. 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.
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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. 
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 pharmacogenomics 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, and direct transmission 
of clinical laboratory data from a central laboratory, IWRS, and PRO data into the Sponsor's 
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database. 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 pharmacogenomics 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 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 
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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of a double blind, randomized, placebo-controlled trial. Arthritis Rheum 2005;52(10): 3279–89.
33.
Mei Y, Pan F, Gao J, et al. Increased serum IL-17 and IL-23 in the patient with ankylosing spondylitis. Clin 
Rheumatol. 2011;30(2):269-273.
34.
Melis L, Vandooren B, Kruithof E, et al. Systemic levels of IL-23 are strongly associated with disease activity 
in rheumatoid arthritis but not spondyloarthritis. Ann Rheum Dis. 2010;69(3):618-623.
35.
O'Rielly DD, Rahman P. Genetics of susceptibility and treatment response in psoriatic arthritis. Nat Rev 
Rheumatol. 2011;7(12):718-732.
36.
Ostergaard M, Poggenborg RP, Axelsen MB, Pedersen SJ. Magnetic resonance imaging in spondyloarthritis -
how to quantify findings and measure response. Best Pract Res Clin Rheumatol. 2010;24:637-657.
37.
Poddubnyy D, Hermann K-G, Callhoff J, Listing J, Sieper J. Ustekinumab for the treatment of patients with 
active ankylosing spondylitis: results of a 28-week, prospective, open-label, proof-of-concept study (TOPAS). 
Ann Rheum Dis. 2014;73(5):817-823.
38.
Poddubnyy D, Sieper J. Similarities and differences between nonradiographic and radiographic axial 
spondyloarthritis: a clinical, epidemiological and therapeutic assessment. Curr Opin Rheumatol. 
2014;26(4):377-383.
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39.
Rahman P, Inman RD, Maksymowych WP, Reeve JP, Peddle L, Gladman DD. Association of Interleukin 23 
Receptor Variants with Psoriatic Arthritis. J Rheumatol. 2009;36(1):137-140.
40.
Raychaudhuri SP, Raychaudhuri SK, Genovese MC. IL-17 receptor and its functional significance in psoriatic 
arthritis. Mol Cell Biochem. 2012;359(1-2):419-429.
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42.
Reveille JD, Sims AM, Danoy P, et al. Genome-wide association study of ankylosing spondylitis identifies 
non-MHC susceptibility loci. Nat Genet. 2010;42(2):123-127.
43.
Ritchlin C, Rahman P, Kavanaugh A, et al. Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, 
ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-
tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-
controlled, randomised PSUMMIT 2 trial. Ann Rheum Dis. 2014;73:990-999.
44.
Romero-Sanchez C, Jaimes DA, Londoño J, et al. Association between Th-17 cytokine profile and clinical 
features in patients with spondyloarthritis. Clin Exp Rheumatol. 2011;29(5):828-834.
45.
Rudwaleit M, Haibel H, Baraliakos X, Listing J, Marker-Hermann E, Zeidler HBJ. The early disease stage in 
axial spondylarthritis:  Results from the German Sponyloarthritis inception Cohort. Arthritis Rheum. 
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2014;57(1):38-43.
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Sherlock JP, Joyce-Shaikh B, Turner SP, et al. IL-23 induces spondyloarthropathy by acting on ROR-γt+ 
CD3+CD4-CD8- entheseal resident T cells. Nat Med. 2012;18:1069–1076.
49.
Sieper J, Braun J, Baraliakos X, et al. Secukinumab, a monoclonal antibody to interleukin-17A, significantly 
improves signs and symptoms of active ankylosing spondylitis: results of a phase 3, randomized, placebo-
controlled trial with subcutaneous loading and maintenance dosing. Arthritis Rheum. ACR/ARHP Annual 
Meeting. 2014;66:S232. Abstract 536.
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handbook: a guide to assess spondyloarthritis. Ann Rheum Dis. 2009;68(2):ii1-ii44.
51.
van der Heijde D, Landewé R, Feldtkeller E. Proposal of a linear definition of the Bath Ankylosing Spondylitis 
Metrology Index (BASMI) and comparison with the 2-step and 10-step definitions. Ann Rheum Dis. 
2008;67:489-493.
52.
van der Heijde D, Lie E, Kvien T K, et al. A highly discriminatory ASAS-endorsed disease activity score in 
patients with ankylosing spondylitis: For the Assessment of SpondyloArthritis international Society (ASAS). 
Ann Rheum Dis. 2009;68:1811–1818.
53.
van der Heijde D, Sieper J, Maksymowych WP, Assessment of SpondyloArthritis international Society, et al. 
2010 Update of the international ASAS recommendations for the use of anti-TNF agents in patients with axial 
spondyloarthritis. Ann Rheum Dis. 2011;70(6):905-908.
54.
van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A 
proposal for modification of the New York criteria. Arthritis Rheum. 1984;27(4):361-368.
55.
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item selection. Med Care. 1992;30(6):473 483.
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APPENDIX A: 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 In Tube 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 3000g.  Following centrifugation, 
plasma is harvested from each tube, frozen, and shipped on dry ice to the central laboratory.  The central 
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laboratory will perform an ELISA to quantify the amount of IFN-present in the plasma using 
spectrophotometry and computer software analysis.
The central 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.
In countries in which the QuantiFERON®-TB Gold test is not considered approved/registered, a 
tuberculin skin test is additionally required.
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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APPENDIX B: 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.
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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APPENDIX C: HBV SCREENING AND MONITORING
Subjects must undergo screening for hepatitis B virus (HBV). At a minimum, this includes 
testing for HBsAg (HBV surface antigen), anti-HBs (HBV surface antibody), and anti-HBc total 
(HBV core antibody total): 

Subjects who test negative for all HBV screening tests (ie, HBsAg-, anti-HBc-, and 
anti-HBs-) are eligible for this study.

