Conditions: Axial Spondyloarthritis
Keywords: Ankylosing Spondylitis Ustekinumab Golimumab STELARA
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 315
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the efficacy of ustekinumab, in adult anti-TNF(alpha) refractory participants with active radiographic axial spondyloarthritis (AxSpA), as measured by the reduction in signs and symptoms of radiographic AxSpA.

Detailed description:
This is a Phase 3, multicenter (when more than one hospital or medical school team work on a medical research study), randomized (study medication assigned to participants by chance), double-blind (neither the researchers nor the participants know what treatment the participant is receiving), placebo-controlled (an inactive substance; a pretend treatment \[with no drug in it\] that is compared in a clinical trial with a drug to test if the drug has a real effect) study. The study consists of 3 phases; Screening (up to 8 weeks), Treatment phase: placebo-controlled (Week 0 to 24) and active treatment (Week 24 to Week 52), and Safety Follow-up (up to 12 weeks). Participants will be randomly assigned to 1 of 3 treatment groups: placebo, ustekinumab 45 mg and ustekinumab 90 mg. The total duration of study will be up to 64 weeks. Participants will be primarily assessed for Assessment of SpondyloArthritis International Society (ASAS) 40 response at Week 24. Participants' safety will be monitored throughout the trial.

Arms:
arm 1: Placebo subcutaneous (SC) injection at Weeks 0, 4, and 16. At Week 24 all participants (with the exception of participants who qualified for early escape \[EE\]) will be re-randomized to receive either ustekinumab 45 or 90 milligram (mg) SC injection at Weeks 24 and 28 followed by every 12 weeks (q12w) dosing, with the last administration of study agent at Week 52. Participants who meet EE criteria (less than \[\<\] 10 percent \[%\] improvement from baseline in both total back pain and morning stiffness measures at both Week 12 and Week 16) will be administered open-label golimumab 50 mg SC administrations at Week 16 and every 4 weeks (q4w) thereafter through Week 52. arm 2: Ustekinumab 45 mg SC injection at Weeks 0 and 4, followed by q12w dosing, with the last administration of study agent at Week 52. At Week 24, participants will receive placebo SC injection to maintain the blind. Participants who meet EE criteria (\<10% improvement from baseline in both total back pain and morning stiffness measures at both Week 12 and Week 16) will be administered open-label golimumab 50 mg SC administrations at Week 16 and q4w thereafter through Week 52. arm 3: Ustekinumab 90 mg SC injection at Weeks 0 and 4, followed by q12w dosing, with the last administration of study agent at Week 52. At Week 24, participants will receive placebo SC injection to maintain the blind. Participants who meet EE criteria (\<10% improvement from baseline in both total back pain and morning stiffness measures at both Week 12 and Week 16) will be administered open-label golimumab 50 mg SC administrations at Week 16 and q4w thereafter through Week 52.

Interventions: intervention 1: Placebo intervention 2: Ustekinumab 45 mg intervention 3: Ustekinumab 90 mg intervention 4: Golimumab 50 mg
Intervention descriptions: intervention 1: Placebo subcutaneous (SC) injection at Weeks 0, 4, and 16 in Group 1. intervention 2: Ustekinumab 45 mg SC injection at Weeks 24 and 28 followed by every 12 weeks (q12w) dosing, with the last administration of study agent at Week 52 in Group 1. Participants will start with ustekinumab 45 mg SC injection at Weeks 0 and 4, followed by q12w dosing, with the last administration of study agent at Week 52 in Group 2. intervention 3: Ustekinumab 90 mg SC injection at Weeks 24 and 28 followed by q12w dosing, with the last administration of study agent at Week 52 in Group 1. Participants will start with ustekinumab 90 mg SC injection at Weeks 0 and 4, followed by q12w dosing, with the last administration of study agent at Week 52 in Group 3. intervention 4: Participants who meet EE criteria (less than \[\<\] 10 percent \[%\] improvement from baseline in both total back pain and morning stiffness measures at both Week 12 and Week 16) will be administered open-label golimumab 50 mg SC administrations at Week 16 and every 4 weeks (q4w) thereafter through Week 52 in Group 1, 2 and 3.

Protocol document:
Prot_001.pdf: 
1
Approved, 13 July 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 Anti-TNFα Refractory 
Subjects With Active Radiographic Axial Spondyloarthritis
  
Protocol CNTO1275AKS3002; Phase 3
AMENDMENT 1
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:  2015-000288-16 
Status:
Approved
Date:
13 July 2015
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-ERI-96426906, 3.0
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.
NCT02438787


Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
2
Approved, 13 July 2015
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................... 8
TIME AND EVENTS SCHEDULE .............................................................................................................. 14
ABBREVIATIONS ...................................................................................................................................... 17
1.
INTRODUCTION................................................................................................................................ 19
1.1.
Disease Background...................................................................................................................... 19
1.2.
Overall Rationale for the Study...................................................................................................... 20
1.2.1.
Scientific Rationale for Use of Anti-IL-12/23p40 Therapy in Radiographic AxSpA .................... 20
1.2.2.
Rationale for Ustekinumab in Axial Spondyloarthritis................................................................. 21
1.2.3.
CNTO1275PSA3001 and CNTO1275PSA3002 PsA Studies.................................................... 21
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 ............................................................................................... 23
1.3.
Dose Justification........................................................................................................................... 24
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 26
2.1.
Objectives ...................................................................................................................................... 26
2.2.
Hypothesis ..................................................................................................................................... 26
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 27
3.1.
Overview of Study Design.............................................................................................................. 27
3.1.1.
Study Population......................................................................................................................... 28
3.1.2.
Study Phases and Duration of Treatment .................................................................................. 29
3.1.3.
Study Control, Randomization, and Blinding.............................................................................. 29
3.2.
Study Design Rationale.................................................................................................................. 29
4.
SUBJECT POPULATION.................................................................................................................. 30
4.1.
Inclusion Criteria ............................................................................................................................ 31
4.2.
Exclusion Criteria ........................................................................................................................... 35
4.3.
Prohibitions and Restrictions ......................................................................................................... 39
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 40
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 41
6.1.
Dosing Regimen and Blinding........................................................................................................ 41
6.2.
Study Agent Administration and Timing......................................................................................... 42
7.
TREATMENT COMPLIANCE............................................................................................................ 43
8.
CONCOMITANT THERAPY.............................................................................................................. 43
8.1.
Methotrexate, Sulfasalazine, or Hydroxychloroquine .................................................................... 43
8.2.
Corticosteroid Therapy................................................................................................................... 44
8.3.
Nonsteroidal Anti-inflammatory Drugs and Other Analgesics........................................................ 44
8.4.
Disease Modifying Antirheumatic Drugs/Systemic Immunosuppressives ..................................... 45
8.5.
Biologic Agents or Investigational Agents...................................................................................... 45
8.6.
Complementary Therapies............................................................................................................. 45
9.
STUDY EVALUATIONS .................................................................................................................... 46
NCT02438787


Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
3
Approved, 13 July 2015
9.1.
Study Procedures........................................................................................................................... 46
9.1.1.
Overview..................................................................................................................................... 46
9.1.2.
Screening Phase ........................................................................................................................ 46
9.1.3.
Treatment Phase ........................................................................................................................ 48
9.1.4.
Posttreatment Phase (Follow-Up) .............................................................................................. 49
9.2.
Efficacy........................................................................................................................................... 49
9.2.1.
Evaluations ................................................................................................................................. 49
9.2.1.1.
Assessment of SpondyloArthritis International Society Response Criteria............................. 49
9.2.1.2.
Bath Ankylosing Spondylitis Disease Activity Index................................................................ 50
9.2.1.3.
Bath Ankylosing Spondylitis Functional Index......................................................................... 50
9.2.1.4.
Patient’s Global Assessment................................................................................................... 50
9.2.1.5.
Total Back Pain ....................................................................................................................... 50
9.2.1.6.
Night Back Pain ....................................................................................................................... 50
9.2.1.7.
Morning Stiffness..................................................................................................................... 50
9.2.1.8.
Musculoskeletal Assessments................................................................................................. 50
9.2.1.8.1.
Bath Ankylosing Spondylitis Metrology Index ...................................................................... 51
9.2.1.8.2.
Chest Expansion .................................................................................................................. 52
9.2.1.8.3.
Enthesitis Index.................................................................................................................... 52
9.2.1.9.
Ankylosing Spondylitis Disease Activity Score........................................................................ 52
9.2.1.10.
Imaging Evaluations ................................................................................................................ 53
9.2.1.10.1.
X-ray of Sacroiliac Joints...................................................................................................... 53
9.2.1.11.
36-Item Short-form Health Survey........................................................................................... 53
9.2.1.12.
Medical Outcomes Study Sleep Scale .................................................................................... 54
9.2.1.13.
Ankylosing Spondylitis Quality of Life (ASQoL) Questionnaire............................................... 54
9.2.1.14.
Functional Assessment of Chronic Illness Therapy−Fatigue Questionnaire........................... 54
9.2.1.15.
EuroQol 5 Dimension Questionnaire....................................................................................... 54
9.2.2.
Endpoints.................................................................................................................................... 55
9.3.
Pharmacokinetics and Immunogenicity ......................................................................................... 56
9.3.1.
Serum Collection and Handling .................................................................................................. 56
9.3.2.
Analytical Procedures................................................................................................................. 57
9.3.2.1.
Pharmacokinetics of Ustekinumab .......................................................................................... 57
9.3.2.2.
Immunogenicity [Antibodies to Ustekinumab] ......................................................................... 57
9.4.
Pharmacodynamic Evaluations...................................................................................................... 57
9.4.1.
Serum and Whole Blood Biomarkers ......................................................................................... 57
9.4.2.
Microbiome Substudy ................................................................................................................. 57
9.5.
Pharmacogenomic (DNA) Evaluations .......................................................................................... 58
9.6.
Health Economics .......................................................................................................................... 58
9.6.1.
Work Productivity and Activity Impairment Questionnaire.......................................................... 58
9.7.
Safety Evaluations ......................................................................................................................... 58
9.8.
Sample Collection and Handling.................................................................................................... 61
10.
SUBJECT COMPLETION/WITHDRAWAL....................................................................................... 62
10.1.
Completion ..................................................................................................................................... 62
10.2.
Discontinuation of Study Treatment............................................................................................... 62
10.3.
Withdrawal from the Study............................................................................................................. 63
11.
STATISTICAL METHODS................................................................................................................. 64
11.1.
Subject Information ........................................................................................................................ 65
11.2.
Sample Size Determination ........................................................................................................... 65
11.3.
Efficacy Analyses ........................................................................................................................... 65
11.3.1.
Primary Endpoint Analysis.......................................................................................................... 65
11.3.2.
Major Secondary Analyses......................................................................................................... 66
11.3.3.
Other Planned Efficacy Analyses ............................................................................................... 67
11.4.
Pharmacokinetic Analyses............................................................................................................. 68
11.5.
Immunogenicity Analyses .............................................................................................................. 68
11.6.
Pharmacodynamic Biomarker Analyses ........................................................................................ 68
11.7.
Pharmacokinetic/Pharmacodynamic Analyses.............................................................................. 68
NCT02438787


Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
4
Approved, 13 July 2015
11.8.
Biomarker and Microbiome Analyses ............................................................................................ 68
11.9.
Pharmacogenomic Analyses ......................................................................................................... 68
11.10.
Health Economics Analyses .......................................................................................................... 69
11.11.
Safety Analyses ............................................................................................................................. 69
11.12.
Interim Analysis.............................................................................................................................. 69
11.13.
Data Monitoring Committee ........................................................................................................... 70
12.
ADVERSE EVENT REPORTING ...................................................................................................... 70
12.1.
Definitions ...................................................................................................................................... 71
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 71
12.1.2.
Attribution Definitions.................................................................................................................. 72
12.1.3.
Severity Criteria .......................................................................................................................... 72
12.2.
Special Reporting Situations.......................................................................................................... 73
12.3.
Procedures..................................................................................................................................... 73
12.3.1.
All Adverse Events...................................................................................................................... 73
12.3.2.
Serious Adverse Events ............................................................................................................. 74
12.3.3.
Pregnancy................................................................................................................................... 75
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 75
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 75
13.1.
Procedures..................................................................................................................................... 76
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 76
14.
STUDY AGENT INFORMATION....................................................................................................... 76
14.1.
Physical Description of Study agents............................................................................................. 76
14.2.
Packaging ...................................................................................................................................... 77
14.3.
Labeling.......................................................................................................................................... 77
14.4.
Preparation, Handling, and Storage............................................................................................... 77
14.5.
Drug Accountability ........................................................................................................................ 77
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 78
16.
ETHICAL ASPECTS ......................................................................................................................... 78
16.1.
Study-Specific Design Considerations........................................................................................... 78
16.2.
Regulatory Ethics Compliance....................................................................................................... 78
16.2.1.
Investigator Responsibilities ....................................................................................................... 78
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 79
16.2.3.
Informed Consent ....................................................................................................................... 80
16.2.4.
Privacy of Personal Data ............................................................................................................ 81
16.2.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 82
16.2.6.
Country Selection ....................................................................................................................... 82
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 82
17.1.
Protocol Amendments.................................................................................................................... 82
17.2.
Regulatory Documentation ............................................................................................................ 83
17.2.1.
Regulatory Approval/Notification ................................................................................................ 83
17.2.2.
Required Prestudy Documentation............................................................................................. 83
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 84
17.4.
Source Documentation................................................................................................................... 84
17.5.
Case Report Form Completion ...................................................................................................... 85
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 86
17.7.
Record Retention ........................................................................................................................... 86
17.8.
Monitoring ...................................................................................................................................... 87
17.9.
Study Completion/Termination....................................................................................................... 87
17.9.1.
Study Completion ....................................................................................................................... 87
17.9.2.
Study Termination....................................................................................................................... 87
17.10.
On-Site Audits ................................................................................................................................ 88
17.11.
Use of Information and Publication................................................................................................ 88
NCT02438787


Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
5
Approved, 13 July 2015
REFERENCES............................................................................................................................................ 90
APPENDIX A:
QUANTIFERON®-TB GOLD TESTING........................................................................ 93
APPENDIX B:
TUBERCULIN SKIN TESTING ..................................................................................... 95
APPENDIX C:
HEPATITIS B VIRUS (HBV) SCREENING WITH HBV DNA TESTING ...................... 97
INVESTIGATOR AGREEMENT ................................................................................................................. 98
LAST PAGE................................................................................................................................................ 98
LIST OF IN-TEXT TABLES AND FIGURES 
TABLES
Table 1:
Times and Events from Study Initiation Through Week 64 ...................................................... 14
Table 2:
Scores (S) for the five components of the BASMIlin.................................................................. 51
Table 3:
Power to detect a significant treatment difference in achieving an ASAS 40 Response 
at Week 24................................................................................................................................ 65
Table 4:
Critical values and 1-sided alpha levels for the interim analysis and final analysis ................. 66
FIGURES
Figure 1:
Proportion of subjects with BASDAI 50 responses at Week 24 in CNTO1275PSA3001 
and CNTO1275PSA3002 trials in subjects with active PsA ..................................................... 22
Figure 2:
Summary of Efficacy Results in Investigator Initiated Study in AS (TOPAS)........................... 24
Figure 3:
Schematic Overview of the Study............................................................................................. 28
Figure 4:
Overview of Multiplicity Control................................................................................................. 67
NCT02438787


Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
6
Approved, 13 July 2015
PROTOCOL AMENDMENTS
Protocol Version
Issue Date
Original Protocol
09 April 2015
Amendment 1
13 July 2015
Amendments below are listed beginning with the most recent amendment.
Amendment 1 (13 July 2015)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.
The overall reason for the amendment:  To clarify that the Sponsor intends to enroll up to 10% of the study 
population with total spinal ankylosis.
Applicable Section(s)
Description of Change(s)
Rationale: All subjects regardless of self-administration or assisted administration of study agent must return to the 
study site for assessment of primary and major secondary endpoints, and safety assessments at the required study 
time points.
Time and Events 
Schedule Table
Footnote f
Subjects in the 3 treatment groups who qualify for early escape will have different 
dosing and assessment schedules. These subjects may begin self-administration of 
open-label golimumab at home. Subjects unable to have injection golimumab 
administered away from study site will be required to return to the site for administration 
of study agent injection. Early escape subjects will return to the study site at Week 24 
for assessments related to the primary and major secondary endpoints (ASAS 
response, BASDAI, BASFI, ASDAS [CRP]) and Week 24 safety assessments, then at 
Weeks 28, 40, and 52 for BASDAI and safety assessments, and lastly the final safety 
visit/Week 64.
Rationale: Clarification of the Sponsor’s intention to enroll up to 10% of the study population with total spinal 
ankyloses has been made by deletion exclusion criterion #10.
Section 4.2 Exclusion 
Criteria #10
Have total spinal ankylosis.
Rationale: Two separate visits at screening for subjects have been eliminated.
Section 9.1.2
Screening Phase
The screening visit may be divided 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.  
Rationale: Details regarding the physical examination assessment have been added.
NCT02438787


Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
7
Approved, 13 July 2015
Applicable Section(s)
Description of Change(s)
Section 9.7 Safety 
Evaluations
Physical examination
A physical examination will be performed at screening and the Week 64/Final safety 
follow up visit.  The chest, abdomen, and extremities should be examined, but 
otherwise the examination can be a focused one based upon the individual’s medical 
history and manifestations of spondyloarthritis, including axial and extra-articular 
(uveitis, psoriasis, inflammatory bowel disease, etc.).
Rationale:  Clarification on the posttreatment assessments for subjects who discontinue study agent administration
has been made.
Section 10.3 
Withdrawal from the 
Study
If a subject withdraws from the study before the end of the treatment, posttreatment 
assessments should be obtained (Section 9.1.4).  If a subject discontinues study agent 
administrations before the end of the treatment but does not withdraw consent for study 
participation, posttreatment assessments should be obtained (Section 9.1.4).
Rationale:  Clarification of reporting of subject pregnancies and pregnancy outcomes has been made.
Section 12.3.3 
Pregnancy
Any subject who becomes pregnant during the study must be promptly withdrawn from the 
study and discontinue further study treatment.  Pregnancies must be reported by study-
site personnel within 24 hours of knowledge of the event using the appropriate 
pregnancy notification form.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events and 
must be reported using the Serious Adverse Event Form.
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
NCT02438787


Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
8
Approved, 13 July 2015
SYNOPSIS  
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating the 
Efficacy and Safety of Ustekinumab in the Treatment of Anti-TNFα Refractory Subjects With 
Active Radiographic Axial Spondyloarthritis 
Ustekinumab is a fully human monoclonal antibody (mAb) that binds to the IL-12/23p40 protein subunit 
of human interleukin (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 (AS), 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 anti-TNFα refractory 
subjects with active radiographic AxSpA, as measured by the reduction in signs and symptoms of 
radiographic AxSpA.
Secondary Objectives
The secondary objectives are to assess the effect of treatment with ustekinumab in anti-TNFα refractory 
subjects with active radiographic AxSpA on the following:

Efficacy related to improving physical function, range of motion, health-related quality of life, and 
other health outcomes.