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.

Subjects who test positive only for surface antibody (anti-HBs+) are eligible for this study.

Subjects who test positive for surface antigen (HBsAg+) are NOT eligible for this study, 
regardless of the results of other hepatitis B tests.

Subjects who test positive only for core antibody (anti-HBc+) must undergo further testing 
for the presence of hepatitis B virus 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. 
For subjects who are not eligible for this study due to HBV test results, consultation with a 
physician with expertise in the treatment of hepatitis B virus infection is recommended.  
Eligibility based on hepatitis B virus test results
Hepatitis B test result
Action
Hepatitis B 
surface antigen
(HBsAg)
Hepatitis B 
surface antibody
(anti-HBs)
Hepatitis B core 
antibody
(anti-HBc total)
Include
—
—
—
—
+
—
—
+
+
Exclude
+
— or +
— or +
Require testing for 
presence HBV DNA*
—
—
+
* If HBV DNA is detectable, exclude from the clinical study. If HBV DNA testing 
cannot be performed, or there is evidence of chronic liver disease, exclude from the 
clinical study.  
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INVESTIGATOR AGREEMENT
LAST PAGE
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SAP_001.pdf: 
1
Approved, Date: 8 December 2017
Janssen Research & Development *
Statistical Analysis Plan
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating 
the Efficacy and Safety of Ustekinumab in the Treatment of Subjects With Active 
Nonradiographic Axial Spondyloarthritis
Protocol CNTO1275AKS3003; 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 Infectious Diseases BVBA; Janssen R&D Ireland; 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.
Status:
Approved
Date:
8 December 2017
Prepared by:
Janssen Research & Development  
Document No.: EDMS-ERI-153234444
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.
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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
ABBREVIATIONS ........................................................................................................................................ 4
1.
INTRODUCTION.................................................................................................................................. 5
1.1.
Trial Design ...................................................................................................................................... 5
1.2.
Randomization and Blinding ............................................................................................................ 6
1.2.1.
Randomization.............................................................................................................................. 6
1.2.2.
Maintenance of the Blind .............................................................................................................. 7
2.
GENERAL ANALYSIS DEFINITIONS ................................................................................................ 8
2.1.
Visit Windows................................................................................................................................... 8
2.2.
Pooling Algorithm for Analysis Centers............................................................................................ 8
2.3.
Analysis Sets.................................................................................................................................... 8
2.3.1.
Full Analysis Set ........................................................................................................................... 8
2.3.2.
Efficacy Analysis Set (Modified Full Analysis Set) ....................................................................... 8
2.3.3.
Safety Analysis Set....................................................................................................................... 8
2.4.
Definition of Subgroups.................................................................................................................... 9
3.
DATA MONITORING COMMITTEE REVIEW................................................................................... 10
3.1.
Data Monitoring Committee ........................................................................................................... 10
4.
SUBJECT INFORMATION................................................................................................................ 10
4.1.
Demographics and Baseline Characteristics ................................................................................. 10
4.2.
Disposition Information................................................................................................................... 10
4.3.
Treatment Compliance................................................................................................................... 11
4.4.
Extent of Exposure......................................................................................................................... 11
4.5.
Protocol Deviations ........................................................................................................................ 11
4.6.
Prior and Concomitant Medications ............................................................................................... 11
5.
EFFICACY ......................................................................................................................................... 11
5.1.
Data Handling Rules ...................................................................................................................... 11
5.1.1.
Treatment Failure ....................................................................................................................... 11
5.1.2.
Missing Data Imputation ............................................................................................................. 12
5.1.3.
Early Escape............................................................................................................................... 12
5.2.
Primary Efficacy Endpoint .............................................................................................................. 12
5.2.1.
Definition..................................................................................................................................... 12
5.2.2.
Analyses ..................................................................................................................................... 13
5.2.3.
Subgroup Analysis...................................................................................................................... 13
5.3.
Major Secondary Endpoints........................................................................................................... 14
5.3.1.
Proportion of Subjects who Achieve an ASAS 40 Response at Week 24 ................................. 14
5.3.2.
Proportion of Subjects who Achieve at Least a 50% Improvement from Baseline in 
BASDAI at Week 24 ................................................................................................................... 14
5.3.3.
Change from Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) at 
Week 24...................................................................................................................................... 15
5.3.4.
Proportion of Subjects who Achieve ASDAS (CRP) Inactive Disease (<1.3) at Week 24......... 16
5.3.5.
Other Secondary Analyses......................................................................................................... 17
6.
SAFETY............................................................................................................................................. 17
6.1.
Safety Table Presentation.............................................................................................................. 17