Safety.

Pharmacokinetics (PK) and immunogenicity.
Exploratory Objective
The exploratory objectives are to evaluate the effect of ustekinumab on pharmacodynamics, on the 
microbiome, and on pharmacogenomics in anti-TNFα refractory subjects with radiographic 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 radiographic AxSpA, as assessed at 
Week 24 by the composite endpoint of Assessment of SpondyloArthritis International Society (ASAS) 40 
response and the outcome of continuing originally assigned treatment.
OVERVIEW OF STUDY DESIGN
CNTO1275AKS3002 is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study of 
ustekinumab 45 mg and 90 mg in subjects with active radiographic AxSpA and who have been refractory 
to anti-TNFα therapy.
NCT02438787


Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
9
Approved, 13 July 2015
Approximately 483 subjects will be randomized at approximately 150 investigational sites. Subjects will 
be randomly assigned in a 1:1:1 ratio to receive subcutaneous (SC) ustekinumab 45 or 90 mg or placebo 
administrations at Weeks 0, 4, and 16.  Permuted block randomization by interactive web response system 
(IWRS) will be used.  Randomization will be stratified by region.  
At Week 16, subjects in all 3 treatment groups who qualify for early escape (EE; 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 open-label golimumab 50 mg SC injections at Week 16 and 
every 4 weeks (q4w) thereafter through Week 52.  
At Week 24, all remaining placebo subjects who did not meet EE criteria will be rerandomized using 
IWRS to begin receiving ustekinumab 45 or 90 mg at Weeks 24 and 28 followed by q12w therapy with 
the last study agent administration at Week 52 and have the final follow-up visit at Week 64. All subjects 
in the ustekinumab 45 mg and 90 mg treatment groups who do not qualify for EE will continue to receive 
the treatment they were randomized to at Week 0 through Week 52 and have the final follow-up visit at 
Week 64.
Database locks (DBL) will occur at the time of the interim analysis, Week 24, and Week 64.
An independent Data Monitoring Committee (DMC) will be commissioned for this study.
A group sequential design using the O'Brien and Fleming boundary will be applied with 1 interim 
analysis at the time when approximately 50% of subjects have completed the Week 24 visit or end study 
participation before the Week 24 visit.
Subjects will be followed for adverse events (AE) and serious adverse events (SAE) 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 64 visit.
SUBJECT POPULATION
The target study population is adult subjects who have been refractory to anti-TNFα therapy and have 
active radiographic AxSpA, as evidenced by Bath Ankylosing Spondylitis Disease Activity Index 
(BASDAI) ≥4 and a visual analog scale (VAS) for total back pain of ≥4, each on a scale of 0 to 10. All 
subjects are required to have a screening high sensitivity C-reactive protein (hsCRP) level ≥0.300 mg/dL. 
Background treatment with nonsteroidal anti-inflammatory drugs (NSAID), select non-biologic disease-
modifying antirheumatic drugs (DMARD), and low dose corticosteroids will be allowed during the study 
at stable doses through Week 24.

Subjects must have a diagnosis of definite AS, as defined by the 1984 modified New York criteria.

The radiographic criterion and at least 1 clinical criterion must be met:
a.
Radiographic criterion:  Sacroiliitis Grade 2 bilaterally or sacroiliitis Grade 3 to 4 unilaterally 
as assessed by the central reader.
b.
Clinical criteria (at least 1):
1)
Low back pain and stiffness for more than 3 months, which improves with exercise, but is 
not relieved by rest.
2)
Limitation of motion of the lumbar spine in both the sagittal and frontal planes.
3)
Limitation of chest expansion relative to normal values corrected for age and sex.
NCT02438787


Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
10
Approved, 13 July 2015
Screening for eligible subjects will be performed within 8 weeks before the first administrations of the 
study agent.  Subjects with complete ankylosis of the spine, defined as bridging syndesmophytes present 
at all intervertebral levels of the cervical and lumbar spine visualized on lateral-view spinal radiographs 
are permitted to be included in the study, but will be limited to approximately 10% of the study 
population.
Subjects must also meet the inclusion and exclusion criteria.
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: 

Group 1 (placebo): Placebo at Weeks 0, 4, and 16. At Week 24 all subjects (with the exception of 
subjects who qualified for EE) will be rerandomized to receive either ustekinumab 45 or 90 mg SC at 
Weeks 24 and 28 followed by q12w dosing, with the last administration of study agent at Week 52.

Group 2 (ustekinumab 45 mg): Ustekinumab 45 mg at Weeks 0 and 4, followed by q12w dosing,
with the last administration of study agent at Week 52.  At Week 24, subjects will receive placebo
SC to maintain the blind.

Group 3 (ustekinumab 90 mg): Ustekinumab 90 mg at Weeks 0 and 4, followed by q12w dosing, 
with the last administration of study agent at Week 52.  At Week 24, subjects will receive placebo 
SC to maintain the blind.
Subjects who qualify for EE at Week 16 will be administered golimumab 50 mg SC q4w.
To maintain the blind, all randomized subjects will 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.
EFFICACY EVALUATIONS/ENDPOINTS
Efficacy evaluations chosen for this study were established in previous trials of therapeutic biologic 
agents for the treatment of radiographic AxSpA.  Patient reported outcomes (PRO) chosen for this study 
are consistent with clinically relevant measurements that are accepted in the medical literature for other 
studies in AS and applicable regulatory guidance documents. 
Axial spondyloarthritis response evaluations include:

Assessment in Ankylosing Spondylitis Response Criteria

Bath Ankylosing Spondylitis Functional Index (BASFI)

Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)

Patient’s Global Assessment

Total Back Pain

Night Back Pain

Morning Stiffness
NCT02438787


Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
11
Approved, 13 July 2015

Musculoskeletal Assessments
-
Bath Ankylosing Spondylitis Metrology Index (BASMI)
-
Chest Expansion
-
Maastricht Ankylosing Spondylitis Enthesitis Score

Ankylosing Spondylitis Disease Activity Score

Imaging Evaluations
-
X-rays of sacroiliac joints

36-item short form health survey (SF-36)

Medical Outcomes Study Sleep Scale

Ankylosing Spondylitis Quality of Life (ASQoL) questionnaire

Functional Assessment of Chronic Illness Therapy - Fatigue Questionnaire

EuroQol 5 Dimension (EQ-5D) Questionnaire

Work Productivity and Activity Impairment Questionnaire (WPAI-SHP)
Primary Endpoint
The primary endpoint is the proportion of subjects achieving an ASAS 40 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 20 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.
PHARMACOKINETIC EVALUATIONS
All serum ustekinumab 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, standard deviation, median, interquartile range, 
minimum, and maximum will be calculated at each sampling time point.
Serum ustekinumab concentrations will be summarized for each treatment group over time. If feasible, a 
population PK analysis using nonlinear mixed effects modeling approach (NONMEM) will be used to 
characterize the disposition characteristics of ustekinumab in the current study. The CL/F and V/F will be 
estimated. The influence of important variables (such as body weight, positive for antibodies to 
ustekinumab, and the use of methotrexate [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.
NCT02438787


Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
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Approved, 13 July 2015
IMMUNOGENICITY EVALUATIONS
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.
PHARMACODYNAMIC EVALUATIONS
Pharmacodynamic markers are considered exploratory.
BIOMARKER AND MICROBIOME EVALUATIONS 
Changes in serum, RNA, fecal microbial profiles, and 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. All biomarker analyses will be summarized in a separate technical 
report.
PHARMACOGENOMIC (DNA) EVALUATIONS
Pharmacogenomic and epigenetics analyses are considered exploratory.
A pharmacogenomic blood sample will be collected to allow for pharmacogenomic research, as necessary 
(where local regulations permit). Subject participation in the pharmacogenomic research is optional.
SAFETY EVALUATIONS
Subject safety evaluations including assessments of the following: adverse events (including injection-site 
reactions and infections), clinical laboratory tests (hematology, chemistry, and pregnancy testing), vital 
signs, physical examinations, concomitant medication review, electrocardiograms, and early detection of 
tuberculosis will be monitored through the end of the study as delineated in the Time and Events 
Schedule.  
Based upon the safety profile of ustekinumab, as well as the golimumab safety data to date, several AEs 
of interest have been identified and will be monitored and assessed in this study. These include: injection 
reactions, major cardiovascular events (MACE), demyelination, hepatobiliary laboratory abnormalities, 
infections including TB, and malignancies.  
STATISTICAL METHODS
Simple descriptive summary statistics, such as n, mean, SD, median, IQ range, minimum, and maximum 
for continuous variables, and counts and percentages for categorical variables will be used to summarize 
most data.
Unless otherwise specified, the Cochran-Mantel-Haenszel (CMH) chi-square test stratified by region 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 
region as covariate if appropriate. All statistical testing will be performed 2-sided.  In addition to 
statistical analyses, graphical data displays (eg, line plots) and subject listings may also be used to 
summarize/present the data.  Specific details will be provided in the Statistical Analysis Plan (SAP).  
Population Set
The population set will be a modified intention-to-treat (mITT; 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.
NCT02438787


Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
13
Approved, 13 July 2015
Endpoint Analyses
Primary Endpoint Analysis
The primary endpoint is the proportion of subjects who achieve an ASAS 40 response at Week 24. The 
primary hypothesis is to compare at Week 24 the composite endpoint of ASAS40 response and the 
outcome of continuing originally assigned treatment. Hence, subjects who early escape to golimumab, 
meet treatment failure criteria, or have missing ASAS assessment are nonresponders for the composite 
endpoint.
The proportion of subjects who achieve the composite endpoint at Week 24 will be compared between the 
ustekinumab groups and placebo group using a CMH test stratified by region at a significance level of 
0.05 (2-sided). Data from all randomized subjects who received at least 1 administration of study 
treatment (mITT) will be analyzed according to their assigned treatment group regardless of their actual 
treatment received. 
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 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 20 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.
Safety Analysis Overview
Routine safety evaluations will be performed. The occurrences and type of AEs, SAEs, and reasonably 
related AEs including injection reactions and infections will be summarized by treatment groups. The 
number of subjects with abnormal laboratory parameters (hematology and chemistry) based on 
NCI-CTCAE toxicity grading will be summarized. 
All safety analyses will be performed using the population of all subjects who received at least 
1 administration of study agent.  
In addition, graphical data displays (eg, line plots) and subject listings may also be used to 
summarize/present data.
NCT02438787


Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
14
Approved, 13 July 2015
TIME AND EVENTS SCHEDULE 
Table 1:
Times and Events from Study Initiation Through Week 64
Phase
Screening
Placebo-controlled and Active treatment
Safety follow-up
Week
-8
0
4
8
12
16
20
24
28
40
52/Final Efficacy Visita
64/Final Safety Visitb
Study Proceduresc
Screening/Administratived
Informed consente
X
Informed consent for pharmacogenomics (DNA; optional)
X
Inclusion/exclusion criteria
X
X
Medical history and demographics
X
Study agent Administration
Randomization
X
X
Study agent administrationf,g
X
X
X
X
X
X
X
Injection site reaction evaluationh
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 testi
X
TB evaluationj
X
X
X
X
X
X
X
X
X
X
X
X
Serum pregnancy testk
X
Urine pregnancy testk
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
Chest X-rayl
X
Concomitant therapy
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
Efficacy Assessments
BASDAI
X
X
X
X
X
X
X
X
X
X
X
BASFI
X
X
X
X
X
X
X
X
X
X
Patient’s Global assessment 
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
Night Back Pain assessment
X
X
X
X
X
X
X
X
X
X
BASMI
X
X
X
X
NCT02438787


Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
15
Approved, 13 July 2015
Table 1:
Times and Events from Study Initiation Through Week 64
Phase
Screening
Placebo-controlled and Active treatment
Safety follow-up
Week
-8
0
4
8
12
16
20
24
28
40
52/Final Efficacy Visita
64/Final Safety Visitb
Study Proceduresc
Chest expansion
X
X
X
X
Enthesitis evaluation
X
X
X
X
IWRS for total back pain and morning stiffness
X
X
SF-36m
X
X
X
X
ASQOLm
X
X
X
X
EQ-5Dm
X
X
X
X
FACIT-Fm
X
X
X
X
MOS-SSm
X
X
X
X
WPAI-SHPm
X
X
X
X
X-ray (SI joints)
Xn
Clinical Laboratory Assessments
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
Xf
X
X
X
hsCRP
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacokinetics/Immunogenicity
Serum ustekinumab concentrationso
X
X
X
X
X
X
X
X
X
X
X
Antibodies to study agento
X
X
X
X
X
X
X
X
Pharmacogenomics (DNA)
Whole blood DNAp
X
X
X
Biomarkers
HLA-B27 statusq
X
Whole blood for RNA gene expression
X
X
X
Serum for biomarker assessment
X
X
X
Microbiome stool sampler
X
X
X
X
NCT02438787


Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
16
Approved, 13 July 2015
Table 1:
Times and Events from Study Initiation Through Week 64
a.
Subjects who discontinue study agent administrations before the Week 24 visit should return for all visits through Week 24. Subjects who discontinue study 
agent after Week 24 and before the Week 52 visit, must return as soon as possible for a final efficacy follow-up visit (refer to Week 52 assessments).
b.
For subjects who discontinue study agent administrations prematurely, a final safety visit (refer to Week 64 assessments) must be performed 12 weeks after last 
study agent administration.
c.
All assessments are to be completed prior to study agent injection, except at Weeks 8, 12, and 20 (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 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 form.
f.
Subjects in the 3 treatment groups who qualify for early escape will have different dosing and assessment schedules. These subjects may begin self-
administration of open-label golimumab at home. Subjects unable to have golimumab administered away from study site will be required to return to the site 
for administration of study agent injection. Early escape subjects will return to the study site at Week 24 for assessments related to the primary and major 
secondary endpoints (ASAS response, BASDAI, BASFI, ASDAS [CRP]) and Week 24 safety assessments, then at Weeks 28, 40, and 52 for BASDAI and 
safety assessments, and lastly the final safety visit/Week 64.
g.
Ustekinumab/placebo study agent SC injections will be administered as indicated in Table 1, except that subjects who qualify for early escape will switch to 
administration of golimumab SC every 4 weeks from Week 16 through Week 52.
h.
Subjects should be monitored for the occurrence of injection site reactions for 30 minutes after the injection.
i.
Only required if QuantiFERON is not registered/approved locally or the tuberculin skin test (TST) is mandated by local health authorities. 
j.
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. 
k.
Pregnancy testing may be repeated at any time at the discretion of investigator or subject, or as required by local regulation.
l.
May be taken within 3 months prior to the first administration of study agent.
m. All visit-specific PRO assessments should be conducted before any tests, procedures, or other consultations for that visit to prevent influencing subjects’ 
perceptions.
n.
An existing x-ray may be sent for central reading in lieu of screening x-ray. If x-ray is not of adequate quality a new screening x-ray must be submitted.
o.
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.
p.
Participation is optional and subjects must sign a separate pharmacogenomics informed consent.
q.
This test should be performed if previous results are not available, in which case a sample will be collected for HLA-B27 at screening.
r.
Only from approximately 100 subjects who consent and are randomized to participate in the microbiome substudy at selected sites.
NCT02438787


Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
17
Approved, 13 July 2015
ABBREVIATIONS  
AE
adverse event
ALT
alanine aminotransferase
AS
ankylosing spondylitis
ASAS
Assessment in SpondyloArthritis international Society
ASDAS
Ankylosing Spondylitis Disease Activity Score
ASQoL
Ankylosing Spondylitis Quality of Life questionnaire
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 
-hCG
-human chorionic gonadotropin
CMH
Cochran-Mantel-Haenszel
DBL
database lock
DMARD
disease-modifying antirheumatic drugs
eCRF
electronic case report form
EE
early escape
EQ-5D
EuroQol 5 Dimension
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HBV
hepatitis B virus
HCQ
hydroxychloroquine
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HLA
human leucocyte antigen
hs-CRP
high sensitivity C-reactive protein
IWRS
interactive web response system
MA
musculoskeletal assessor
mAb
monoclonal antibody
MACE
major cardiovascular events
MCS
Mental Component Summary
mITT
modified intention-to-treat
MOS-SS
Medical Outcomes Study Sleep Scale
MTX
methotrexate
NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for Adverse Events
NONMEM
nonlinear mixed effects modeling approach
NSAID
nonsteroidal anti-inflammatory drugs
PCS
Physical Component Summary
PFS
prefilled syringe
PGA
Patient’s Global Assessment
PK
pharmacokinetic(s)
PQC
Product Quality Complaint
PRO
Patient Reported Outcome
PsA
psoriatic arthritis
q12w
every 12 weeks
q4w
every 4 weeks 
RBC
red blood cell
SAE
serious adverse event
SAP
Statistical Analysis Plan
SC
subcutaneous
SpA
spondyloarthritis
SSZ
sulfasalazine
TB
tuberculosis
TNFα
tumor necrosis factor alpha
NCT02438787


Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
18
Approved, 13 July 2015
TST
tuberculin skin test
ULN
upper limit of normal
VAS
visual analog scale
WPAI-SHP
Work Productivity and Activity Impairment Questionnaire - Specific Health Problem
NCT02438787


Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
19
Approved, 13 July 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 HLA-B27 antigen. 
These disorders 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 human leucocyte antigen (HLA)-B27 and at least 2 typical SpA 
features needs to be present.  AxSpA encompasses the continuum of disease presentation, with 
that 10 to 12% of patients progress from a nonradiographic state to AS.37 Radiographic AxSpA is 
thus synonymous with established AS with radiographic evidence of sacroiliitis defined by the 
modified New York criteria53 and therefore radiographic AxSpA and AS have been used 
interchangeably throughout the document.
While nonsteroidal anti-inflammatory drugs (NSAID) are effective in treating the signs and 
symptoms of AxSpA in many patients, traditional disease-modifying anti-rheumatic drugs 
(DMARD) 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.
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Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
20
Approved, 13 July 2015
While anti-TNFα agents show efficacy in patients with radiographic 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 anti-TNFα therapies, and these products, while efficacious, also have 
significant potential risks.  Current ASAS treatment guidelines note that, according to several 
case report studies and as well as a large retrospective registry study, those patients who do not 
achieve clinical response during treatment with an anti-TNFα agent may often achieve an 
adequate response by switching to a different anti-TNFα agent.6  In those studies, approximately 
30% of patients switched anti-TNFα agents over time, primarily for lack of efficacy. While 
subsequent response rates were lower than in primary responders, over half of the patients who 
switched to another anti-TNFα agent achieved a response. 20  
Therefore, new therapies targeting pathways other than TNFα, especially those with an improved 
benefit/risk profile, may result in improved alternative options for patients with radiographic 
AxSpA.
1.2.
Overall Rationale for the Study
1.2.1.
Scientific Rationale for Use of Anti-IL-12/23p40 Therapy in 
Radiographic AxSpA
Ankylosing spondylitis (radiographic AxSpA) is thought to be triggered by a combination of 
both environmental and genetic factors. Genetically, AS 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.12 The IL-23/Th-17 axis is emerging as an important 
inflammatory pathway, with strong genetic associations with IL23R and polymorphisms having 
been shown in AS,7,13,41 suggesting that IL-23 is involved in the disease pathogenesis.24
Interestingly, protection from AS, as well as from other spondyloarthritis-associated disorders 
like Crohn’s disease and psoriasis, is conferred by an IL23R variant due to reductions in 
responsiveness to IL-23 and downstream factors, including IL-17.15 Genetic as well as clinical 
correlations with the IL-23/Th17 pathway are also evident in another spondyloarthropathy, 
PsA.5,25,35,38,39
In terms of cytokine overexpression, elevated IL-23 levels been reported in AS,46 and increased 
numbers of IL-23 responsive Th17 cells have been demonstrated in peripheral blood 
mononuclear cells from SpA patients.45 IL-23 levels in blood and synovial fluid can be higher 
than normal in SpA patients;33,43 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 
NCT02438787


Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
21
Approved, 13 July 2015
AS.11 Clinical studies of the anti-IL-17 agent, secukinumab, have shown that blocking the Th17 
axis in AS can be an effective approach.4,14,48  
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 study 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.47 While IL-23 and other cytokines, 
including TNF, IL-1, and IL-6, have been shown to mediate inflammatory processes responsible 
for bone resorption,1,10,24 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.17,29,47 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
The benefits of treatment with ustekinumab have been demonstrated in the PsA population.26,31,42
and are summarized in Section 1.2.3, including improvements in symptoms in the subgroups of 
PsA subjects with spondylitis.  Ustekinumab has shown preliminary efficacy in the radiographic 
AxSpA population in a small open-label study (Section 1.2.4).  
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. 26,31,42 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 investigators.  Over 70% of subjects in both trials 
had also evidence of enthesitis based on investigators’ assessment.
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.
NCT02438787


Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
22
Approved, 13 July 2015
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
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 
NCT02438787


Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
23
Approved, 13 July 2015
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.36
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 a
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).36
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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Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
24
Approved, 13 July 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 CNTO1275AKS3001 Phase 3 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. In general, ustekinumab 45 and 
90 mg (for patients weighing >100 kg with moderate to severe psoriasis) 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 radiographic AxSpA are ustekinumab 45 
and 90 mg administered subcutaneously at Weeks 0 and 4, then q12w. The rationale for the 
45 and 90 mg q12w dose regimens is as follows:
NCT02438787


Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
25
Approved, 13 July 2015

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 
and 90 mg. 

Most relevant to the proposed study, CNTO1275PSA3001 and CNTO1275PSA3002 
included a subset of total 256 (27.6%) 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 a 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 (ASAS 40), 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.27,44

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 cardiovascular events (MACE). 
Ustekinumab has been commercially available since 2009 and 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 even though 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 with placebo, and numerically greater with 45 mg as compared with placebo, and 
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.  
NCT02438787


Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
26
Approved, 13 July 2015
Based on these considerations, it is reasonable to study ustekinumab both 45 and 90 mg dose
regimens in the radiographic AxSpA Phase 3 trial as was studied in the Phase 3 PsA and 
psoriasis clinical programs.
In addition to this radiographic AxSpA study, the ustekinumab AxSpA development program 
will include 2 other trials in the AxSpA population which will evaluate 45 and 90 mg 
ustekinumab doses in subjects with radiographic AxSpA who are naïve to anti-TNFα agents 
(CNTO1275AKS3001) 
and 
in 
subjects 
with 
active 
nonradiographic-AxSpA 
(CNTO1275AKS3003).
2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives
Primary Objective
The primary objective of this study is to assess the efficacy of ustekinumab, in adult anti-TNFα 
refractory subjects with active radiographic AxSpA, as measured by the reduction in signs and 
symptoms of radiographic AxSpA.
Secondary Objectives
The secondary objectives are to assess the effect of treatment with ustekinumab in anti-TNFα 
refractory subjects with active radiographic AxSpA on the following:

Efficacy related to improving physical function, range of motion, health-related quality of 
life, and other health outcomes.

Safety.

Pharmacokinetics (PK) and immunogenicity.
Exploratory Objective
The exploratory objectives are to evaluate the effect of ustekinumab on pharmacodynamics, on 
the microbiome, and on pharmacogenomics in anti-TNFα refractory subjects with radiographic 
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 radiographic 
AxSpA, as assessed at Week 24 by the composite endpoint of ASAS 40 response and the 
outcome of continuing originally assigned treatment.
NCT02438787


Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
27
Approved, 13 July 2015
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
CNTO1275AKS3002 is a Phase 3, multicenter, randomized, double-blind, placebo-controlled 
study of ustekinumab 45 mg and 90 mg in subjects with active radiographic AxSpA and who 
have  been refractory to anti-TNFα therapy.
Approximately 483 subjects will be randomized at approximately 150 investigational sites. 
Subjects will be randomly assigned in a 1:1:1 ratio to receive subcutaneous (SC) ustekinumab 45 
or 90 mg or placebo administrations at Weeks 0, 4, and 16. Block randomization will be used.  
Randomization will be stratified by region.
At Week 16, subjects in all 3 treatment groups who qualify for early escape (EE; 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 open-label golimumab 50 mg SC administrations at 
Week 16 and every 4 weeks (q4w) thereafter through Week 52.  These subjects will return to the 
study site at Week 24 for assessments related to primary and major secondary endpoints (ASAS 
response, BASDAI, BASFI, ASDAS), then for BASDAI and safety evaluations at Weeks 28, 40, 
and 52, and for the final safety visit at Week 64.
At Week 24, all remaining placebo subjects who did not meet EE criteria will be rerandomized 
by interactive web response system (IWRS) to begin receiving ustekinumab 45 or 90 mg at 
Weeks 24 and 28 followed by q12w therapy with the last study agent administration at Week 52. 
All subjects in the ustekinumab 45 mg and 90 mg treatment groups who do not qualify for EE 
will continue to receive the treatment they were randomized to at Week 0 through Week 52.
Subjects will be followed for adverse events (AE) 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 64 visit.
An independent Data Monitoring Committee (DMC) will be commissioned for this study. For 
details, refer to Section 11.13.
A group sequential design using the O'Brien and Fleming boundary will be applied with one
interim analysis based on a database lock (DBL) at the time when approximately 50% of subjects 
have completed the Week 24 visit or end study participation before the Week 24 visit.  The 
Sponsor will be kept blinded to the interim data.  Details for the prespecified decision rules will 
be provided in the Interim Analysis Plan.
The other 2 DBLs will occur when all subjects complete the Weeks 24 and 64 visits, 
respectively.
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.
NCT02438787


Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
28
Approved, 13 July 2015
A diagram of the study design is provided below in Figure 3.
Figure 3:
Schematic Overview of the Study    
3.1.1.
Study Population
The target study population is adult subjects who have been refractory to anti-TNFα therapy and 
have active radiographic AxSpA, as evidenced by BASDAI ≥4 and a visual analog scale (VAS)
for total back pain of ≥4, each on a scale of 0 to 10. All subjects are required to have a screening 
high sensitivity C-reactive protein (hsCRP) level ≥0.300 mg/dL. The study population will 
include subjects who have been refractory to anti-TNFtherapy. Background treatment with 
NSAIDs, select non-biologic DMARDs, and low dose corticosteroids will be allowed during the 
study at stable doses through Week 24 and may be adjusted after Week 24.

Subjects must have a diagnosis of definite AS, as defined by the 1984 modified New York 
criteria.
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Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
29
Approved, 13 July 2015

The radiographic criterion and at least 1 clinical criterion must be met:
a.
Radiographic criterion:  Sacroiliitis Grade 2 bilaterally or sacroiliitis Grade 3 to 4 
unilaterally as assessed by the central reader.
b.
Clinical criteria (at least 1):
1)
Low back pain and stiffness for more than 3 months, which improves with exercise, 
but is not relieved by rest.
2)
Limitation of motion of the lumbar spine in both the sagittal and frontal planes.
3)
Limitation of chest expansion relative to normal values corrected for age and sex.
3.1.2.
Study Phases and Duration of Treatment
There will be 3 phases in this study:  Screening, placebo-controlled and active treatment, and 
safety follow-up. The screening phase of up to 8 weeks will allow for sufficient time to perform 
screening study evaluations and determine subject eligibility.  The second treatment phase of the 
study will be the placebo-controlled (Week 0 to 24) and active treatment periods (Week 24 to 
Week 52).  The third phase of the study will be the safety follow-up phase and will be 12 weeks 
from the last administration of study agent.
3.1.3.
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 by IWRS will be used. 
Randomization will be stratified by region.  
Individual subjects and investigators will remain blinded for the duration of the study, until the 
Week 64 DBL has occurred.  Blinded treatment will be used to reduce potential bias during data 
collection and evaluation of clinical endpoints. The first of the 3 DBLs planned for the study will 
be for the interim analysis. The Sponsor will be kept blinded to the interim data.  The other 2 
planned DBLs are at Week 24 and at Week 64. Limited Sponsor personnel will be unblinded to 
subject-level data at the Week 24 DBL 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 radiographic AxSpA. Specifically, the clinical response to 
ustekinumab observed in Phase 3 PsA trials, especially the spondylitis/enthesitis subset of 
subjects and the fact that there is a close genetic/pathophysiologic connection between PsA and 
Axial SpA and the response noted in the open-label ‘TOPAS’ trial supports this approach. The 
dose justification for this study is described in Section 1.3.
NCT02438787


Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
30
Approved, 13 July 2015
Study Population Rationale
The target study population is subjects who have definite AS, as defined by the modified New 
York criteria.  All eligible subjects will be required to have active disease based on symptoms 
(defined as BASDAI score ≥4 and total back pain ≥4) which should assure selection of subjects 
being the most appropriate candidates for a treatment with a biologic. The rationale for studying 
the anti-TNF-refractory population in this clinical trial is that ustekinumab may be a better, 
alternative biologic treatment option over using a second, anti-TNFagent in these patients. 
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.26,31,42
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 64-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 
and safety of ustekinumab in subjects with active radiographic AxSpA over a prolonged period 
of time after reaching steady state. 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 of radiographic AxSpA and to enable the development of safer, more effective, and 
ultimately individualized therapies for patients with radiographic AxSpA.
4.
SUBJECT POPULATION
Screening for eligible subjects will be performed within 8 weeks before administration of the 
study agent.  Subjects with complete ankylosis of the spine, defined as bridging syndesmophytes 
present at all intervertebral levels of the cervical and lumbar spine visualized on lateral-view 
spinal radiographs are permitted to be included in the study, but will be limited to approximately
10% of the study population.
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. 
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Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
31
Approved, 13 July 2015
4.1.
Inclusion Criteria
Each potential radiographic AxSpA subject must satisfy all of the following criteria to be 
enrolled in the study. 
1.
Subjects must be 18 years of age or older (or of legal age of consent in the country 
if older than 18 years)
2.
Subjects must have a diagnosis of definite AS, as defined by the modified 1984 
New York criteria.53 The radiographic criterion must be confirmed by a central x-
ray reader and at least 1 clinical criterion must be met:
a.
Radiographic criterion: Sacroiliitis Grade ≥2 bilaterally or sacroiliitis 
Grade 3 to 4 unilaterally.
b. Clinical criteria (at least 1):
1) Low back pain and stiffness for more than 3 months, which improves 
with exercise, but is not relieved by rest.
2) Limitation of motion of the lumbar spine in both the sagittal and 
frontal planes.
3) Limitation of chest expansion relative to normal values corrected for 
age and sex.
3.
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.
4.
Have an elevated hsCRP level of 0.300 mg/dL at screening.
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 acceptable range on repeat testing in the central 
laboratory.
5.
Refractory to no more than 1 anti-TNFα therapy by either of the following 2 
reasons:

Lack of benefit from anti-TNFα therapy, as assessed by the treating physician, 
after at least 12 weeks of infliximab (Remicade®, Remsima®, Inflectra®, 
Infimab®), certolizumab pegol, etanercept, (Enbrel®, YiSaiPu®, Etanar®), or 
adalimumab (Humira®, Exemptia®). Documented lack of benefit may include 
inadequate improvement in disease activity.

Received 
infliximab 
(Remicade®, 
Remsima®, 
Inflectra®, 
Infimab®), 
certolizumab pegol, etanercept (Enbrel®, YiSaiPu®, Etanar®), or adalimumab 
(Humira®, Exemptia®) and have documented intolerance to anti-TNFα
therapy (eg, infusion/injection site reaction, or other AE(s) that precludes 
continuation of that anti-TNFα agent).
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Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
32
Approved, 13 July 2015
6.
Has 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.
7.
If using NSAIDs or other analgesics for AS, 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 AS, must not have received NSAIDs or other 
analgesics for AS for at least 2 weeks prior to the first administration of the study 
agent.
8.
If using oral corticosteroids, 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.
9.
If using methotrexate (MTX), sulfasalazine (SSZ), or hydroxychloroquine (HCQ), 
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.
10. Subjects with complete ankylosis of the spine, defined as bridging syndesmophytes 
present at all intervertebral levels of the cervical and lumbar spine visualized on 
lateral-view spinal radiographs are permitted to be included in the study, but will be 
limited to approximately 10% of the study population.
11. 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 (IUD) or 
intrauterine system (IUS); 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).
NCT02438787


Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
33
Approved, 13 July 2015
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.  
12. A woman of childbearing potential must have a negative serum (-human chorionic 
gonadotropin [-hCG]) at screening and a negative urine pregnancy test at Week 0 
before randomization.
13. 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. 
14. 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.
15. 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 (Appendix A), or 
have a newly identified positive QuantiFERON®-TB Gold test result 
in which active TB has been ruled out and for which appropriate 
treatment for latent TB has been initiated 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; 
NCT02438787


Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
34
Approved, 13 July 2015
Appendix B), or a newly identified positive TST 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, 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.
-
Subjects with 2 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.
e.
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. 
f.
Have a chest radiograph (both 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.
16. 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 (ULN) 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.
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Radiographic Axial Spondyloarthritis
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17. Subject must be willing and able to adhere to the prohibitions and restrictions 
specified in this protocol.
18. Be able to read, write, understand, and complete study questionnaires.
19. 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. 
20. Each subject must sign a separate informed consent form 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.
21. Are 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.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study. 
1.
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.
2.

Has received infliximab or infliximab biosimilar, within 12 weeks of the first 
study agent administration.  

Has received adalimumab, adalimumab biosimilar, or certolizumab pegol within 
6 weeks of the first study agent administration.  

Has received etanercept or etanercept biosimilar within 6 weeks of the first study 
agent administration. 
Anti-TNFtherapy
Ineligible if last treatment prior to first study 
agent administration is:
Infliximab, infliximab biosimilar
<12 weeks prior
Adalimumab, adalimumab biosimilar, 
certolizumab pegol
<6 weeks prior
Etanercept, etancercept biosimilar or yisaipu
<6 weeks prior
3.
Has ever received golimumab
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4.
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.
5.
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, 
mycophenolate mofetil, gold, and penicillamine. Corticosteroids are not included in this 
criterion; see other eligibility criteria regarding corticosteroids.
6.
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.
7.
Have received epidural, intra-articular, IM, or IV corticosteroids, including 
adrenocorticotropic hormone during the 4 weeks prior to first administration of study 
agent.
8.
Have received any prior biologic therapy other than TNFα inhibitors, including, but not 
limited to ustekinumab, tocilizumab, alefacept, efalizumab, natalizumab, abatacept, 
anakinra, brodalumab, secukinumab, ixekizumab, and B-cell depleting therapies.
9.
Have ever received tofacitinib or any other Janus kinase (JAK) inhibitor.
10. Have total spinal ankylosis.
11. Have a known hypersensitivity to human immunoglobulin proteins.
12. Have used cytotoxic drugs, including chlorambucil, cyclophosphamide, nitrogen 
mustard, or other alkylating agents.
13. Have a history of active granulomatous infection, including histoplasmosis, or 
coccidioidomycosis, prior to screening. Refer to inclusion criterion #15 for information 
regarding eligibility with a history of latent TB.
14. Have had a Bacille Calmette-Guérin (BCG) vaccination within 12 months of screening.
15. 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. 
16. Have had a nontuberculous mycobacterial infection or opportunistic infection 
(eg, cytomegalovirus, pneumocystosis, aspergillosis).
17. 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 #14.
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Radiographic Axial Spondyloarthritis
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18. 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.
19. 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 
intravenous 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.
20. 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 ulcer.
21. Subject has a history of human immunodeficiency virus (HIV) antibody positive, or 
tests positive for HIV at Screening.
22. Has a hepatitis B infection. Subjects must undergo screening for hepatitis B virus 
(HBV; Appendix C). At a minimum, this includes testing for HBsAg (HBV surface 
antigen), anti-HBs (HBV surface antibody), and anti-HBc total (HBV core antibody 
total).
23. 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.
24. Have a history of known demyelinating diseases such as multiple sclerosis or optic 
neuritis (contraindication for the use of anti-TNFα agent as rescue therapy).
25. Has a diagnosis of congestive heart failure Class III or IV.
26. Have current signs or symptoms of severe, progressive, or uncontrolled renal, hepatic, 
hematological, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, cerebral, or 
psychiatric disease. 
27. 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.
28. Subject has a history of malignancy within 5 years before screening (exceptions are 
squamous and basal cell carcinomas of the skin that have 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).
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Radiographic Axial Spondyloarthritis
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29. Subject has known allergies, hypersensitivity, or intolerance to ustekinumab or its 
excipients and/or golimumab or its excipients (refer to the ustekinumab Investigator’s 
Brochure and the golimumab Investigator’s Brochure).
30. Are currently receiving venom immunotherapy (honeybee, wasp, yellow jacket, hornet, 
or fire ant).
31. Subject has taken any disallowed therapies as noted in Section 8, before the planned 
first dose of study agent.
32. 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.
33. 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.
34. 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
35. Have a transplanted organ (with the exception of a corneal transplant performed 
>3 months prior to first administration of study agent).
36. Have or have had a substance abuse (drug or alcohol) problem within the previous 3 
years.
37. Are unwilling or unable to undergo multiple venipunctures because of poor tolerability 
or lack of easy access.
38. 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.
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Radiographic Axial Spondyloarthritis
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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®], commercial golimumab, certolizumab 
pegol, etanercept
[Enbrel®, Etanar®, YiSaiPu®],
and adalimumab
[Humira®, 
Exemptia®]

Biologic agents targeting IL-1ra (anakinra).