6.1.1.
Summaries through Week 16 ..................................................................................................... 17
6.1.2.
Summaries through Week 24 ..................................................................................................... 17
6.1.3.
Summaries through the End of Study......................................................................................... 18
6.2.
Adverse Events .............................................................................................................................. 18
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6.3.
Clinical Laboratory Tests................................................................................................................ 19
6.4.
Vital Signs ...................................................................................................................................... 19
REFERENCE .............................................................................................................................................. 20
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ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AS
ankylosing spondylitis
ASAS
Assessment in SpondyloArthritis international Society
ASDAS
Ankylosing Spondylitis Disease Activity Score
AST
aspartate aminotransferase
AxSpA
axial spondyloarthritis
BASDAI
Bath Ankylosing Spondylitis Disease Activity Index
BASFI
Bath Ankylosing Spondylitis Functional Index
CI
Confidence Interval
CMH
Cochran-Mantel-Haenszel
CRP
c-reactive protein
DAS
disease activity score
DBL
database lock
DMARD 
disease-modifying antirheumatic drugs
DMC
Data Monitoring Committee
eCRF
electronic case report form
HCQ
Hydroxychloroquine
hs-CRP
high sensitivity C-reactive protein
IWRS
interactive web response system
LSMeans
Least-Squares Means
MedDRA
Medical Dictionary for Regulatory Activities
MTX
Methotrexate
NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for Adverse Events
NSAID 
nonsteroidal anti-inflammatory drug
SAE
serious adverse event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SSZ
Sulfasalazine
TEAEs
Treatment emergent adverse events
TNFα
tumor necrosis factor alpha
ULN
upper limit of normal
VAS
visual analog scale
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1.
INTRODUCTION
CNTO1275AKS3003 was terminated by the sponsor on May 22, 2017 after reviewing the results 
of the statistically controlled endpoints for CNTO1275AKS3001 at the Week 24 database lock, 
which showed that the primary and major secondary endpoints were not met for either of the two 
active doses 45 or 90 mgs.  
As a result of the early termination of the study, the originally planned efficacy analyses 
specified in the protocol based on intent-to-treat population would not be useful because about
30% of enrolled subjects had to discontinue study agent administration prior to Week 24 due to 
“Study terminated by sponsor”, which makes missing data imputation rules specified in the 
protocol inappropriate.  With these considerations, only selected efficacy analyses through 
Week 24 including primary and major secondary endpoints will be performed based on the 
subjects who were randomized by November 29, 2016 (approximately 25 weeks prior to the 
study was terminated) and received at least 1 administration of study treatment.  No data analysis 
of imaging data, serum ustekinumab concentrations or antibodies to ustekinumab will be 
provided.  However, all other data, such as, baseline demographics and disease characteristics, 
prior and concomitant medications, study agent discontinuations and study participation status, 
treatment compliance and protocol deviations, and all safety data including adverse events, vital 
signs and laboratory parameters will be summarized.
1.1.
Trial Design
This was a Phase 3 multicenter, randomized, double-blind, placebo-controlled study of the 
efficacy and safety of ustekinumab compared with placebo in adult subjects with active nr-
AxSpA with an inadequate response or intolerance to nonsteroidal anti-inflammatory drugs 
(NSAID). They may have had exposure to no more than 1 anti-tumor necrosis factor alpha 
(TNFα) agent. Approximately 390 subjects were to be randomized at approximately 85 
investigational sites. Subjects were randomly assigned to receive SC ustekinumab 45 mg or 
90 mg or placebo administrations at Weeks 0, 4, and 16. At Week 16, subjects in the placebo 
group who qualify for early escape (subjects with <10% improvement from baseline in both total 
back pain and morning stiffness measures at both Week 12 and Week 16), began receiving 
randomly assigned SC ustekinumab 45 mg or 90 mg administrations at Weeks 16, 20, and 28 and 
q12w thereafter through Week 52 in a blinded fashion. At Week 24, all remaining subjects in the 
placebo group who did not meet early escape criteria were rerandomized to receive ustekinumab 
45 mg or 90 mg at Weeks 24 and 28 followed by q12w therapy through Week 52. Subjects in the 
ustekinumab treatment groups received a placebo administration at Weeks 20 and 24 to maintain 
the blind and continue to receive SC ustekinumab 45 mg or 90 mg at Week 28 and q12w 
thereafter through Week 52. At Week 52, all subjects who achieve inactive disease (Ankylosing 
Spondylitis Disease Activity Score [ASDAS] erythrocyte sedimentation rate [ESR] <1.3) at both 
Week 40 and Week 52 visits were to undergo rerandomization to either remain on ustekinumab 
or receive placebo.
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Subjects who did not achieve inactive disease (ASDAS [ESR] <1.3) at either the Week 40 or 
Week 52 visit were to receive their previously assigned ustekinumab dose at their scheduled 
visits.
All subjects who experienced a flare after Week 52 defined as ASDAS (ESR) >2.1 were given 
the option to discontinue study injections and utilize an alternative therapy per the physicians’ 
discretion or to continue study injections in a blinded fashion. Subjects who elected to continue 
and were rerandomized to placebo at Week 52 were to have ustekinumab injections reinstituted 
at their next scheduled visit. Subjects who elected to continue and were rerandomized to 
ustekinumab at Week 52 were to continue with ustekinumab dose at their scheduled visits.
An independent Data Monitoring Committee (DMC) were commissioned for this study. 
Subjects were to be followed for adverse events (AEs) and SAEs at least 12 weeks following the 
last study treatment administration. 
1.2.
Randomization and Blinding
1.2.1.
Randomization
A central randomization was implemented in this study using an interactive web response system
(IWRS).  When a subject was eligible for randomization at a study site, the randomization 
requestor at that study site contacted the IWRS using the requester’s own user identification and 
personal identification number and provided the relevant subject details to uniquely identify that
subject. Based on computer-generated randomization schedules prepared before the study under
the supervision of the Sponsor, the IWRS assigned a unique treatment code, which dictated the 
treatment assignment and matching study agent kit for that subject.  Randomization at Week 0 
and the re-randomization at Weeks 16, 24, and 52 were conducted using permuted block method 
by the IWRS.
At Week 0, approximately 390 subjects were to be randomized in a blinded fashion in a 1:1:1 
ratio to 1 of the 3 treatment groups. The Randomization was stratified by MRI/hsCRP status 
(MRI+/hsCRP+; MRI+/hsCRP-; MRI-/hsCRP+) and by the status of previous exposure to anti-
TNFα (naïve, TNF-IR, or other).
To maintain the blind, all randomized subjects were to receive each administration of
ustekinumab/placebo as 2 SC injections totaling 1.5 mL in 2 different locations as follows:

Placebo: 0.5 mL placebo injection and 1.0 mL placebo injection.

Ustekinumab 45 mg: 0.5 mL ustekinumab 45 mg injection and 1.0 mL placebo injection.

Ustekinumab 90 mg: 1.0 mL ustekinumab 90 mg injection and 0.5 mL placebo injection.
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1.2.2.
Maintenance of the Blind
The study blind was maintained for the duration of the study until after the final database lock 
(DBL).
However, if it was necessary for a subject's safety, the study blind may have been broken and the 
identity of the study agent ascertained. The study agent number was entered in the case report 
form when the study agent was administered. The study agents were identical in appearance and 
packaged in identical containers.
The investigator was not provided with randomization codes. The codes were to be maintained 
within the IWRS, which had 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 treatment allocation) 
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 time of DBL and unblinding.
An investigator may have been unblinded to a given subject’s treatment allocation when specific 
emergency treatment would have been dictated by knowing the treatment status of the subject.  
In such cases, the investigator may have determined the identity of the treatment by contacting
the IWRS provider. It was strongly recommended that the investigator contact the Sponsor or its 
designee if possible to discuss the particular situation prior to unblinding via IWRS.  Telephone 
contact with the Sponsor or its designee was to be available 24 hours per day, 7 days per week.  
In the event that the investigator was unable to contact the Sponsor, or emergency unblinding 
was considered medically necessary, the investigator may have determined the identity of the 
treatment via IWRS.  However, the Sponsor should have been informed as soon as possible.  The 
date, time, and reason for the unblinding should have been documented in the appropriate section 
of the eCRF, and in the source document.  The documentation received from the IWRS
indicating the code break should have been retained with the subject's source documents in a 
secure manner (e.g., sealed envelope) so as to not unblind the treatment assignment to the 
subject, the study site, or Sponsor personnel.  The investigator was also advised not to reveal the 
study treatment assignment to the subject, the study site, or Sponsor personnel. Subjects who 
have had their treatment assignment unblinded were expected to continue to return for scheduled 
evaluations.  Further study agent administrations should have been discussed with the study 
responsible physician.
A given subject’s treatment assignment may have been unblinded to the Sponsor, Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and site personnel to fulfill regulatory 
reporting requirements for suspected unexpected serious adverse reactions (SUSARs).  A 
separate code break procedure was to be available for use by Janssen Global Medical Safety 
(GMS) to allow for unblinding of individual subjects to comply with specific requests from 
regulatory or health authorities.
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The study responsible physician remained blinded through the end of the study to subject level 
treatment assignment and dosing regimen. Investigative sites and subjects were to remain 
blinded to treatment assignment for the duration of the study, until after the final DBL.
An independent, external DMC monitored the safety of the study in an unblinded fashion on a 
regular basis and whenever it was deemed necessary.  The DMC’s roles and responsibilities, the 
safety data for DMC review, and other related information (such as, the general procedures, 
communications, etc.) were defined and documented in the DMC charter.
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Visit Windows
Unless otherwise specified, nominal visits will be used for the summaries and listings over time 
with no visit windows applied.
2.2.
Pooling Algorithm for Analysis Centers
Unless otherwise specified, data from all investigational centers/sites will be pooled by region 
for analyses.
2.3.
Analysis Sets
2.3.1.
Full Analysis Set
Full Analysis Set includes all subjects who were randomized and received at least one 
administration of study agent, i.e., the modified Intent-to-Treat (mITT) population.
2.3.2.
Efficacy Analysis Set (Modified Full Analysis Set)
The efficacy analysis data set (Modified Full Analysis Set) includes subjects who were 
randomized by November 29, 2016 (approximately 25 weeks prior to the study was terminated
on May 22, 2017) and received at least 1 administration of study treatment.  
In the efficacy analyses, subjects will be analyzed according to their assigned treatment group 
regardless of their actual treatment received. 
2.3.3.
Safety Analysis Set
The safety analysis set through the end of the study (beyond week 24) includes all subjects who 
received at least 1 (partial or complete) administration of study agent, i.e., the treated population.
In the safety analyses, subjects will be analyzed according to the treatment they actually 
received, regardless of their randomized treatments.
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2.4.
Definition of Subgroups
To evaluate the consistency in the primary efficacy endpoint (proportion of subjects who achieve 
ASAS 20 response at Week 24) over demographics, baseline characteristics, prior and baseline 
medication use, subgroup analyses will be performed when the number of subjects in the 
subgroups permits (eg, at least 15 subjects per treatment group for a given subgroup).  The
subgroups for subgroup analyses may include, but are not limited to, the following:
1.
Subgroups defined by demographics:
a)
Gender (male, female)
b)
Race (White, Black or African American, Asian, Other)
c)
Geographic region (Asia Pacific, Europe, Latin America)
d)
Age (< 30 years, ≥30 years)
e)
Body mass index: (Normal [<25 kg/m2], Overweight [≥25 kg/m2 to <30 kg/m2], Obese 
[≥30 kg/m2]) 
2.
Subgroups defined by baseline characteristics:
a)
HLA-B27 (positive, negative)
b)
Years since inflammatory back pain first appeared (≤10 years, >10 years) 
c)
BASDAI (<= 6, > 6)
d)
BASFI (<= 5, > 5)
e)
BASMI (<= median, > median)
f)
Total back pain VAS (<= 7, > 7) in a 0 to 10 scale
h)
Laboratory CRP at baseline (<1.0 mg/dL, >=1.0 mg/dL)
g)
MRI-CRP entry criteria
o
Met only CRP criteria
o
Met only MRI criteria
o
Met both CRP and MRI criteria
o
All who met CRP criteria
o
All who met MRI criteria
h)
Anti-TNF experience
a.
Anti-TNF naïve
b.
Anti-TNF-IR
c.
Anti-TNF stopped due to other reason
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3.
Subgroups defined by medication (baseline or prior) use:
a)
Use of NSAIDs at baseline (yes, no)
b)
Use of oral corticosteroids at baseline (yes, no)
c)
Use of DMARDs (SSZ/MTX/HCQ) at baseline (yes, no)
d)
Number of DMARDs used in the past (none, 1, at least 2)
3.
DATA MONITORING COMMITTEE REVIEW
3.1.
Data Monitoring Committee
The independent DMC monitored data on an ongoing basis to ensure the continuing safety of the 
subjects enrolled in this study. The committee were to meet periodically to review interim data. 
After the review, the DMC made recommendations regarding the continuation of the study. Any 
safety concerns were to be communicated to the Sponsor.
The content of the safety summaries, the DMC role and responsibilities and the general 
procedures (including communications) and their recommendations on the study conduct were
defined and documented in the DMC charter prior to the first DMC review.
4.
SUBJECT INFORMATION
4.1.
Demographics and Baseline Characteristics
The baseline measurement is defined as the closest measurement taken at or before the first study 
agent administration (Week 0) unless otherwise stated.
Demographic and baseline characteristics will be summarized based on the Full Analysis Set by 
the randomized treatment group. In addition, selected baseline summaries will be performed 
based on the Modified Full Analysis Set.
Subjects’ demographic data including age, race, sex, height, weight and BMI at baseline will be
summarized. Baseline disease characteristics and baseline disease activity assessments will be 
summarized. Baseline concomitant medication usage will also be summarized. The number of 
subjects will also be summarized by geographic region, country, and investigational site.
4.2.
Disposition Information
The number of subjects screened, randomized and treated will be summarized by treatment
group. Subjects who discontinued study agent through Week 24, and through the end of the 
study, and the reasons for discontinuing will also be summarized by randomized treatment
group. Likewise, subjects who terminated study participation and the reasons for termination
will also be summarized.
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4.3.
Treatment Compliance
Subjects will be summarized by the study agent lot(s) received.  Subjects will also be 
summarized by the treatment group to which the subjects were randomized versus the actual 
treatment received during the study.
See Section 4.5 Protocol Deviations for the summary related to incorrect study agent or dose 
received and administrations missed.  
4.4.
Extent of Exposure
The cumulative dose of ustekinumab (mg) received will be summarized by treatment group. 
The number of administrations will be summarized by treatment group.  The average follow-up 
time will also be provided by treatment group in the safety tables.
4.5.
Protocol Deviations
Subjects who did not meet study selection criteria (e.g. AxSpA disease criteria, medication 
criteria, laboratory criteria, and medical history criteria) will be summarized and listed by 
randomized treatment group.  
Major protocol deviations will be identified in a blinded fashion prior to database lock. Subjects 
with major protocol deviations will be tabulated separately and presented by treatment group for 
the following categories including subjects who entered the study but did not meet entry criteria, 
subjects who received the wrong medication or incorrect dose, subjects who received disallowed 
medication, and “other.”
4.6.
Prior and Concomitant Medications
Medications taken by subjects prior to starting the study and concomitant medications will be
summarized by medication and randomized treatment group. 
5.
EFFICACY
5.1.
Data Handling Rules
Data handling rules discussed in this section will be applied to efficacy analyses through 
Week 24 when it is appropriate.  In addition, selected data may also be reported using
observed data without applying these data handling rules.  
5.1.1.
Treatment Failure
A subject who meets any one of the following treatment failure criteria will be considered a 
treatment failure from that point onward.
Treatment failure criteria:

Initiate new DMARDs, biologics or systemic immunosuppressives for AxSpA.

Increase SSZ, MTX, or hydroxychloroquine dose above baseline dose for AxSpA.
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
Initiate treatment with oral, IV, or IM, corticosteroids for AxSpA.

Increase the dose of oral corticosteroids above baseline dose for AxSpA.