Tocilizumab or any other biologic targeting IL-6 or IL-6 receptor.

Tofacitinib or other JAK inhibitor.

B-cell depleting agents (eg, rituximab).

Cytotoxic drugs such as cyclophosphamide, chlorambucil, nitrogen mustard, or other 
alkylating agents.

Abatacept.

Anti-IL-17 agents (eg, brodalumab, secukinumab, and ixekizumab). 

Anti-integrin therapy (eg, natalizumab or vedolizumab).

Investigational drugs other than the study agent.
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Radiographic Axial Spondyloarthritis
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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 interactive web response system 
(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.  Randomization at Week 0 and the rerandomization at Week 24 for placebo 
subjects will be conducted using permuted block method by the IWRS.
At Week 0, eligible subjects will be randomly assigned to receive ustekinumab 45 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 region.
At Week 16, subjects in all 3 treatment groups who meet EE criteria: <10% improvement from 
baseline in both total back pain and morning stiffness measures at both Week 12 and Week 16, 
will begin receiving open-label golimumab 50 mg q4w through Week 52. At Week 24, all 
remaining placebo subjects not meeting EE criteria will crossover to ustekinumab 45 mg or 
90 mg randomly at Weeks 24 and 28 followed by q12w therapy through Week 52.
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.
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Radiographic Axial Spondyloarthritis
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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 
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: 

Group 1 (placebo): Placebo SC at Weeks 0, 4, and 16. At Week 24 all subjects (with the 
exception of subjects who qualified for EE) will be rerandomized to receive either 
ustekinumab 45 or 90 mg SC at Weeks 24 and 28 followed by q12w dosing, with the last 
administration of study agent at Week 52.

Group 2 (ustekinumab 45 mg): Ustekinumab 45 mg SC at Weeks 0 and 4, followed by q12w 
dosing, with the last administration of study agent at Week 52.  At Week 24, subjects will 
receive placebo SC to maintain the blind.
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Stelara® (ustekinumab)
Radiographic Axial Spondyloarthritis
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
Group 3 (ustekinumab 90 mg): Ustekinumab 90 mg SC at Weeks 0 and 4, followed by q12w 
dosing, with the last administration of study agent at Week 52.  At Week 24, subjects will 
receive placebo SC to maintain the blind.
Subjects who qualify for EE at Week 16 will be administered open-label golimumab 50 mg SC 
q4w.
To maintain
the blind, all randomized subjects will 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.
Early Escape
At Week 16, subjects in all 3 treatment groups who qualify for EE criteria (<10% improvement 
from baseline in both total back pain and morning stiffness measures at both Week 12 and 
Week 16) will begin receiving open-label golimumab 50 mg SC administrations at Week 16 and 
q4w thereafter through Week 52.  These subjects will return to the study site at Week 24 for 
assessments related to the primary and major secondary endpoints (ASAS response, BASDAI, 
BASFI, ASDAS [CRP]), then for BASDAI and safety evaluations at Weeks 28, 40, and 52, and 
for the final safety visit at Week 64.  
At the discretion of the investigator and subject and after appropriate and documented training, 
subjects who qualify for EE in all 3 treatment groups will self-administer golimumab 50 mg SC,
initially at the investigative site under the supervision of a health care professional.  A caregiver 
may also be trained to administer study agent.
Subjects (or a caregiver) who are able to self-administer will be supplied golimumab 50 mg 
prefilled syringe (PFS) for self-administration away from the site, ie, at home.  Subjects unable 
to have injection administered away from site will be required to return to the site every 4 weeks 
for administration of study agent injection by a health care professional.  
Study personnel will instruct subjects on how to store medication for at-home use. 
At the Week 24 DBL, the data will be unblinded for analysis to the Sponsor only, and not to 
investigative study site and/or subjects. Subjects and investigative study sites will remain blinded 
until after the final Week 64 DBL.
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.
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Radiographic Axial Spondyloarthritis
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Approved, 13 July 2015
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.
For subjects who qualify for EE at Week 16 and begin self-administration at home, the 
investigator or designated study personnel will maintain a log of all golimumab 50 mg PFS 
dispensed and returned.  When golimumab is self-administered by subjects at home, the amount 
of golimumab (number of syringes) dispensed will be recorded and compared with the amount 
(number of syringes) returned.
Subjects will receive instructions on compliance with study treatment when they begin self-
administration SC of golimumab 50 mg at home. During the course of the study, the investigator 
or designated study research personnel will be responsible for providing additional instruction to 
reeducate any subject who is not compliant with taking the golimumab.
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 Week 52, dose adjustment in 
MTX, SSZ, and HCQ is allowed, except the dose should not be increased above the study entry 
level dose.  After Week 52, the dose can be adjusted as needed.
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Radiographic Axial Spondyloarthritis
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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, these medications can be introduced and 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, 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, oral corticosteroids 
can be introduced and adjusted as needed.
Intravenous, intramuscular, or epidural administration of corticosteroids for the treatment of 
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 
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 
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Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
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Approved, 13 July 2015
analgesics generally should not be changed unless the subject develops unacceptable side effects.
After Week 24, dose adjustment is allowed. 
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 generally should not be changed unless the subject 
develops unacceptable side effects. After Week 24, dose adjustment in analgesic patches is 
allowed.
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.
In this trial, 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, commercial golimumab, anakinra, etanercept, adalimumab, 
infliximab, tocilizumab, alefacept, efalizumab, rituximab, natalizumab, abetacept, commercial 
ustekinumab, brodalumab, secukinumab, ixekizumab), cytotoxic agents (eg, chlorambucil, 
cyclophosphamide, nitrogen mustard, other alkylating agents), tildrakizumab and other 
anti-IL-23 biologics, 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, 
pharmacokinetic, 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 221 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.
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After written informed consent has been obtained and within a period of 8 weeks before 
randomization, all screening evaluations will be performed.  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 provide 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, 
the subject may be enrolled without treatment for latent TB, if active TB is ruled out, their chest 
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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 C-reactive protein (CRP) 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 Informed Consent Form (ICF) and failed to meet 1 or more 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 re-test 
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 re-test 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 Phase
Treatment phases include the placebo-controlled (Week 0 to 24) and active treatment phases 
(Week 24 to 52).  At Week 0, eligible subjects will be randomly assigned to receive 1 of 3 
treatments:  Placebo, ustekinumab 45 mg, or ustekinumab 90 mg.  Safety and efficacy 
assessments will be performed as noted in Table 1.  Details for the early detection of active TB 
are provided in Section 9.7.
At Week 16, subjects in the placebo treatment group who qualify for EE will be treated with 
open-label golimumab 50 mg q4w through Week 52. At Week 24, all remaining subjects in the 
placebo group will cross over to receive ustekinumab 45 or 90 mg.  
At Week 16, subjects in the ustekinumab 45 mg and 90 mg treatment groups who qualify for EE 
will be treated with open-label golimumab 50 mg q4w through Week 52.  All other subjects will 
continue to receive the treatment regimen assigned at Week 0.
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Starting at the Week 16 visit subjects in all 3 treatment groups who qualify for EE may begin 
self-administration of golimumab.  For details, see Section 7.
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 52 visit assessments will be asked to return for a final 
safety visit at Week 64.
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
before the Week 52 visit, the efficacy-related assessments for the Week 52 visit (Table 1) should 
be performed as soon as possible. All subjects who discontinue study agent prematurely should 
return 12 weeks after their last dose for safety-related assessments (refer to the Week 64 visit in
Table 1).
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 202,49,52 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.
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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 Bath Ankylosing Spondylitis Disease Activity Index19 is defined below:
Subject self-assessment using a visual analog scale (VAS; 0 to 10) on the following criteria:
A.
Fatigue
B.
Spinal pain
C.
Joint pain
D.
Enthesitis
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.8 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
Morning stiffness will be measured by the average of the responses to 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).
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A musculoskeletal assessor (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 52.
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 
at the study site, and especially through Week 24.  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 adequate 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 
calculation50 as shown in Table 2. A musculoskeletal assessor (MA; see 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.
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
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 based on assessments 
when analysis is performed.
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 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:

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 (DAS) for use in AS, the Ankylosing 
Spondylitis Disease Activity Score (ASDAS).30,51 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 (hsCRP (mg/L) +1).
Major improvement in ASDAS (CRP) is defined as a decrease ≥2.0. Inactive disease is defined 
as an ASDAS (CRP) score <1.3.
Clinically important improvement in ASDAS (CRP) is defined as a decrease ≥1.1 (www.asas-
group.org).
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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. An existing x-ray may be sent for central 
reading in lieu of screening x-ray. All subjects will have x-rays of SI joints as specified in
Table 1.  Detailed information on the acquisition of x-rays will be provided in the 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.53

Grade 0:  normal

Grade 1:  suspicious changes

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)
9.2.1.11.
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.54 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.55
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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 MOS-SS 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 (ASQoL) is a self-administered patient-
reported outcomes instrument.16 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 radiographic AxSpA, FACIT-F 
has demonstrated strong internal consistency and test-retest 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 meaningful9 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.18 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 40 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 20 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 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 BASMI.

The change from baseline in chest expansion.

The change from baseline in the MASES enthesitis scores in subjects with enthesitis at 
baseline.
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
The change from baseline in inflammation (average of the last 2 questions of the BASDAI 
concerning morning stiffness).

The change from baseline in total back pain

The change from baseline in night back pain

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 EQ-5D VAS and in EQ-5D index.

The change from baseline in FACIT-Fatigue.

The change from baseline in WPAI.
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 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.
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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 
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 to 
ustekinumab). All samples will be tested by the Sponsor or Sponsor's designee.
9.4.
Pharmacodynamic Evaluations
9.4.1.
Serum and Whole Blood 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 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 
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 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 radiographic AxSpA or response to ustekinumab. Samples will be collected at 
baseline, Week 4, Week 24, and Week 52.
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.
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9.5.
Pharmacogenomic (DNA) Evaluations
In addition to HLA-B27 genotyping prior to study agent administration, 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, ie, modifications in DNA characteristics other than its sequence.  Only DNA 
research related to ustekinumab or to the pathobiology of AxSpA will be performed.  Genome 
wide pharmacogenetics testing as well as methylation testing will be undertaken in this study in 
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.40 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 11.13.
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 WBC count.
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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:
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 adverse event 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 cells (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 will be conducted at 
screening. 

Urine pregnancy testing for women of childbearing potential.
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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.  
Height and Weight
Height and weight will be measured as specified in the Time and Events Schedule.
Physical Examination
A physical examination will be performed at screening and the Week 64/Final safety follow up 
visit.  The chest, abdomen, and extremities should be examined, but otherwise the examination 
can be a focused one based upon the individual’s medical history and manifestations of 
spondyloarthritis, including axial and extra-articular (uveitis, psoriasis, inflammatory bowel 
disease, etc.).
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.  For injections administered at the study site, subjects should be carefully 
monitored for the occurrence of injection-site reactions for 30 minutes after the injection.
Allergic Reactions
Through Week 52, all subjects except those who qualify for EE and who choose to self-
administer open-label golimumab 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 PO or NSAIDs
and 
diphenhydramine 25 mg PO or IV may be administered.
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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.)
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.
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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 64 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 52, he/she must return for 
specific efficacy and final safety visits (see Section 9.1.4).
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.
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
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.
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 discontinues study agent administrations before the end of the treatment but does not 
withdraw consent for study participation, 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.
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
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.
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.
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 
region 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 region as covariate if appropriate. 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 (mITT; 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.
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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 CRP) will be summarized by 
treatment group.
11.2.
Sample Size Determination
The sample size of 483 subjects 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). 
Table 3:
Power to detect a significant treatment difference in achieving an ASAS 40 Response at 
Week 24
Treatment group
Sample size
ASAS 40 response
Power
1
Placebo
ustekinumab
161
161
15%
25%
0.6123
2
Placebo
161
15%
0.9004
ustekinumab
161
30%
3
placebo
ustekinumab
161
161
15%
35%
0.9876
4
placebo
ustekinumab
161
161
15%
40%
0.9993
11.3.
Efficacy Analyses 
11.3.1.
Primary Endpoint Analysis
The primary endpoint is the proportion of subjects who achieve an ASAS 40 response at 
Week 24. The primary hypothesis is to compare at Week 24 the composite endpoint of ASAS 40 
response and the outcome of continuing originally assigned treatment. Hence, subjects who early 
escape to golimumab, meet treatment failure criteria, or have missing ASAS assessment are 
nonresponders for the composite endpoint.
The proportion of subjects who achieve the composite endpoint at Week 24 will be compared 
between the ustekinumab groups and placebo group using a CMH test stratified by region at a 
significance level of 0.05 (2-sided).  Data from all randomized subjects who received at least 1 
administration of study treatment (mITT) will be analyzed according to their assigned treatment 
group regardless of their actual treatment received.
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The critical values of the group sequential test design were calculated for the O'Brien and 
Fleming design. The following table outlines the critical values and 1-sided alpha levels for the 
interim analysis and the final analysis (Table 4):
Table 4:
Critical values and 1-sided alpha levels for the interim analysis and final analysis
Information rate
Bounds reject H0
Significant level
(one-sided)
Alpha spent
0.5
2.797
0.0026
0.0026
1.0
1.977
0.0240
0.0250
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.
11.3.2.
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 
(Figure 4). 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 20 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.
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Figure 4:
Overview of Multiplicity Control
* p < 0.05 refers to the rejection of null hypothesis according to the group sequential design 
specified in Section 11.3.1. 
Because of regional differences in the regulatory approach to the statistical methods for 
controlling the type I error for the primary and secondary hypotheses, a different multiple 
comparison procedure will be prespecified and added to the SAP to address the requirement of 
regions with the family-wise control of the primary and secondary endpoints across doses.
11.3.3.
Other Planned Efficacy Analyses
In addition to the primary and major secondary analyses, statistical analyses 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 Sections 9.2.2 will be summarized 
over time by treatment groups.
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11.4.
Pharmacokinetic Analyses 
All serum ustekinumab 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 nonlinear mixed effects modeling approach
(NONMEM) will be used to characterize the disposition characteristics of ustekinumab in the 
current study. The CL/F and 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.
Pharmacodynamic Biomarker Analyses 
Pharmacodynamic markers are considered exploratory and results will be summarized in a 
separate technical report.
11.7.
Pharmacokinetic/Pharmacodynamic Analyses
If data permit, the relationships between serum ustekinumab concentration and efficacy may be
explored.
11.8.
Biomarker and Microbiome Analyses 
Changes in serum, RNA, fecal microbial 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.
11.9.
Pharmacogenomic Analyses 
Pharmacogenomic and epigenetic analyses are considered exploratory and results will be 
summarized in a separate technical report.
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11.10. Health Economics Analyses 
1.
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.
2.
The change from baseline in impact of disease on overall health status via EQ-5D-5L will be 
descriptively summarized by treatment group over time and compared between treatment 
groups at Week 24.
11.11. Safety Analyses
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). All reported adverse events 
with onset during the treatment phase (ie, treatment-emergent AEs and AEs that have worsened 
since baseline) will be included in the analysis. For each adverse event, 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 adverse event, or who experience a severe 
or a serious adverse event.
Based upon the safety profile of ustekinumab, as well as the golimumab safety data to date, 
several AEs of interest have been identified and will be monitored and assessed in this study. 
These 
include: 
injection 
reactions, 
MACE, 
demyelination, 
hepatobiliary 
laboratory 
abnormalities, infections including TB, and malignancies. 
Clinical Laboratory Tests
Routine safety evaluations will be performed. Adverse events, 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 (NCI-CTCAE)
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.
11.12. Interim Analysis
An interim analysis based on the group sequential design will be conducted when approximately 
50% of subjects have completed the Week 24 visit or ended study participation before the 
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Week 24 visit. O’Brien-Fleming alpha spending function will be used to determine the critical 
value for early stopping for efficacy of the primary endpoint. In addition, futility stopping rules 
will be specified in the interim analysis plan.  An independent DMC will review these interim 
analysis results and make recommendations to the Sponsor whether the study should be stopped 
for futility or efficacy.
11.13. Data Monitoring Committee
The independent DMC will monitor data on an ongoing basis to ensure the continuing safety of 
the subjects enrolled in this study and to review the interim analysis results. 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 are independent of the Sponsor.  None of the members will be participating in the 
current study. The independent 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 (SAE) 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 
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information; all clinical studies conducted by the Sponsor or its affiliates will be conducted in 
accordance with those procedures.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not 
related to that medicinal (investigational or non-investigational) product. (Definition per 
International Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The Sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event 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.
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Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For ustekinumab, the expectedness of an 
adverse event will be determined by whether or not it is listed in the Investigator's Brochure with 
a marketing authorization, the expectedness of an adverse event 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 adverse event 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 adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria 
An assessment of severity grade will be made using the following general categorical 
descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
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Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a Sponsor study agent that may require expedited reporting and/or 
safety evaluation include, but are not limited to:

Overdose of a Sponsor study agent

Suspected abuse/misuse of a Sponsor study agent

Inadvertent or accidental exposure to a Sponsor study agent

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 adverse events 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 adverse events, regardless of seriousness, severity, or presumed relationship to study agent, 
must be recorded using medical terminology in the source document and the CRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection"). Investigators must record in the CRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to Sponsor
instructions.
The Sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The Sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). The 
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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. 
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 serious adverse events 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 serious adverse events 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 a serious 
adverse event 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 serious adverse events 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 a 
serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization) 
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that occurs during the course of a subject's participation in a study must be reported as a serious 
adverse event, except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons 
such as pending placement in long-term care facility)

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 serious adverse events. Any adverse event that results in a prolongation of the 
originally planned hospitalization is to be reported as a new serious adverse event.

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 a serious 
adverse event.
12.3.3.
Pregnancy 
Any subject who becomes pregnant during the study must be promptly withdrawn from the study 
and discontinue further study treatment.  Pregnancies must be reported by study-site personnel 
within 24 hours of knowledge of the event using the appropriate pregnancy notification form.
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.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered serious adverse events and must be reported using 
the Serious Adverse Event Form.
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, 
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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 a serious adverse event, the study-site personnel must report the 
PQC to the Sponsor according to the serious adverse event reporting timelines (refer to 
Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be 
maintained for further investigation if requested by the Sponsor.
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 agents
Ustekinumab for this study will be supplied as a sterile solution in a single use 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. 
Golimumab will be supplied as a sterile liquid for SC injection in single-use PFSs.  Each PFS 
contains 50 mg (0.5 mL fill of liquid) of golimumab, in addition to histidine, sorbitol and 
polysorbate 80 at pH 5.5. No preservatives are present.  
Liquid placebo will be supplied in both a 0.5 mL and a 1 mL PFS. 
The needle cover on the PFS for ustekinumab and its placebo and golimumab contains dry 
natural rubber (a derivative of latex), which may cause allergic reactions in individuals 
sensitive to latex.
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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 
Ustekinumab product 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.
Golimumab must also be stored at controlled temperatures ranging from 36°F to 46°F 
(2°C to 8°C). Golimumab must be handled in strict accordance with the protocol and the container 
label and be stored in a limited access area or in a locked cabinet under appropriate environmental 
conditions.
Subjects who are able and who have been appropriately trained in the self-administration of 
golimumab self-administer study agent at home in accordance with Section 7.  Study personnel 
will instruct subjects on how to transport, store and administer medication for at-home use as 
indicated for this protocol.  
Refer to the Site Investigational Product Procedures Manual for additional guidance on the 
preparation and handling of ustekinumab and golimumab.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study agents received at the site is 
inventoried and accounted for throughout the study. The study agents administered to the subject 
must be documented on the drug accountability form. All study agents 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 agents 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 agents 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.
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Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes. 
Study agents 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 agents will be supplied only 
to subjects participating in the study. Study agents may not be relabeled or reassigned for use by 
other subjects. The investigator agrees neither to dispense the study agents from, nor store it at, 
any site other than the study sites agreed upon with the Sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Investigator Brochure

Site Investigational Product Procedures Manual Laboratory Manual and laboratory supplies

Electronic PRO device and user manual

IWRS user guide and user manual

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 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential adverse events of the study, and provide their consent voluntarily will be enrolled.
The total blood volume to be collected in this study from each subject will be approximately 
191 mL for the main study and 30 mL for optional DNA testing, 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.
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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 or electronic materials to be provided to the 
subjects)

Investigator's Brochure (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 (unless not required, as documented by the 
IEC/IRB)

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the ICF, applicable recruiting materials, and 
subject compensation programs, and the Sponsor has received a copy of this approval. This 
approval letter must be dated and must clearly identify the IEC/IRB and the documents being 
approved.
Approval for the collection of optional samples for research and for the corresponding ICF must 
be obtained from the IEC/IRB. Approval for the protocol can be obtained independent of this 
optional research component.
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 or electronic materials to be provided to subjects
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
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 Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the 
study agent

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study. The 
reapproval should be documented in writing (excluding the ones that are purely administrative, 
with no consequences for subjects, data, or study conduct).
At the end of the study, the investigator (or Sponsor where required) will notify the IEC/IRB 
about the study completion.
16.2.3.
Informed Consent
Each subject must give written consent according to local requirements after the nature of the 
study has been fully explained. The ICF(s) must be signed before performance of any study-
related activity. The ICF(s) that 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 
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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.  A limited number of subjects will be asked to consent to 
participate in a microbiome substudy.  Refusal to participate in the microbiome substudy will not 
result in ineligibility for the clinical study.
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 
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 
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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 radiographic AxSpA, to understand responses to treatment 
in subjects with radiographic AxSpA, differential drug responders, and to develop tests/assays 
related to ustekinumab and radiographic 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 
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 
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situations, this contact should be made before implementing any departure from the protocol. In 
all cases, contact with the Sponsor must be made as soon as possible to discuss the situation and 
agree on an appropriate course of action. The data recorded in the CRF and source documents 
will reflect any departure from the protocol, and the source documents will describe this 
departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the Sponsor before shipment of study agent to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated clinical trial agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the Sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators
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
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 adverse events and follow-up of adverse events; 
concomitant medication; drug receipt/dispensing/return records; study agent administration 
information; and date of study completion and reason for early discontinuation of study agent or 
withdrawal from the study, if applicable. 
In addition, the author of an entry in the source documents should be identifiable.
At a minimum, the type and level of detail of source data available for a subject should be 
consistent with that commonly recorded at the study site as a basis for standard medical care. 
Specific details required as source data for the study will be reviewed with the investigator 
before the study and will be described in the monitoring guidelines (or other equivalent 
document).
The following subject- and investigator-completed AS scales and assessments designated by the 
Sponsor will be recorded directly into an electronic device and will be considered source data:  
PGA, SF-36, MOS-SS, ASQoL, EQ-5D, FACIT-F, WPAI-SHP, AxSpA response evaluations 
(BASDAI, BASFI, Total back pain, Night back pain), and Musculoskeletal assessments 
(BASMI, enthesitis index, chest expansion).
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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 (eDC) will be used for this study. The study data will be transcribed by 
study-site personnel from the source documents onto an electronic CRF, and transmitted in a 
secure manner to the Sponsor within the timeframe agreed upon between the Sponsor and the 
study site. The electronic file will be considered to be the CRF.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the subject's source documentation. All data relating to the 
study must be recorded in CRFs prepared by the Sponsor. Data must be entered into CRFs in 
English. Study site personnel must complete the CRF as soon as possible after a subject visit, and 
the forms should be available for review at the next scheduled monitoring visit.
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.
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.
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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 
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.
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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.
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:
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
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 
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 
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Radiographic Axial Spondyloarthritis
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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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Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
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Approved, 13 July 2015
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Radiographic Axial Spondyloarthritis
Clinical Protocol CNTO1275AKS3002 Amendment 1
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Approved, 13 July 2015
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50.
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.
51.
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.
52.
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-TNFα agents in patients with axial 
spondyloarthritis. Ann Rheum Dis. 2011;70(6):905-908.
53.
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.
54.
Ware JE, Kosinski M, Keller SD.  Interpretation: Norm-Based. In: SF-36 Physical and Mental Health 
Summary Scales: A User’s Manual. Boston, MA: The Health Institute; 1994:8:1-8:42.
55.
Ware JE Jr, Sherbourne CD. The MOS 36 item short form health survey (SF 36), I. Conceptual framework and 
item selection. Med Care. 1992;30(6):473 483.
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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 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.  
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To perform the test using the In-Tube format, blood is drawn through standard venipuncture into 
supplied tubes that already contain the M. tuberculosis-specific antigens.  Approximately 3 tubes 
will be needed per subject, each requiring 1 mL of blood.  One tube contains the M. tuberculosis-
specific antigens, while the remaining tubes contain positive and negative control reagents.  
Thorough mixing of the blood with the antigens is necessary prior to incubation.  The blood is 
then incubated for 16 to 24 hours at 37C, after which tubes are centrifuged for approximately 15 
minutes at 2000 to 3000 g.  Following centrifugation, plasma is harvested from each tube, 
frozen, and shipped on dry ice to the central laboratory.  The central 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.
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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:
HEPATITIS B VIRUS (HBV) SCREENING WITH HBV DNA 
TESTING
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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Stelara® (ustekinumab)
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INVESTIGATOR AGREEMENT
LAST PAGE
NCT02438787

SAP_000.pdf: 
14 April 2017 1 
Approved Date: 14 April 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 Anti-TNFĮ Refractory 
Subjects With Active Radiographic Axial Spondyloarthritis 
 
Protocol CNTO1275AKS3002; 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: 
14 April 2017 
Prepared by: 
Janssen Research & Development  
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. 
NCT02438787


STELARA® (ustekinumab) 
Statistical Analysis Plan CNTO1275AKS3002  
14 April 2017 2 
Approved Date: 14 April 2017  
TABLE OF CONTENTS 
TABLE OF CONTENTS .......................................................................................................................... 2
ABBREVIATIONS ................................................................................................................................... 5
1.
INTRODUCTION ............................................................................................................................ 7
1.1.
Trial Objectives ........................................................................................................................... 7
1.2.
Trial Design................................................................................................................................. 7
1.3.
Statistical Hypotheses for Trial Objectives ................................................................................... 9
1.4.
Sample Size Justification ............................................................................................................ 9
1.5.
Randomization and Blinding ...................................................................................................... 10
1.5.1.
Randomization ....................................................................................................................... 10
1.5.2.
Maintenance of the Blind........................................................................................................ 11
2.
GENERAL ANALYSIS DEFINITIONS .......................................................................................... 12
2.1.
Visit Windows ........................................................................................................................... 12
2.2.
Pooling Algorithm for Analysis Centers ...................................................................................... 12
2.3.
Analysis Sets ............................................................................................................................ 13
2.3.1.
Efficacy Analysis Set.............................................................................................................. 13
2.3.2.
Safety Analysis Set ................................................................................................................ 13
2.3.3.
Pharmacokinetics Analysis Set .............................................................................................. 13
2.3.4.
Immunogenicity Analysis Set ................................................................................................. 13
2.4.
Definition of Subgroups ............................................................................................................. 13
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW ..................................... 14
3.1.
Interim Analysis......................................................................................................................... 14
3.2.
Data Monitoring Committee ....................................................................................................... 15
4.
SUBJECT INFORMATION ........................................................................................................... 16
4.1.
Demographics and Baseline Characteristics .............................................................................. 16
4.2.
Disposition Information .............................................................................................................. 16
4.3.
Treatment Compliance .............................................................................................................. 16
4.4.
Extent of Exposure .................................................................................................................... 16
4.5.
Protocol Deviations ................................................................................................................... 17
4.6.
Prior and Concomitant Medications ........................................................................................... 17
5.
EFFICACY ................................................................................................................................... 17
5.1.
Analysis Specifications .............................................................................................................. 17
5.1.1.
Level of Significance .............................................................................................................. 17
5.1.1.1.
Multiplicity Adjustment for Testing Procedures .................................................................... 17
5.1.2.
Data Handling Rules .............................................................................................................. 20
5.1.2.1.
Treatment Failure ............................................................................................................... 20
5.1.2.2.
Missing Data Imputation...................................................................................................... 21
5.1.2.3.
Early Escape ...................................................................................................................... 21
5.2.
Primary Efficacy Endpoint.......................................................................................................... 21
5.2.1.
Definition ............................................................................................................................... 21
5.2.2.
Analysis Methods ................................................................................................................... 22
5.2.3.
Sensitivity Analyses ............................................................................................................... 23
5.2.4.
Analysis Methods ................................................................................................................... 24
5.2.5.
Supportive Analyses .............................................................................................................. 24
5.3.
Major Secondary Endpoints ...................................................................................................... 25
5.3.1.
Proportion of Subjects who Achieve an ASAS 20 Response at Week 24 ................................ 25
5.3.1.1.
Definition ............................................................................................................................ 25
5.3.1.2.
Analysis Methods ................................................................................................................ 25
5.3.1.3.
Sensitivity Analyses ............................................................................................................ 25
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5.3.2.
Proportion of Subjects who Achieve at Least a 50% Improvement from Baseline in BASDAI 
at Week 24 ............................................................................................................................ 26
5.3.2.1.
Definition ............................................................................................................................ 26
5.3.2.2.
Analysis Methods ................................................................................................................ 26
5.3.2.3.
Sensitivity Analyses ............................................................................................................ 26
5.3.3.
Change from Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) at Week 24 .. 27
5.3.3.1.
Definition ............................................................................................................................ 27
5.3.3.2.
Analysis Methods ................................................................................................................ 27
5.3.3.3.
Sensitivity Analyses ............................................................................................................ 27
5.3.4.
Proportion of Subjects who Achieve ASDAS (CRP) inactive disease (<1.3) at Week 24 ......... 28
5.3.4.1.
Definition ............................................................................................................................ 28
5.3.4.2.
Analysis Methods ................................................................................................................ 28
5.3.4.3.
Sensitivity Analyses ............................................................................................................ 28
5.4.
Estimands of Primary and Major Secondary Endpoints .............................................................. 29
5.5.
Other Secondary Endpoints ...................................................................................................... 31
5.5.1.
Definition of Other Secondary Endpoints ................................................................................ 31
5.5.1.1.
Low Disease Activity (ASAS Partial Remission) .................................................................. 31
5.5.1.2.
ASAS 5/6 Response ........................................................................................................... 31
5.5.1.3.
A 20%, 50%, 70%, 90% Improvement from baseline in BASDAI .................................. 31
5.5.1.4.
ASDAS (CRP) .................................................................................................................... 31
5.5.1.5.
ASDAS (CRP) Inactive Disease (<1.3) ................................................................................ 31
5.5.1.6.
ASDAS (CRP) Major Improvement (Decrease 2.0) ............................................................ 31
5.5.1.7.
ASDAS (CRP) Clinically Important Improvement (Decrease1.1) ........................................ 31
5.5.1.8.
Bath Ankylosing Spondylitis Metrology Index (BASMI) ........................................................ 32
5.5.1.9.
Chest Expansion................................................................................................................. 32
5.5.1.10.
MASES Enthesitis Scores ................................................................................................... 33
5.5.1.11.
Inflammation ....................................................................................................................... 33
5.5.1.12.
Total Back Pain .................................................................................................................. 33
5.5.1.13.
Night Back Pain .................................................................................................................. 33
5.5.1.14.
Patient Global Assessment ................................................................................................. 33
5.5.1.15.
36-Item Short-form Health Survey ....................................................................................... 34
5.5.1.16.
Medical Outcomes Study Sleep Scale (MOS-SS) ............................................................... 35
5.5.1.17.
Ankylosing Spondylitis Quality of Life (ASQoL) Questionnaire ............................................. 35
5.5.1.18.
EuroQol 5 Dimension Questionnaire (EQ-5D) ..................................................................... 35
5.5.1.19.
Functional Assessment of Chronic Illness Therapy-Fatigue  Questionnaire (FACIT-
Fatigue) .............................................................................................................................. 36
5.5.2.
Analysis Methods for Other Secondary Endpoints .................................................................. 36
6.
SAFETY ....................................................................................................................................... 38
6.1.
Safety Table Presentation ......................................................................................................... 38
6.1.1.
Summaries through Week 16 ................................................................................................. 38
6.1.2.
Summaries through Week 24 ................................................................................................. 39
6.1.3.
Summaries through Week 64 ................................................................................................. 39
6.2.
Adverse Events ......................................................................................................................... 40
6.3.
Clinical Laboratory Tests ........................................................................................................... 40
6.4.
Vital Signs ................................................................................................................................. 41
6.5.
Electrocardiogram ..................................................................................................................... 41
7.
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................ 41
7.1.
Pharmacokinetics ...................................................................................................................... 41
7.1.1.
PK Treatment Groups Through Week 24 ............................................................................... 43
7.1.2.
PK Treatment Groups Through Week 52 ............................................................................... 43
7.1.3.
PK Treatment Groups Through Week 64 ............................................................................... 43
7.2.
Immune Response .................................................................................................................... 44
7.2.1.
Immunogenicity Treatment Groups Through Week 24 ............................................................ 45
7.2.2.
Immunogenicity Treatment Groups Through Week 52 ............................................................ 45
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Statistical Analysis Plan CNTO1275AKS3002  
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7.3.
Pharmacodynamics................................................................................................................... 45
7.4.
Pharmacokinetic/Pharmacodynamic Relationships .................................................................... 45
7.5.
Microbiome Substudy ................................................................................................................ 45
7.6.
Pharmacogenomics .................................................................................................................. 46
8.
HEALTH ECONOMICS ................................................................................................................ 46
8.1.
Definition................................................................................................................................... 46
8.1.1.
Work Productivity and Activity Impairment Questionnaire ....................................................... 46
8.2.
Analysis Methods ...................................................................................................................... 46
 
 
 
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ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
AS 
ankylosing spondylitis 
ASAS 
Assessment in SpondyloArthritis international Society
ASDAS 
Ankylosing Spondylitis Disease Activity Score
ASQoL 
Ankylosing Spondylitis Quality of Life questionnaire
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
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
EE 
early escape 
EQ-5D 
EuroQol 5 Dimension 
EU 
European Union 
FDA 
Food and Drug Administration
GCP 
Good Clinical Practice
HCQ 
Hydroxychloroquine 
HRQOL 
Health-related quality of life
hs-CRP 
high sensitivity C-reactive protein
IB 
Investigator’s Brochure
ICF 
Informed consent form
ICH 
International Conference on Harmonisation
IEC 
Independent ethics committee
ITT 
Intent-to-Treat 
IWRS 
interactive web response system
LLOQ 
Lower limit of quantification
LOCF 
last observation carried forward
LSMeans 
Least-Squares Means 
MA 
musculoskeletal assessor
mAb 
monoclonal antibody 
MCS 
Mental Component Summary
MedDRA 
Medical Dictionary for Regulatory Activities
mITT 
MMRM 
modified intention-to-treat 
Mixed Model for Repeated Measures
MOS-SS 
Medical Outcomes Study Sleep Scale
MRI 
magnetic resonance imaging
mSASSS 
modified Stoke Ankylosing Spondylitis Spinal Score
MTX 
Methotrexate 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NONMEM 
nonlinear mixed effects modeling approach
NSAID  
nonsteroidal anti-inflammatory drug
PCS 
Physical Component Summary
PD 
Pharmacodynamics 
PFS 
prefilled syringe 
NCT02438787


STELARA® (ustekinumab) 
Statistical Analysis Plan CNTO1275AKS3002  
14 April 2017 6 
Approved Date: 14 April 2017  
PGA 
Patient’s Global Assessment
PK 
Pharmacokinetics 
PQC 
Product Quality Complaint
PRO 
Patient Reported Outcome
PsA 
psoriatic arthritis 
q4w 
every 4 weeks  
q12w 
every 12 weeks  
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan
SC 
Subcutaneous 
SF-36 
36-item short form health survey
SpA 
Spondyloarthritis 
SSZ 
Sulfasalazine 
TB 
Tuberculosis 
TEAEs 
Treatment emergent adverse events
TNFĮ 
tumor necrosis factor alpha
TST 
tuberculin skin test 
ULN 
upper limit of normal 
US 
United States 
VAS 
visual analog scale 
WBC 
white blood cell (count)
WPAI-SHP 
Work Productivity and Activity Impairment Questionnaire - Specific Health Problem
 
 
 
NCT02438787


STELARA® (ustekinumab) 
Statistical Analysis Plan CNTO1275AKS3002  
14 April 2017 7 
Approved Date: 14 April 2017  
1. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) contains definitions of analysis sets, derived variables, and 
statistical methods for all planned analyses.  
1.1. 
Trial Objectives 
This Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study is to 
evaluate the efficacy and safety of ustekinumab (previously named CNTO1275), a human anti- IL-
12/23p40 monoclonal antibody, administered subcutaneously (SC) in adult subjects with active 
radiographic AxSpA and who have been refractory to anti-TNFĮ.     
The primary objective is to assess the efficacy of ustekinumab in adult anti-TNFĮ refractory 
subjects with active radiographic AxSpA, as measured by the reduction in signs and symptoms of 
radiographic AxSpA. 
The secondary objectives are to assess the effect of treatment with ustekinumab in adult anti-TNFĮ 
refractory subjects with active radiographic AxSpA on the following: 
x 
Efficacy related to improving physical function, range of motion, health-related quality of life, 
other health outcomes 
x 
Safety 
x 
Pharmacokinetics (PK) and immunogenicity 
1.2. 
Trial Design 
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study of ustekinumab 45 
mg and 90 mg in adult anti-TNFĮ refractory subjects with active radiographic AxSpA. 
The study consists of a screening phase of up to 8 weeks, a blinded treatment phase of approximately 
1 year (i.e., 52 weeks) including a placebo controlled period from Week 0 to Week 24 and an active 
controlled period from Week 24 to Week 52, and, a safety follow-up phase of 12 weeks after the last 
administration of study treatment.  An overview of the study design is provided in Figure 1. 
 