Discontinue study treatment due to lack of efficacy.
For dichotomous responder-type endpoints, subjects will be considered non-responders at the 
visit at and after treatment failure regardless of the actual measurements.  Treatment failure 
rules will not be applied to continuous endpoints.
5.1.2.
Missing Data Imputation
For dichotomous responder-type endpoints, missing responses at a post baseline visit will be 
imputed as a non-responder (NRI). 
For a composite dichotomous endpoint with missing 
response status due to missing data in any of its components, the endpoint will be set to a non-
responder status (NRI). 
For continuous endpoints, no missing data imputation rules will be applied, unless otherwise 
stated.  
5.1.3.
Early Escape
For all subjects regardless of the treatment groups who met early escape criteria based on ePRO 
data from CRF Health, the following adjustments will be made to subsequent data through 
Week 24:

The subject will be considered a non-responder for response endpoints at Week 20 and 
Week 24;

The measurement value at Week 20 and Week 24 will be set as missing for a continuous 
endpoint.   
5.2.
Primary Efficacy Endpoint
The primary endpoint is proportion of ASAS 20 responders at Week 24.
5.2.1.
Definition
A 20% improvement in response according to the criteria of the ASAS (ASAS 20) is defined as:
1.
An improvement of ≥20% from baseline and absolute improvement from baseline of at least 
1 on a 0 to 10 scale in at least 3 of the following 4 domains:
i. Patient global
ii. Total back pain
iii. Function (Bath Ankylosing Spondylitis Functional Index [BASFI])
iv. Inflammation (average of the last 2 questions of the BASDAI concerning 
morning stiffness)
2.
Absence of deterioration from baseline (≥20% and worsening of at least 1 on a 0 to 10 scale) 
in the potential remaining domain.
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Following
are
the
definitions
of
each
of
the
forgoing
disease
assessment
criteria
(components) that are used in the determination of ASAS 20 response:
a)
Patient’s Global Assessment: a measure from 0 (very well) to 10 (very poor) on a 0 to 10 cm
VAS scale.
b)
Total back pain: the average total back pain over the past week on a VAS (0 to 10 cm;
0 = no pain, 10 = most severe pain).
c)
The BASFI is a subject’s self-assessment represented as a mean (VAS; 0 to 10 cm) of
10 questions, 8 of which relate to the subject’s functional anatomy and 2 of which relate to a 
subject’s ability to cope with everyday life.1  An increase along the scale indicates a 
worsening condition. (Section 5.3.2 for details)
d)
Inflammation (average of the last 2 questions of the BASDAI concerning morning stiffness) 
(See Section 5.3.3 for BASDAI definition).
If a subject’s baseline value for a component is zero (ie, no disease activity as measured by that 
component), the subject should be considered as not achieving 20% improvement from baseline 
for that component since there is no room for improvement.
5.2.2.
Analyses
1.
The proportion of ASAS 20 responders at Week 24 will be analyzed using Cochran-Mantel-
Haenszel (CMH) test stratified by the combined MRI/hsCRP status and the status of 
previous exposure to anti TNFα agents to summarize the difference between each
ustekinumab group and the placebo group. A 95% confidence interval for the treatment 
difference will be calculated. Treatment Failure, Missing Data Imputation, and Early Escape 
rules will be applied.
2.
The proportion of ASAS 20 responders at Week 24 based on the observed data will also be 
analyzed similarly (retrieved dropout analysis).  No Treatment Failure, Missing Data 
Imputation, or Early Escape rules will be applied in this analysis.
3.
Each component of the ASAS 20 endpoint will be summarized by treatment group with 
Treatment Failure and Early Escape rules applied.  No missing data imputation rule will be 
applied.
5.2.3.
Subgroup Analysis
ASAS 20 at Week 24, over demographic, baseline characteristics, and prior or baseline 
medication use, will be summarized using 95% CI for the treatment differences. 
The subgroups are described in Section 2.4.
If needed, some of the cut-off points may be 
changed to increase sample sizes within categories.
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5.3.
Major Secondary Endpoints
This section outlines the definition and analyses of the major secondary endpoints.
The major secondary endpoints are listed below:
1.
The proportion of subjects who achieve an ASAS 40 response at Week 24
2.
The proportion of subjects who achieve at least a 50% improvement from baseline in
BASDAI at Week 24
3.
The change from baseline in BASFI at Week 24
4.
The proportion of subjects who achieve ASDAS (CRP) inactive disease (<1.3) at Week 24
5.3.1.
Proportion of Subjects who Achieve an ASAS 40 Response at 
Week 24 
ASAS 40 is defined as a ≥40% improvement in 3 of 4 domains, with an absolute improvement of 
at least 2 on a 0 to 10 scale, and no deterioration at all in the remaining domain.
The proportion of ASAS 40 responders at Week 24 will be analyzed using Cochran-Mantel-
Haenszel (CMH) test stratified by the combined MRI/hsCRP status and the status of previous 
exposure to anti TNFα agents to summarize the difference between each ustekinumab group and 
the placebo group.  A 95% confidence interval for the treatment difference will be calculated. 
Treatment Failure, Missing Data Imputation, and Early Escape rules will be applied.
ASAS 40 response status at Week 24 will also be determined based on the observed data at 
Week 24 (retrieved dropout analysis).  That is, no Treatment Failure, Missing Data Imputation, 
or Early Escape rules will be applied.
5.3.2.
Proportion of Subjects who Achieve at Least a 50% Improvement 
from Baseline in BASDAI at Week 24
The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) is a summary of six self-
assessments using a VAS (0 to 10 cm) based on the following criteria:2
A. Fatigue
B. Spinal pain 
C. Joint pain 
D. Enthesitis
E. Qualitative of morning stiffness
F. Quantitative of morning stiffness
The BASDAI is a continuous parameter and is defined as follows: 
BASDAI=0.2(A+B+C+D+0.5[E+F])
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The index will be calculated if at least 3 of the 5 components are present.  Otherwise BASDAI 
is missing.  Percent improvement from baseline is calculated as baseline value minus post-
baseline value divided by baseline value.
The proportion of subjects with at least 50% improvement from baseline in BASDAI at Week 24 
will be analyzed using Cochran-Mantel-Haenszel (CMH) test stratified by the combined 
MRI/hsCRP status and the status of previous exposure to anti TNFα agents to summarize the 
difference between each ustekinumab group and the placebo group.  A 95% confidence interval 
for the treatment difference will be calculated. Treatment Failure, Missing Data Imputation, and 
Early Escape rules will be applied.
The 50% improvement from baseline at Week 24 will also be determined based on the observed 
data at Week 24 (retrieved dropout analysis).  That is, no Treatment Failure, Missing Data 
Imputation, or Early Escape rules will be applied.
5.3.3.
Change from Baseline in Bath Ankylosing Spondylitis Functional 
Index (BASFI) at Week 24