 
NCT02438787


STELARA® (ustekinumab) 
Statistical Analysis Plan CNTO1275AKS3002  
14 April 2017 8 
Approved Date: 14 April 2017  
Figure 1: 
Schematic Overview of the Study 
 
 
 
 
At Week 0, approximately 483 subjects are to be randomized in a blinded fashion in a 1:1:1 ratio to 1 
of the following 3 treatment groups using permuted block randomization stratified by the region 
(North America, Latin America, Western Europe, Europe, and Asia Pacific): 
x 
Group 1 (placebo): Placebo SC at Weeks 0, 4, and 16. At Week 24 all subjects (with the 
exception of subjects who qualified for EE) will be rerandomized to receive either ustekinumab 
45 or 90 mg SC at Weeks 24 and 28 followed by q12w dosing, with the last administration of 
study agent at Week 52. 
x 
Group 2 (ustekinumab 45 mg): Ustekinumab 45 mg SC at Weeks 0 and 4, followed by q12w 
dosing, with the last administration of study agent at Week 52. At Week 24, subjects will receive 
placebo SC to maintain the blind. 
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STELARA® (ustekinumab) 
Statistical Analysis Plan CNTO1275AKS3002  
14 April 2017 9 
Approved Date: 14 April 2017  
x 
Group 3 (ustekinumab 90 mg): Ustekinumab 90 mg SC at Weeks 0 and 4, followed by q12w 
dosing, with the last administration of study agent at Week 52. At Week 24, subjects will receive 
placebo SC to maintain the blind. 
Subjects in all 3 treatment groups who have <10% improvement from baseline in both total back pain 
and morning stiffness measures at both Week 12 and Week 16 will be considered as meeting EE 
criteria.  Subjects who meet EE criteria will begin receiving open label golimumab 50 mg SC 
administrations at Week 16 and every 4 weeks (q4w) thereafter through Week 52. 
The end of the study is defined as the last visit for the last subject.  The last visit is the Week 64 visit. 
There are 3 database locks (DBL) planned. The first database lock, which is for the purpose of 
interim analysis, occurs when approximately 50% of subjects have completed the Week 24 visit or 
end study participation before the Week 24 visit. The other 2 DBL will occur when all subjects 
complete the Week 24, and Week 64 visits respectively. 
1.3. 
Statistical Hypotheses for Trial Objectives 
The primary endpoint in this study is the proportion of subjects achieving an ASAS 40 response at 
Week 24. This endpoint was chosen because it is well accepted by regulatory authorities and the 
clinical AS community. 
The null hypothesis is that there is no difference between either of the ustekinumab groups and the 
placebo group with respect to reduction in signs and symptoms of radiographic AxSpA as measured 
by ASAS 40 response at Week 24.   
1.4. 
Sample Size Justification 
The sample size of 483 subjects was chosen to achieve 90% power to detect a treatment difference 
between either ustekinumab group 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 study (the ASAS 
40 response rate is 16% in placebo and 48% in active).9  
Table 1 shows the results of the power estimates for detecting a significant difference in the ASAS 40 
response rates between the ustekinumab treatment group and the placebo treatment group.  
 
 
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STELARA® (ustekinumab) 
Statistical Analysis Plan CNTO1275AKS3002  
14 April 2017 10 
Approved Date: 14 April 2017  
 
Table 1: 
Power to detect a significant treatment difference in achieving an ASAS 40 Response at Week 
24 
 
Treatment group                Sample size                ASAS 40 response                     Power 
1                          Placebo                             161                                  15%                                0.6123 
ustekinumab                        161                                 25%
2                          Placebo                             161                                  15%                               0.9004 
ustekinumab                        161                                 30%
3                          Placebo                             161                                  15%                                0.9876 
ustekinumab                        161                                 35%
4                          Placebo                             161                                  15%                                0.9993 
ustekinumab                        161                                 40%
 
1.5. 
Randomization and Blinding 
1.5.1. 
Randomization 
A central randomization is to be implemented in this study using an interactive web response system 
(IWRS).  When a subject is eligible for randomization at a study site, the randomization requestor at 
that study site will contact the IWRS using the requester’s own user identification and personal 
identification number and provide 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 will then assign a unique treatment code, which will dictate the treatment 
assignment and matching study agent kit for that subject.  Randomization at Week 0 and the re-
randomization at Week 24 for placebo subjects will be conducted using permuted block method by 
the IWRS. 
At Week 0, approximately 483 subjects will be randomized in a blinded fashion in a 1:1:1 ratio to 1 
of the 3 treatment groups. The Randomization will be stratified by region (North America, Latin 
America, Western Europe, Europe, and Asia Pacific). 
To maintain the blind, all randomized subjects will receive each administration of 
ustekinumab/placebo as 2 SC injections totaling 1.5 mL in 2 different locations as follows: 
x 
Placebo: 0.5 mL placebo injection and 1.0 mL placebo injection. 
x 
Ustekinumab 45 mg: 0.5 mL ustekinumab 45 mg injection and 1.0 mL placebo injection. 
x 
Ustekinumab 90 mg: 1.0 mL ustekinumab 90 mg injection and 0.5 mL placebo injection. 
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STELARA® (ustekinumab) 
Statistical Analysis Plan CNTO1275AKS3002  
14 April 2017 11 
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1.5.2. 
Maintenance of the Blind 
The study blind will be maintained for the duration of the study until after the final Week 64 database 
lock (DBL). 
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. 
An investigator may be unblinded to a given subject’s treatment allocation when specific emergency 
treatment would be dictated by knowing the treatment status of the subject.  In such cases, the 
investigator may determine the identity of the treatment by contacting the IWRS provider.  It is 
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 will be available 24 hours per day, 7 days per week.  In the event that the investigator is 
unable to contact the Sponsor, or emergency unblinding is considered medically necessary, the 
investigator may determine the identity of the treatment via IWRS.  However, the Sponsor must be 
informed as soon as possible.  The date, time, and reason for the 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 (e.g., sealed envelope) so as to not unblind the treatment assignment to the subject, the study 
site, or Sponsor personnel.  The investigator is 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 are expected to continue to return for scheduled evaluations.  Further 
study agent administrations should be discussed with the study responsible physician. 
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STELARA® (ustekinumab) 
Statistical Analysis Plan CNTO1275AKS3002  
14 April 2017 12 
Approved Date: 14 April 2017  
A given subject’s treatment assignment may be 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 will 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. 
The study responsible physician will remain blinded through the end of the study to subject level 
treatment assignment and dosing regimen. At the Week 24 DBL, the data will be unblinded for 
analysis to the Sponsor only, and not to investigative study site and/or subjects. Identification of 
Sponsor personnel who will have access to the unblinded subject level data will be documented prior 
to unblinding. Investigative sites and subjects will remain blinded to treatment assignment for the 
duration of the study, till after the final Week 64 DBL. 
An independent, external DMC will monitor the safety of the study in unblinded fashion on a regular 
basis and whenever deemed necessary.  In addition, the DMC will review unblinded efficacy data 
from interim analysis.   The DMC’s roles and responsibilities, the safety data for DMC review, and 
other related information (such as, the general procedures, communications, etc.) was defined and 
documented in the DMC charter.  The Sponsor medical monitor will review safety data in a blinded 
manner as the study is ongoing. 
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.  
For PK analyses, if a subject has an administration more than +/- 7 days of the scheduled dosing date, 
the concentration data collected between such a dosing visit and the subsequent dosing visit will be 
excluded from the by-visit data analyses. For the Week 24 visit, if the PK sampling time deviates 
more than +/- 3 days of the scheduled date, the PK concentration at this visit will be excluded from 
the by-visit data analyses. 
2.2. 
Pooling Algorithm for Analysis Centers 
Unless otherwise specified, data from all investigational centers/sites will be pooled by region for 
analyses. 
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STELARA® (ustekinumab) 
Statistical Analysis Plan CNTO1275AKS3002  
14 April 2017 13 
Approved Date: 14 April 2017  
2.3. 
Analysis Sets 
2.3.1. 
Efficacy Analysis Set 
The efficacy analysis data 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.   
In the efficacy analyses, subjects will be analyzed according to their assigned treatment group 
regardless of their actual treatment received.   
2.3.2. 
Safety Analysis Set 
The safety analysis set 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. 
2.3.3. 
Pharmacokinetics Analysis Set 
The pharmacokinetics (PK) analysis set includes all subjects who received at least 1 complete 
administration of ustekinumab and had at least 1 valid blood sample drawn for PK analysis. 
In the PK analyses, subjects will be analyzed according to the treatment they actually received, 
regardless of their randomized treatments. 
2.3.4. 
Immunogenicity Analysis Set 
The immunogenicity analysis set includes all subjects who received at least 1 (partial or complete) 
administration of ustekinumab and who have appropriate samples for detection of antibodies to 
ustekinumab (ie, subjects with at least 1 appropriate sample obtained after their first dose of 
ustekinumab). 
In the immunogenicity analyses, subjects will be analyzed according to the treatment they actually 
received, regardless of their randomized treatments. 
2.4. 
Definition of Subgroups 
To evaluate the consistency in the primary efficacy endpoint (proportion of subjects who achieve 
ASAS 40 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: 
NCT02438787


STELARA® (ustekinumab) 
Statistical Analysis Plan CNTO1275AKS3002  
14 April 2017 14 
Approved Date: 14 April 2017  
1. Subgroups defined by demographics: 
a) Gender (male, female) 
b) Race (White, Black or African American, Asian, Other) 
c) Geographic region (North America, Latin America, Western Europe, Europe, and Asia 
Pacific) 
d) Age (< 65 years,  65 years) 
e) Body mass index: (Normal [<25 kg/m2], Overweight [ 25 kg/m2 to <30 kg/m2], Obese [ 30 
kg/m2])  
f) Body weight: as quartiles  
 
2. Subgroups defined by baseline characteristics:  
a) Years since inflammatory back pain first appeared (<= 10 years, > 10 years) 
 
b) AS duration (<= 5 years, > 5 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 
 
g) HLA-B27 (positive, negative) 
 
h) Laboratory CRP at baseline (<1.0 mg/dL, >=1.0 mg/dL) 
 
i) 
Complete ankylosis (yes, no) 
 
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. 
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW 
3.1. 
Interim Analysis   
The interim analysis will be conducted when approximately 50% of subjects have completed the 
Week 24 visit or ended study participation before the Week 24 visit.   
The objectives of the interim analysis are: 
x To evaluate the level of significance for the primary endpoint based on O’Brien-Fleming alpha 
spending.  If p-value is less than the predetermined significance level (0.0026) for both 45 mg and 
90 mg doses of ustekinumab, the DMC will recommend stopping enrollment in the study because 
of superior efficacy.   
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STELARA® (ustekinumab) 
Statistical Analysis Plan CNTO1275AKS3002  
14 April 2017 15 
Approved Date: 14 April 2017  
x To determine whether the probability of meeting the primary endpoint at the end of the study was 
sufficiently low to consider terminating the study based on the data accrued up to the interim 
analysis. If the p-value is greater than 0.5 for both 45 mg and 90 mg doses of ustekinumab, the 
DMC may recommend terminating the study due to futility. This is a non-binding futility rule.  
The results from the summary of each component of the primary endpoint and safety data may 
also be considered.   
The final decision will be made by the Sponsor Committee. For the details of the interim analysis, 
refer to the interim analysis plan.   
3.2. 
Data Monitoring Committee 
The independent DMC will monitor data on an ongoing basis to ensure the continuing safety of the 
subjects enrolled in this study. 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 are independent of the Sponsor. None of the members will be participating in the current 
study. The independent DMC consists of 3 medical experts in a relevant therapeutic area and 1 
statistician. The members of the committee were specified prior to study initiation. The major 
function of this committee is 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.  
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. 
In addition, the independent Statistical Support Group (SSG) at DMC will perform the interim 
analysis described in Section 3.1 and the DMC members review findings from the interim analysis.  
If the p-value for both comparisons (45 mg versus placebo and 90 mg versus placebo) is significantly 
favorable to ustekinumab at the interim analysis, then the DMC should recommend stopping 
enrollment of more subjects, but no efficacy claim will be made based on the interim analysis results.  
All enrolled subjects will be followed through Week 24 for the Week 24 database lock and 
submission. In addition, all subjects enrolled in the study will be followed through Week 64 to obtain 
information about long-term efficacy and safety.     
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STELARA® (ustekinumab) 
Statistical Analysis Plan CNTO1275AKS3002  
14 April 2017 16 
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If the null hypothesis is accepted (ie, futility shown), upon careful review of the interim results for the 
primary endpoint and recent safety data, the DMC may recommend stopping the study.   
The final decision will be made by the Sponsor Committee. 
The content of the safety summaries and interim analyses, 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. 
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 characteristic will be summarized for all subjects randomized into the 
study by the randomized treatment group.   
Subjects’ demographic data including age, race, sex, height, weight and BMI at baseline will be 
summarized. Baseline disease characteristics including duration of disease 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 Weeks 24, and 52, 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. 
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. 
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. 
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Statistical Analysis Plan CNTO1275AKS3002  
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4.5. 
Protocol Deviations 
Subjects who did not meet study selection criteria (e.g. AS disease criteria, medication criteria, 
laboratory criteria, and medical history criteria) will be summarized and listed by randomized 
treatment group.   
Subjects with major protocol deviations will be identified in the blind fashion prior to database lock. 
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. 
Analysis Specifications 
5.1.1. 
Level of Significance 
The primary endpoint is planned to be analyzed in the interim analysis based on O’Brien Fleming 
alpha spending, the 1-sided significance level is 0.0026. Consequently, the 1-sided significance level 
for the final primary endpoint analysis is 0.024 (0.048 2-sided) if the study continues. Unless 
otherwise stated, all treatment group comparisons except for the primary endpoint will be performed 
at a 2-sided alpha level of 0.05. 
5.1.1.1. 
Multiplicity Adjustment for Testing Procedures 
The primary endpoint of this study is the proportion of subjects who achieve an ASAS 40 response at 
Week 24. 
There are 4 major secondary endpoints in this study: 
1. 
The proportion of subjects who achieve an ASAS 20 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 
 
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STELARA® (ustekinumab) 
Statistical Analysis Plan CNTO1275AKS3002  
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Global multiplicity adjustment (countries outside the United States): The primary endpoint will 
be tested to compare the 90 mg ustekinumab group with the placebo group at a 2-sided 0.048 level of 
significance first.  If it is significant, the primary endpoint will be tested to compare the 45 mg 
ustekinumab group with the placebo group at a 2-sided 0.048 level of significance. Within an 
ustekinumab dose treatment group, the hypotheses for the major secondary endpoints will be tested 
only if the primary endpoint is significant for that ustekinumab dose treatment group. The hypotheses 
of the major secondary endpoints will be tested in a fixed sequence at the 2-sided Į level of 0.05 as 
follows (Figure 2).  If a given comparison is not significant, the remaining treatment group 
comparisons in the sequence will be considered as supportive analyses. 
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Statistical Analysis Plan CNTO1275AKS3002  
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Figure 2: 
Global Multiplicity Control 
 
 
 
 
 
 
 
 
 
US-specific multiplicity adjustment: Because of regional differences in the regulatory requirement 
for controlling the type I error for the primary and secondary endpoints, a different multiple 
comparison procedure (Figure 3) is also pre-specified to address the FDA requirement for the family-
wise control of the primary and secondary endpoints across doses. Basically, the hypotheses are 
divided into 2 families.  The first family (F1) contains the comparisons between ustekinumab 90 mg 
and placebo for the primary endpoint and the first 3 major secondary endpoints.  The second family 
(F2) contains the comparisons between ustekinumab 45mg and placebo for the primary endpoint and 
the first 3 major secondary endpoints as well as the comparisons between each ustekinumab dose and 
placebo for the last major secondary endpoint.  F2 will be tested only if all comparisons in F1 reach 
statistical significance.   
Within F1, the primary endpoint will be tested at a 2-sided 0.048 level of significance followed by the 
testing of the 3 major secondary endpoints in a fixed sequence at a 2-sided 0.05 level of significance. 
F2 will be tested similarly if all comparisons in F1 are significant.   
Within F2, the primary endpoint will be tested at a 2-sided 0.048 level of significance followed by the 
testing of the first 3 major secondary endpoints in a fixed sequence at a 2-sided 0.05 level of 
significance and then the last major secondary endpoint will be tested for ustekinumab 90 mg versus 
placebo and then for ustekinumab 45 mg versus placebo at a 2-sided 0.05 level of significance.  
Within each family an endpoint will be tested only if the null hypothesis of no difference between the 
ustekinumab dose and placebo was rejected at the pre-specific level of the significance for all the 
endpoints above it in the sequence. 
BASFI (90 mg) change from 
baseline at Week 24 
ASDAS (90 mg) inactive disease 
(<1.3)   at Week 24 
BASDAI50 (90 mg) response at 
Week 24 
ASAS40 (90 mg) response at Week 
24 
ASAS20 (90 mg) response at Week 
24 
ASAS40 (45 mg) response at Week 
24 
ASAS20 (45 mg) response at Week 
24 
BASDAI50 (45 mg) response at 
Week 24
BASFI (45 mg) change from 
baseline at Week 24 
ASDAS (45 mg) inactive disease 
(<1.3) at Week 24  
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Figure 3: 
US Specific Multiplicity Adjustment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.1.2. 
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.  No data imputation rules will be applied for the 
analyses after Week 24. 
5.1.2.1. 
Treatment Failure 
A subject who meets any one of the following treatment failure criteria will be considered a 
treatment failure from that point onward. 
ASAS20 (45 mg) response at 
Week 24 
BASFI (90 mg) change from 
baseline at Week 24 
BASDAI50 (45 mg) response 
at Week 24
BASFI (45 mg) change from 
baseline at Week 24 
ASAS40 (45 mg) response at 
Week 24 
ASDAS (45 mg) inactive 
disease (<1.3) at Week 24  
ASDAS (90 mg) inactive 
disease (<1.3)   at Week 24
BASDAI50 (90 mg) response 
at Week 24 
ASAS40 (90 mg) response at 
Week 24 
ASAS20 (90 mg) response at 
Week 24 
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Statistical Analysis Plan CNTO1275AKS3002  
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Treatment failure criteria: 
x 
Initiate new DMARDs, biologics or systemic immunosuppressives for AS. 
x 
Increase SSZ, MTX, or hydroxychloroquine dose above baseline dose for AS. 
x 
Initiate treatment with oral, IV, or IM, corticosteroids for AS. 
x 
Increase the dose of oral corticosteroids above baseline dose for AS. 
x 
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. 
5.1.2.2. 
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.   
5.1.2.3. 
Early Escape 
For a subject who enters early escape at Week 16 based on IWRS, the following adjustments will be 
made to subsequent data through Week 24: 
x 
The subject will be considered a non-responder for response endpoints at Week 20 and Week 24; 
x 
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 40 responders at Week 24.  
5.2.1. 
Definition 
ASAS response is a composite measurement of change in AS signs and symptoms.  
A 40% improvement in response according to the criteria of the ASAS International Working Group 
(ASAS 40)1,12,15 is defined as: 
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1. 
An improvement of  40% from baseline and absolute improvement from baseline of at 
least 2 on a 0 to 10 cm scale in at least 3 of the following 4 domains: 
i.    Patient global 
ii.   Total back pain 
iii.  Function (BASFI) 
iv.  Inflammation (average of the last 2 questions of the BASDAI concerning morning stiffness) 
2. 
No worsening at all in the remaining domain. 
Following are the definitions of each of the forgoing disease assessment criteria (components) that 
are used in the determination of ASAS40 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.3  An increase along the scale indicates a worsening 
condition. (Section 5.3.3.1 for details) 
d) Inflammation (average of the last 2 questions of the BASDAI concerning morning stiffness) 
(See Section 5.3.2.1 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 40% improvement from baseline for 
that component since there is no room for improvement. 
5.2.2. 
Analysis Methods 
Analyses 
To address the primary hypothesis, a Cochran-Mantel-Haenszel (CMH) test stratified by region 
(North America, Latin America, Western Europe, Europe, and Asia Pacific) will be used to test 
the difference between the ustekinumab group and the placebo group for the proportion of ASAS 
40 responders at Week 24.  A 95% confidence interval for the treatment difference will be 
calculated based on the Wald statistic18. 
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The adjusted proportion difference will be estimated as ݀௔ௗ௝ൌσ
ݓ௝
ସ
௝ୀଵ
݀௝ ,  
where ݓ௝ൌ
ቆ
೙భೕ೙మೕ
೙భೕశ೙మೕ
ቇ
σ
ቆ
೙భೕ೙మೕ
೙భೕశ೙మೕ
ቇ
ర
ೕసభ
 , ݊௜௝ is the number of subjects who are in the ith treatment and the jth  stratum;  
݀௝ൌ
௫భೕ
௡భೕെ
௫మೕ
௡మೕ
 , ݔ௜௝݊௜௝
Τ
 is the estimated proportion of responders in the ith treatment and the jth  
stratum, where i=1,2 for treatments and j=1,2,3,4 for regions. 
Let ݎ௜௝ൌݔ௜௝݊௜௝
Τ
 ,  the Wald-type 95% confidence interval is defined as  
݀௔ௗ௝േͳǤͻ͸ඨ෍
ݓ௝
ଶሺݎଵ௝൫ͳ െݎଵ௝൯
݊ଵ௝
൅ݎଶ௝ሺͳ െݎଶ௝ሻ
݊ଶ௝
ሻ
ସ
௝ୀଵ
 
 
Data handling rules 
The data handling rules in Section 5.1.2.1 Treatment Failure, Section 5.1.2.2 Missing Data 
Imputation, and Section 5.1.2.3 Early Escape will be applied.  
5.2.3. 
Sensitivity Analyses 
To test the robustness of the primary endpoint analysis, the following sensitivity analysis will be 
performed. 
1. An analysis similar to that described in Section 5.2.2 will be performed with Treatment 
Failure, Missing Data Imputation, and Early Escape rules applied. However, subjects who 
discontinued study agent for any reason prior to Week 24 will be considered as ASAS 40 non-
responders at Week 24. 
2. An analysis similar to that described in Section 5.2.2 will be performed with Treatment 
Failure and Early Escape rules applied.  However, Missing Data Imputation rule will not be 
applied. 
3. ASAS 40 response status at Week 24 will 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. 
4. An analysis similar to that described in Section 5.2.2 will be performed with Missing Data 
Imputation and Early Escape rules applied. However, if at any one of the pre-week 24 visits 
(i.e., Weeks 4, 8, 12, 16, and 20) a subject meets any one of the treatment failure criteria and 
is an ASAS 40 non-responder at that visit, this subject should be considered a non-responder.  
Otherwise, the subject should be considered a responder for the primary efficacy analysis at 
Week 24 unless the subject’s ASAS 40 result at Week 24 is a non-responder. 
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5. An analysis similar to that described in Section 5.2.2 will be performed with Missing Data 
Imputation and Early escape rules applied.  However, Treatment Failure rule will not be applied. 
6.  “Tipping Point analysis via exhaustive scenarios” will be performed to evaluate 
various deviations from the assumption of non-response.  For subjects with missing response 
data at Week 24, responder status will be imputed in an increasing manner by subject level for 
each treatment group.  Specifically, for each subject, a responder / non-responder status will be 
imputed starting with the scenario where all subjects being non-responders up to the scenario 
where all subjects are responders.  This would include all possible scenarios of responder status 
for all missing data, including scenarios where subjects on ustekinumab have worse outcomes 
than subjects on placebo.  For each scenario, an analysis similar to that described in Section 5.2.2 
will be performed. 
7. The following “Tipping Point” analysis based on multiple imputations will be performed to 
evaluate various deviations from the assumption of non-response. 
For the tipping point analysis, a ȡ will be assumed for each treatment group’s response rate to the 
imputed value for missing values based on a Bernoulli distribution. This will be repeated N 
(N=100) times to generate N multiple imputations. 
For a given value of ȡ, the analysis similar to Section 5.2.2 based on the multiple imputation      
approach will be carried out and the corresponding 95% CIs will be constructed to compare the 
difference in proportions in ASAS 40 responders between the placebo and each of ustekinumab 
groups. The analysis will be repeated for a range of values for ȡ (i.e. 0% to 100% in increments of 
10% independently, for both the placebo and the ustekinumab group); and thus will include 
scenarios where subjects on ustekinumab have worse outcomes than subjects on placebo. If the 
number of missing subjects is less than 10 in both placebo and ustekinumab groups, then the 
range of values for ȡ would be 0% to 100% in increments of 25%. It should be noted that when 
the amount of missing data is small then this analysis should be interpreted with extra caution. 
5.2.4. 
Analysis Methods 
To evaluate the consistency in the primary efficacy endpoint, ASAS 40 at Week 24, over 
demographic, baseline characteristics, and prior or baseline medication use, subgroup analyses will be 
performed.  If needed, some of the cut-off points may be changed to increase sample sizes within 
categories.  
Proportion difference and the respective 95% CIs will be used for all subgroup mentioned in this 
section.  In addition, the nominal p-values based on CMH test controlling region for the subgroups 
will also be provided.  The 95% CI for the treatment differences will also be calculated based on the 
Wald statistics. . 
The subgroups are described in Section 2.4. 
5.2.5. 
Supportive Analyses 
To evaluate the consistency of the primary endpoint, a supportive summary of each component of 
the composite endpoint will be summarized by treatment group with Treatment Failure and Early 
Escape rules applied.  No missing data imputation rule will be applied. 
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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 20 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 20 Response at Week 24  
5.3.1.1. 
Definition  
ASAS 20 is defined as a 20% improvement in 3 of the 4 ASAS response domains (Section 5.2.1), 
with an absolute improvement of at least 1 on a 0 to 10 cm scale, and absence of 
deterioration from baseline ( 20% and worsening of at least 1 on a 0 to 10 cm scale) in the 
potential remaining domain.  
5.3.1.2. 
Analysis Methods 
A Cochran-Mantel-Haenszel (CMH) test stratified by region (North America, Latin America, 
Western Europe, Europe, and Asia Pacific) will be used to test the difference between the 
ustekinumab group and the placebo group for the proportion of ASAS 20 responders at Week 24.  A 
95% confidence interval for the treatment difference will be calculated based on the Wald statistic. 
Data handling rules 
Similarly, to the primary endpoint, Treatment Failure, Missing Data Imputation, and Early Escape 
rules will be applied.  
5.3.1.3. 
Sensitivity Analyses 
ASAS 20 response status at Week 24 will 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. 
 
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5.3.2. 
Proportion of Subjects who Achieve at Least a 50% Improvement from 
Baseline in BASDAI at Week 24 
5.3.2.1. 
Definition 
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:6 
A. Fatigue 
B. Spinal pain  
C. Joint pain  
D. Enthesits 
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])  
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. 
5.3.2.2. 
Analysis Methods 
A Cochran-Mantel-Haenszel (CMH) test stratified by region (North America, Latin America, 
Western Europe, Europe, and Asia Pacific) will be used to test the difference between the 
ustekinumab group and the placebo group for the proportion of subjects with at least 50% 
improvement from baseline in BASDAI at Week 24.  A 95% confidence interval for the treatment 
difference will be calculated based on the Wald statistic. 
Data handling rules 
Similarly, to the primary endpoint, Treatment Failure, Missing Data Imputation, and Early Escape 
rules will be applied.  
5.3.2.3. 
Sensitivity Analyses 
The 50% improvement from baseline at Week 24 will 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. 
 
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5.3.3. 
Change from Baseline in Bath Ankylosing Spondylitis Functional Index 
(BASFI) at Week 24 
5.3.3.1. 
Definition 
The Bath Ankylosing Spondylitis Functional Index (BASFI) is calculated as the mean of 10 VAS 
from the following questions (Table 2), 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.3 
Table 2: 
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. 
5.3.3.2. 
Analysis Methods 
The analysis will be performed using a Mixed Model for Repeated Measures (MMRM) based on data 
using early escape rule only. 
The independent variables for this model are treatment group, region (North America, Latin 
America, Western Europe, Europe, and Asia Pacific), baseline BASFI score, visit week, and an 
interaction of treatment and visit week.  An unstructured (UN) variance-covariance matrix for 
repeated measures within a subject will be used unless there are issues related to convergence. 
5.3.3.3. 
Sensitivity Analyses 
1. An ANCOVA model will be used to test 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 region (North America, Latin 
America, Western Europe, Europe, and Asia Pacific) as independent variables.  A 95% 
confidence interval for the difference in LSMeans and p-value will be calculated based on 
contrast test statistics. 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. 
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2. Tipping point analysis based on multiple imputations will be performed only if the amount of 
missing data is not negligible. 
5.3.4. 
Proportion of Subjects who Achieve ASDAS (CRP) inactive disease (<1.3) 
at Week 24 
5.3.4.1. 
Definition 
The ASAS has developed a disease activity score (DAS) for use in AS, the Ankylosing Spondylitis 
Disease Activity Score (ASDAS).2,10,14  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.11  For non-ASDAS summaries of CRP, if the value is <LLOQ, then half of the value of LLOQ 
will be used for numerical calculations. 
5.3.4.2. 
Analysis Methods 
A Cochran-Mantel-Haenszel (CMH) test stratified by region (North America, Latin America, 
Western Europe, Europe, and Asia Pacific) will be used to test the difference between the 
ustekinumab group and the placebo group for the proportion of subjects who achieve ASDAS (CRP) 
inactive disease (<1.3) at Week 24.  A 95% confidence interval for the treatment difference will be 
calculated based on the Wald statistic. 
Data handling rules 
Similarly to the primary endpoint, Treatment Failure, Missing Data Imputation, and Early Escape 
rules will be applied.  
5.3.4.3. 
Sensitivity Analyses 
ASDAS (CRP) inactive disease status at Week 24 will 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. 
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5.4. 
Estimands of Primary and Major Secondary Endpoints 
The following Table 3 outlines the targeted estimands of primary and major secondary efficacy 
endpoints including related sensitivity analyses.   
Table 3: 
Estimands of Primary and Major Secondary Endpoints Estimands of Primary and Major 
Secondary Endpoints 
Variable 
Analysis 
Estimand/change in assumption(s) 
Primary endpoint: 
proportion of ASAS 
40 responders at 
Week 24 
Primary analysis 
Difference in the probability of ASAS40 
response and remaining on study treatment and 
not adding/modifying ancillary therapies. 
 
Sensitivity analysis 1 
Same estimand as for the primary analysis but 
consider subjects with study agent 
discontinuation prior to Week 24 for any reason 
as non-responder. 
 
Sensitivity analysis 2 
Same estimand as for the primary analysis but 
exclude subjects with missing data (ie, ASAS40 
response cannot be determined due to missing 
components). 
 
Sensitivity analysis 3 
Difference in probability of ASAS40 response 
regardless of adherence or use of ancillary 
therapies (i.e., de facto estimand based on the 
observed data). 
 
Sensitivity analysis 4 
Same estimand as for the primary analysis but 
consider only the cases with non-response status 
and meeting treatment failure criteria as 
treatment failure.
 
Sensitivity analysis 5 
Same estimand as for the primary analysis but no 
treatment failure rule is applied in this analysis.
 
Sensitivity analysis 6 
(Tipping point analysis 
via exhaustive 
scenarios) 
Same estimand as for the primary analysis but 
the response for missing data will be varied to 
evaluate various deviations from the assumption 
of non-response.
 
Sensitivity analysis 7 
(Tipping point analysis 
based on multiple 
imputations)
Same estimand as for the primary analysis but 
the response for missing data will be varied to 
evaluate various deviations from the assumption 
of non-response.
1st Major secondary 
endpoint: proportion 
of subjects who 
achieve an ASAS 20 
response at Week 24 
Main analysis 
Difference in the probability of ASAS20 
response and remaining on study treatment and 
not adding/modifying ancillary therapies. 
 
Sensitivity analysis 2
Difference in probability of ASAS20 response 
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Table 3: 
Estimands of Primary and Major Secondary Endpoints Estimands of Primary and Major 
Secondary Endpoints 
regardless of adherence or use of ancillary 
therapies (i.e., de facto estimand based on 
observed data).
2nd Major secondary 
endpoint: proportion 
of subjects who 
achieve at least a 
50% improvement 
from baseline in 
BASDAI at Week 24 
Main analysis 
Difference in the probability of BASDAI50 
response and remaining on study treatment and 
not adding/modifying ancillary therapies. 
 
Sensitivity analysis 1 
Difference in probability of BASDAI50 
response regardless of adherence or use of 
ancillary therapies (i.e., de facto estimand based 
on the observed data).
3rd Major secondary 
endpoint: change 
from baseline in 
BASFI at Week 24 
Main analysis 
Difference in change from baseline in BASFI 
and remaining on study treatment (values set 
missing after early escape). 
MMRM is used for the analysis. 
 
Sensitivity analysis 1 
Same estimand as for the main analysis but 
assume the change from baseline in BASFI does 
not change after discontinuation or early escape. 
ANCOVA is used for the analysis. 
 
Sensitivity analysis 2 
(Tipping point analysis 
based on multiple 
imputations)  
 
This analysis will be 
performed only if the 
amount of missing data 
is not negligible 
Same estimand as for the main analysis but the 
value for missing data will be varied to evaluate 
various MNAR assumptions 
4th Major secondary 
endpoint: proportion 
of subjects who 
achieve ASDAS 
(CRP) inactive 
disease (<1.3) at 
Week 24 
Main analysis 
Difference in the probability of achieving 
ASDAS (CRP) inactive disease status and 
remaining on study treatment and not 
adding/modifying ancillary therapies. 
 
Sensitivity analysis 1 
Difference in probability of achieving ASDAS 
(CRP) inactive disease status regardless of 
adherence or use of ancillary therapies (i.e., de 
facto estimand based on the observed data).
 