The Bath Ankylosing Spondylitis Functional Index (BASFI) is calculated as the mean of 10
VAS from the following questions (Table 1), each of length 10 cm (0 – 10). Eight of the scales
relate to functional capacity of subjects while the other 2 relate to a subject’s ability to cope 
with everyday life. An increase along the scale indicates a worsening condition.
Table 1:
The Bath Ankylosing Spondylitis Functional Index
1. Putting on your socks or panty hose without help or aids (a sock aid, for example).
2. Bending forward from the waist to pick up a pen from the floor without an aid.
3. Reaching up to a high shelf without help or aids (a helping hand, for example).
4. Getting up out of an armless dining room chair without using your hands or any other help.
5. Getting up off the floor without help from lying on your back.
6. Standing unsupported for 10 minutes without discomfort.
7. Climbing 12-15 steps without using a handrail or walking aid, one foot on each step.
8. Looking over your shoulder without turning your body.
9. Doing physically demanding activities (for example, physical therapy exercises, gardening 
or sports).
10. Doing a full day’s activities, whether it be at home or at work.
In case of missing responses, the mean score will be based on the available data from a minimum 
of 5 questions. Otherwise, BASFI is considered missing.
The analysis for BASFI at Week 24 will be performed using a Mixed Model for Repeated 
Measures (MMRM) based on data with early escape rule applied only.  The independent 
variables for this model are treatment group, MRI/hsCRP status and the status of previous 
exposure to anti-TNFα, baseline BASFI score, visit week, and an interaction of treatment and 
visit week.  An unstructured (UN) variance-covariance matrix for repeated measures within a 
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subject will be used unless there are issues related to convergence.  A 95% confidence interval 
for the difference in LSMeans and nominal p-value will be calculated.
An ANCOVA model will also be used to summarize the difference between the ustekinumab 
group and the placebo group, with change from baseline in the BASFI scores at Week 24 being 
the dependent variable, and treatment group, baseline BASFI and MRI/hsCRP status and the 
status of previous exposure to anti-TNFα as independent variables.  A 95% confidence interval 
for the difference in LSMeans and nominal p-value will be calculated based on contrast.  Last 
observed value (including baseline value) will be used to replace missing values and Week 16 
values will be used to replace Week 24 values for early escaped subjects.
5.3.4.
Proportion of Subjects who Achieve ASDAS (CRP) Inactive Disease 
(<1.3) at Week 24
The ASAS has developed a disease activity score (DAS) for use in AS, the Ankylosing 
Spondylitis Disease Activity Score (ASDAS).  For this study the following formula will be used 
to calculate the ASDAS score:
ASDAS (CRP) = 0.121 x Total back pain + 0.058 x Duration of morning stiffness + 0.110 x
Patient global assessment + 0.073 x Peripheral pain/ swelling + 0.579 x Ln (CRP (mg/L) +1).
Where: 
Total back pain is BASDAI question 2 (VAS 0-10 cm);
Duration of morning stiffness is BASDAI question 6 (VAS 0-10 cm);
Patient global assessment is patient global activity (VAS 0-10 cm);
Peripheral pain/swelling is BASDAI question 3 (VAS 0-10 cm);
CRP:   C-reactive protein the natural log in mg/L + 1.  
When the hsCRP level is <2 mg/L, a value of 2 mg/L should be used to calculate the ASDAS
score.  For non-ASDAS summaries of CRP, if the value is <LLOQ, then half of the value of
LLOQ will be used for numerical calculations.
The proportion of subjects who achieve ASDAS (CRP) inactive disease (<1.3) at Week 24 will 
be analyzed using CMH test stratified by the combined MRI/hsCRP status and the status of 
previous exposure to anti TNFα agents to summarize the difference between each ustekinumab 
group and the placebo group.  A 95% confidence interval for the treatment difference will be 
calculated.
The proportion of subjects who achieve ASDAS (CRP) inactive disease (<1.3) at Week 24 based 
on the observed data will also be analyzed similarly (retrieved dropout analysis).  No Treatment 
Failure, Missing Data Imputation, or Early Escape rules will be applied in this analysis.
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5.3.5.
Other Secondary Analyses
1. The numbers of subjects who achieved ASAS 40 response, ASAS 20 response, at least a 
50% improvement from baseline in BASDAI, and ASDAS (CRP) inactive disease status will 
be summarized through Week 24.  Both ASAS 40 and ASAS 20 response over time will also 
be presented in separate figures.
2. The change from baseline in BASFI and the change from baseline in hsCRP (mg/dL) will be 
summarized through Week 24.
6.
SAFETY
Safety will be assessed by summarizing the occurrences and types of AEs, vital signs
(pulse, blood pressure, weight and height) and the laboratory parameters at Week 16, Week 24, 
and through the end of the study.
Subjects who received at least 1 study agent administration will be included in the analysis
(Safety analysis set) according to the treatment they actually received, regardless of the treatment 
they were randomized to.
6.1.
Safety Table Presentation
If a subject discontinues study participation, the follow-up time will stop at the day of study 
participation discontinuation.  The safety summary tables will be presented through the following
periods: through Week 16, Week 24, and the end of study.
The treatment group descriptions for all study periods are also outlined below.
6.1.1.
Summaries through Week 16
The safety tables will have the column headings below:
Placebo
Ustekinumab
45 mg
90 mg
Combined
6.1.2.
Summaries through Week 24
Please note after Week 16, AE rates across treatment groups are no longer based upon subjects’ 
initial randomized treatment assignments and/or initially assigned treatment (due to early escape), 
and the number of subjects and/or the lengths of follow-up may differ among the groups.
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See the column headings below for the safety tables through Week 24:
Ustekinumab
Placeboa
Placebo 45 mgb
Placebo 90 mgb
45 mg 
90 mg
Combined
a Excludes adverse events that occurred following early escape to ustekinumab.
b Only includes adverse events that occurred following early escape to ustekinumab.
6.1.3.
Summaries through the End of Study
Subjects who were randomized to placebo and did not qualify for early escape are re-randomized 
at Week 24 to receive either ustekinumab 45 mg or ustekinumab 90 mg. These summaries
through the end of study will be based on subjects who have been treated with ustekinumab and 
will exclude subjects who only received placebo. 
See below for a sample layout.
Placebo->Ustekinumaba
Ustekinumab
Ustekinumab Combined
45 mg
90 mg
45 mg 
90 mg
45 mg 
90 mg
All 
Ustekinumab
a Only includes adverse events that occurred following early escape or crossover to ustekinumab.  Adverse events 
are counted from the first dose of ustekinumab to the end of the study.
6.2.
Adverse Events
Treatment-emergent AEs will be summarized by system organ class and preferred term
defined by MedDRA.
The following treatment-emergent AE summary tables will be provided for this study:

Any AEs

SAEs

AEs with severe intensity

AEs and SAEs that are reasonably related to study agent

AEs leading to discontinuation of study agent

Injection site reactions

Infections and infections requiring oral or parenteral anti-microbial treatment

Serious infections
In addition to the summary tables, a listing of subjects who died and listings of subjects with the 
following AEs will be presented: SAEs, AEs leading to discontinuation of study agent, 
anaphylactic reactions, serum sickness reactions, malignancy, active tuberculosis, opportunistic 
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STELARA® (ustekinumab)  
Statistical Analysis Plan CNTO1275AKS3003
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Approved, Date: 8 December 2017
infections, injection site reactions, and hepatobiliary events (defined as ALT ≥3 × ULN and
bilirubin ≥2 × ULN).
Injection site reactions and infection:

An injection site reaction is defined as any adverse reaction at a SC study agent 
injection site and is captured in the eCRF.

An infection is identified as any AE that was recorded as an infection by the investigator on 
the eCRF.
Since safety should be assessed relative to exposure, the following summaries will be presented:

Proportion of subjects receiving scheduled study agent administrations at each study 
agent administration visit by treatment group

Summary of cumulative ustekinumab dose by treatment group
In addition, all AE summary tables will include average weeks of follow-up and average number 
of administrations for each treatment group.
6.3.
Clinical Laboratory Tests
Tests of hematologic function and clinical chemistry consisted of laboratory measurements of:
Hematology: hemoglobin, neutrophils, lymphocytes, platelets, and Leukocytes.
Chemistry: creatinine, bilirubin, alkaline phosphatase, ALT/SGPT, AST/SGOT, sodium, 
potassium, albumin, and glucose
NCI-CTCAE grades will be used in the summary of laboratory data (Grade 1 – 4).  The
proportion of subjects for each laboratory parameter with maximum Grades will be presented. 
Proportion of subjects with maximum ALT/AST will be provided for the categories: >1 to 
<2xULN, ≥2 to ≤3xULN, >3 to ≤5xULN, >5 to <8xULN, and ≥8xULN.
A listing of subjects with post-baseline abnormal laboratory results based on CTCAE grades ≥3 
will also be provided.
6.4.
Vital Signs
Markedly abnormal vital signs will be summarized by treatment group and listed.
NCT02407223


STELARA® (ustekinumab)  
Statistical Analysis Plan CNTO1275AKS3003
20
Approved, Date: 8 December 2017
REFERENCE
1.
Calin A, Garrett S, Whitelock H, et al. A new approach to defining functional ability in ankylosing 
spondylitis:the development of the Bath Ankylosing Spondylitis Functional Index. J Rheumatol. 
1994;21(12):2281-2285.
2.
Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, Calin A. A new approach to defining disease 
status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J Rheumatol.1994; 
21(12):2286-2291.
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