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5.5. 
Other Secondary Endpoints  
In addition to the primary, major secondary endpoints, other secondary endpoints will be analyzed 
over time through Week 52 unless otherwise specified. 
5.5.1. 
Definition of Other Secondary Endpoints 
5.5.1.1. 
Low Disease Activity (ASAS Partial Remission) 
Low level of disease activity will be measured by criteria for “ASAS partial remission,” defined as a 
value below 2 on a scale of 0 to 10 cm in each of the 4 ASAS domains described above 
(Section 5.2.1). 
5.5.1.2. 
ASAS 5/6 Response 
ASAS 5/6 is defined as a 20% improvement in any 5 of the 6 domains of spinal pain (VAS 0 to 10 
cm), patient global (VAS 0 to 10 cm), function (BASFI score), morning stiffness (from 
BASDAI), CRP, and spine mobility (lumbar side flexion).  The spine mobility is based on the 
measured values of lumbar spine flexion, and not the converted values used to determine BASMI.  
Improvement is shown by an increase in lumbar spine flexion. 
Any component with missing score at baseline will be excluded from the analyses.  Except for 
spine mobility, 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. In addition, all other 5 
components should be >=20% improvement to be qualified as a responder. 
5.5.1.3. 
A 20%, 50%, 70%, 90% Improvement from baseline in BASDAI 
The definition of the improvement from baseline in BASDAI is defined in Section 5.3.2.1. 
5.5.1.4. 
ASDAS (CRP) 
The definition of the ASDAS (CRP) is defined in Section 5.3.4.1. 
5.5.1.5. 
ASDAS (CRP) Inactive Disease (<1.3) 
The definition of the ASDAS (CRP) is defined in Section 5.3.4.1. 
5.5.1.6. 
ASDAS (CRP) Major Improvement (Decrease 2.0) 
The definition of the ASDAS (CRP) is defined in Section 5.3.4.1.  
Major improvement in ASDAS is defined as a decrease from baseline 2.0.   
5.5.1.7. 
ASDAS (CRP) Clinically Important Improvement (Decrease1.1) 
The definition of the ASDAS (CRP) is defined in Section 5.3.4.1.  
Clinically important improvement in ASDAS is defined as a decrease from baseline 1.1. 
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5.5.1.8. 
Bath Ankylosing Spondylitis Metrology Index (BASMI) 
The BASMI is represented as an aggregate score of 5 components (ranging from 0 to 10) and will 
be calculated using the van der Heijde calculation13 as shown in Table 4. 
 
Table 4: 
Equations proposed for the conversion of the assessments (A) into scores (S) 
for the five components of the BASMIlin 
 
S = 0 if: 
Between 0 and 10: 
S = 10 if: 
Lateral lumbar flexion* (cm) 
A t21.1 
S = (21.1 - A)/2.1 
A d0.1 
Tragus-to-wall distance* (cm) 
A d8 
S = (A - 8)/3
A t38 
Lumbar flexion (modified Schober) (cm)
A t7.4 
S = (7.4 - A)/0.7
A d0.4 
Intermalleolar distance (cm) 
A t124.5 
S = (124.5-A)/10
A d24.5 
Cervical rotation angle* (q) 
A t89.3 
S = (89.3-A)/8.5
A d4.3 
*   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 and the scores (S) will be 
calculated programmatically based on assessments when analysis is performed. 
5.5.1.9. 
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. 
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5.5.1.10. 
MASES Enthesitis Scores 
Enthesitis will be assessed using the Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) 
index in this study.7
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: 
x 
1st costochondral joint, left and right; 
x 
7th costochondral joint, left and right; 
x 
posterior superior iliac spine, left and right; 
x 
anterior superior iliac spine, left and right; 
x 
iliac crest, left and right; 
x 
5th lumbar spinous process; 
x 
proximal insertion of Achilles tendon, left and right. 
Entheses are scored as either 0 (nontender) or 1 (tender).  The enthesitis index is a total score of 13 
evaluated sites as listed above with a range from 0 to 13.   
5.5.1.11. 
Inflammation 
Inflammation is defined as average of the last 2 questions of the BASDAI concerning morning 
stiffness). It is one of the components of ASAS 40.  One question measures overall level of morning 
stiffness from the time you wake up in the last 7 days on a VAS (0 to 10 cm; 0 = no stiffness, 10 = 
very severe stiffness).  The other question measures duration of morning stiffness from the time you 
wake up on a VAS (0 to 10 cm; 0 = 0 hours, 10 = 2 or more hours). 
5.5.1.12. 
Total Back Pain 
The total back pain is one of the components of ASAS 40.  It is measured on a VAS (0 to 10 cm; 0 = 
no pain, 10 = most severe pain). 
40% improvement in Total Back Pain 
If a subject’s baseline value is zero (ie. no pain), the subject should be considered as not 
achieving 40% improvement from baseline since there is no room for improvement. 
5.5.1.13. 
Night Back Pain 
Subjects will be asked to assess their nighttime back pain during the past week on a VAS (0 to 10 
cm; 0 = no pain, 10 = most severe pain). 
5.5.1.14. 
Patient Global Assessment 
The Patient’s Global Assessment of Disease Activity is one of the components of ASAS 40.  It is 
measured on a VAS (0 to 10 cm; 0 = very well, 10 = very poor). 
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40% improvement in Patient Global Assessment 
If a subject’s baseline value is zero (ie. no pain), the subject should be considered as not 
achieving 40% improvement from baseline since there is no room for improvement. 
5.5.1.15. 
36-Item Short-form Health Survey  
The SF-36 is a health-related quality of life instrument with 36 questions. Version 2 will be used. 
This instrument yields an 8-scale profile of functional health and well-being scores as well as 
psychometrically-based physical and mental health summary measures. The 8 multi-item scales of 
SF-36 instrument are as follows: 
x 
limitations in physical functioning due to health problems; 
x 
limitations in usual role activities due to physical health problems; 
x 
bodily pain; 
x 
general mental health (psychological distress and well-being); 
x 
limitations in usual role activities due to personal or emotional problems; 
x 
limitations in social functioning due to physical or mental health problems; 
x 
vitality (energy and fatigue); 
x 
general health perception. 
These scales are scored from 0 to 100 with higher scores indicating better health. The 2 aggregate 
summary scores, the Physical Component Summary (PCS) and the Mental Component Summary 
(MCS), are based on the 8 subscales.  The PCS, MCS, and the 8 subscales 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. 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 treatments16,17. High scores indicate better 
health for both summary scores (PCS and MCS) and all 8 subscales.  
For partially answered questionnaires, if more than 50% of the items within each scale are left 
unanswered, that scale score for the subject will be assigned as missing. If at least 50% of the items 
within each scale are answered, the missing item scores will be imputed with the average score for the 
subject across completed items in the same scale. 
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5.5.1.16. 
Medical Outcomes Study Sleep Scale (MOS-SS)  
The extent of sleep problems will be assessed using the Medical Outcomes Study Sleep Scale (MOS-
SS).8 The MOS Sleep Scale is a generic health measure, assessing a health-related quality of life 
(HRQOL) concept- sleep that is relevant to everyone’s health status and well-being and known to be 
directly affected by disease and treatment.  MOS-SS measures six dimensions of sleep, including 
initiation, maintenance (eg, staying asleep), quantity, adequacy, somnolence (eg, drowsiness), and 
respiratory impairments (eg, shortness of breath, snoring). A composite sleep problems index score 
can also be generated.   
The scale uses predominantly Likert-type questions to evaluate sleep. Scales range from 1 
(meaning “all of the time”) to 6 (“none of the time”), and require respondents to indicate how 
frequently during the previous 4 weeks they have experienced certain sleep-related issues. 
Several of these items are reverse scored. Another Likert-type item queries sleep latency (1 = “0–15 
min” and 5 = “more than 60 min”). Finally, a fill-in-the blank question asks participants to estimate 
the average number of hours they have slept each night in the past month – a response of 8 h or 
greater receives a 1, while answers below 8 h receive 0. 
5.5.1.17. 
Ankylosing Spondylitis Quality of Life (ASQoL) Questionnaire  
Ankylosing spondylitis quality of life questionnaire is a self-administered patient-reported outcomes 
instrument.4  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 0–18.  Higher scores indicate worse health related 
quality of life. Subjects can complete the instrument in less than four minutes. 
5.5.1.18. 
EuroQol 5 Dimension Questionnaire (EQ-5D) 
The EQ-5D is a standardized measure of health status developed by the EuroQoL Group in order to 
provide a simple, generic measure of health for clinical and economic appraisal.5  Applicable to a 
wide range of health conditions and treatments, it provides a simple descriptive profile and a single 
index value for health status that can be used in the clinical economic evaluation of health care. The 
EQ-5D descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. There are 3 response options: no problems, some problems, 
severe problems. The EQ VAS records the respondent’s self-rated health on a vertical, visual analog 
scale where the endpoints are labeled “Best imaginable health state” and “Worst imaginable health 
state.” The EQ VAS is used as a quantitative measure of health outcome as judged by the individual 
respondent.  The US model will be used for analyses. 
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5.5.1.19. 
Functional Assessment of Chronic Illness Therapy-Fatigue 
 Questionnaire (FACIT-Fatigue) 
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.  
5.5.2. 
Analysis Methods for Other Secondary Endpoints 
Unless otherwise specified, the analysis population will be the FAS defined in Section 2.3.1. The 
following endpoints will be summarized by treatment groups. 
Summaries over time will be for all visits data collected through Week 52.  Simple descriptive summary 
statistics, such as n, mean, SD, median, IQ range, minimum, and maximum for continuous variables, 
and counts and percentages for discrete variables will be used to summarize most data. 
Nominal p-values will be provided at each visit through Week 24. 
1.  For dichotomous endpoints, Cochran-Mantel-Haenszel (CMH) test stratified by region (North 
America, Latin America, Western Europe, Europe, and Asia Pacific) will be used. A 95% 
confidence interval for the treatment difference will be calculated based on the Wald 
statistic. 
2.  For continuous endpoints, a Mixed Model for Repeated Measures (MMRM) will be used. 
The independent variables for this model are treatment group, region (North America, Latin 
America, Western Europe, Europe, and Asia Pacific), baseline value, visit week, and an interaction 
of treatment and visit week.  An unstructured (UN) variance-covariance matrix for repeated measures 
within a subject will be used unless there are issues related to convergence. 
The following Table 5 outlines the efficacy endpoints, type of the analyses, and the data handling 
rules used through Week 24.  After Week 24, no treatment failure rule and no missing data 
imputation rules will be applied.  All early escaped subjects will be excluded in the analyses after 
Week 24.  
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Table 5: 
Analyses and data handling rules for other secondary endpoints through Week 24 
 
Endpoints 
Data handling rules  
 
 
Treatment 
Failure
Missing data 
imputation 
Early 
escape 
1 
The proportion of subjects who achieve an ASAS 40 
response 
 
¥ 
 
¥ 
 
¥ 
2 
The proportion of subjects who achieve an ASAS 20 
response  
¥ 
 
 ¥ 
 ¥ 
3 
The proportion of subjects who achieve low disease 
activity (ASAS partial remission)
¥ 
 
¥ 
¥ 
4 
The proportion of subjects who achieve an ASAS 5/6 
response 
 
¥ 
 
¥ 
 
¥ 
5 
The change from baseline in BASFI
 
 
¥
6 
The proportion of subjects who achieve a 20%, 50%,
70%, 90% improvement from baseline in BASDAI
 
¥ 
 
¥ 
 
¥ 
7 
The change from baseline in BASDAI
 
 
¥
8 
The change from baseline in ASDAS (CRP)
 
 
¥
9 
The proportion of subjects who achieve ASDAS (CRP)
inactive disease (<1.3) 
¥ 
 
¥ 
¥ 
10 
The proportion of subjects who achieve ASDAS (CRP) 
major improvement (decrease 2.0) 
 
¥ 
 
¥ 
 
¥ 
11 
The proportion of subjects who achieve ASDAS (CRP) 
clinically important improvement (decrease 1.1)
 
¥ 
 
¥ 
 
¥ 
12 
The change from baseline in BASMI 
 
 
¥ 
13 
The change from baseline in each component of BASMI
 
¥
14 
The change from baseline in the PCS and MCS scores of
SF-36 
 
 
¥
15 
The proportion of Subjects Who Achieved at Least a 5 
Unit Improvement From Baseline in the PCS and MCS 
scores of SF-36 
 
¥ 
 
¥ 
 
¥ 
16 
The change from baseline in SF-36 subscales
 
¥
17 
The change from baseline in hsCRP
 
 
¥
18 
The change from baseline in chest expansion
 
 
 
¥
19 
The change from baseline in night back pain 
 
 
¥ 
20 
The change from baseline in M A S E S enthesitis
scores in subjects with enthesitis at baseline
 
 
¥
21 
The change from baseline in the Patient's Global
Assessment of Disease Activity 
 
 
 
¥ 
22 
The change from baseline in the Patient’s Assessment
of Total Back Pain 
 
 
¥
23 
The change from baseline in inflammation (average of 
the last 2 questions of the BASDAI concerning morning 
stiffness) 
 
 
 
¥ 
24 
The proportion of subjects who achieve a 40%
improvement from baseline in the Patient's Global 
Assessment of Disease Activity
¥ 
 
¥ 
¥ 
25 
The proportion of subjects who achieve a 40%
improvement from baseline in the Patient’s Assessment of 
Total Back Pain. 
 
¥ 
 
¥ 
 
¥ 
26 
The proportion of subjects who achieve a 40%
improvement from baseline in BASFI 
¥ 
 
¥ 
¥ 
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Table 5: 
Analyses and data handling rules for other secondary endpoints through Week 24 
27 
The proportion of subjects who achieve a 40%
improvement from baseline in the Inflammation (average 
of the last 2 questions of the BASDAI concerning 
morning stiffness) 
 
¥ 
 
¥ 
 
¥ 
28 
The change from baseline in composite scores of MOS-SS
 
 
¥ 
29 
The change from baseline in ASQoL scores
 
¥ 
30 
The change from baseline in EQ-5D VAS and in EQ-5D
index 
 
 
¥ 
31 
The change from baseline in FACIT-Fatigue
 
¥ 
32 
The proportion of Subjects Who Achieved at Least a 4-
Unit Improvement From Baseline in FACIT-Fatigue 
 
¥ 
 
¥ 
 
¥ 
 
In addition, the change from baseline in BASDAI after Week 24 through Week 52 will be 
summarized based on observed data for early escape subjects only. 
6. 
SAFETY 
Safety will be assessed by summarizing the occurrences and types of AEs, vital signs (pulse, 
blood pressure, weight and height) and the changes in the laboratory parameters. 
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 treatments 
they are 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 Week 64. 
The treatment group descriptions for all study periods are also outlined below. 
6.1.1. 
Summaries through Week 16 
1. Placebo: Subjects received placebo only through Week 16. 
2. Ustekinumab 45 mg: Subjects who received at least one dose of 45 mg ustekinumab and 
never received 90 mg through Week 16.  Subjects may have inadvertently received placebo 
prior to Week 16.  Subjects may have missed one or more ustekinumab 45 doses. 
3. Ustekinumab 90 mg: Subjects who received at least one dose of 90 mg ustekinumab 
through Week 16.  Subjects may have inadvertently received placebo or ustekinumab 45 
mg prior to Week 16.  Subjects may have missed one or more ustekinumab 90 mg doses. 
4. Ustekinumab Combined: Combined 2 and 3 above.  
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The treatment groups above are mutually exclusive for 1, 2, and 3.  The safety tables will have the 
column headings below: 
 
Placebo 
 
Ustekinumab 
 
45 mg 
 
90 mg 
 
Combined 
 
6.1.2. 
Summaries through Week 24 
Based on the protocol, subjects who qualified for early escape begin to receive golimumab at Week 
16.  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/or crossover), and the number of subjects and/or the lengths of follow-up may differ among the 
groups.  
See the column headings below for the safety tables through Week 24: 
 
Placebo/ 
Early Escape 
 
Ustekinumab 45 mg/ 
Early Escape 
Ustekinumab 90 mg/ 
Early Escape 
 
Placeboa 
 
(Placeboo
Golimumab)b 
 
45 mg Onlya 
 
(45 mg o 
Golimumab)b 
 
90 mg Onlya 
 
(90 mg o 
Golimumab)b 
 
Ustekinumab 
Only 
Combineda 
a Includes all subjects, but adverse events for subjects who early escaped at Week 16 are only counted up to Week 16. 
b Only includes subjects who early escaped at Week 16.  Adverse events are counted from early escape onward. 
6.1.3. 
Summaries through Week 64 
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 
Week 64 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 Onlyb 
Ustekinumab Combined 
 
Placeboo
45 mg  
 
Placeboo
90 mg 
 
45 mg  
 
90 mg  
 
45 mg  
 
90 mg 
 
All 
Ustekinumab  
a Placebo subjects who crossed over at Week 24. 
b Adverse events for subjects who early escaped at Week 16 are only counted up to Week 16. 
 
Selected safety summaries and listings will also be performed through Week 64 for subjects who 
early escaped to golimumab. 
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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: 
x 
Any AEs 
x 
SAEs 
x 
AEs with severe intensity 
x 
AEs and SAEs that are reasonably related to study agent 
x 
AEs leading to discontinuation of study agent 
x 
Injection site reactions 
x 
Infections and infections requiring oral or parenteral anti-microbial treatment 
x 
Serious infections 
In addition to the summary tables, the incidence per 100 subject-years for select events including but 
not limited to serious infection and malignancies will be provided, and 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 infections, injection site reactions, and  hepatobiliary events (defined as 
ALT  3 × ULN and bilirubin  2 × ULN). 
Injection site reactions and infection: 
x 
An injection site reaction is defined as any adverse reaction at a SC study agent 
injection site and is captured in the eCRF. 
x 
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: 
x 
Proportion of subjects receiving scheduled study agent administrations at each study agent 
administration visit by treatment group 
x 
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 
The laboratory parameters include but are not limited to the following: 
Hematology: RBC, hemoglobin, hematocrit, neutrophils, lymphocytes, monocytes, eosinophils, 
platelets, and WBC count. 
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Chemistry: BUN/urea, creatinine, total bilirubin, alkaline phosphatase, ALT/SGPT, AST/SGOT, 
bicarbonate, sodium, potassium, calcium, albumin, chloride, phosphate, glucose, and total protein. 
NCI-CTCAE grades will be used in the summary of laboratory data (Grade 0 – 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, and >5 to <8xULN.  These will also be provided by TB prophylaxis status. 
A listing of subjects with post-baseline abnormal laboratory results based on CTCAE grades >=3 will 
also be provided. 
6.4. 
Vital Signs  
Vital signs are collected at every study visit, Week 0, 4, 8, 12, 16, 20, 24, 28, 40, 52, and 64.  
Markedly abnormal vital signs will be summarized by treatment group and listed. 
 
 
 
6.5. 
Electrocardiogram  
This section does not apply to this study. 
7. 
PHARMACOKINETICS/PHARMACODYNAMICS  
7.1. 
Pharmacokinetics  
Pharmacokinetics (PK) samples for measuring serum ustekinumab concentrations will be collected 
from all subjects at the specified visits as shown in the schedule of events of the protocol. Samples 
will be collected at Weeks 0, 4, 8, 12, 16, 20, 24, 28, 40, 52, and 64.  All PK evaluations will be 
based on the subjects who receive at least 1 injection of ustekinumab (PK analysis set). No 
imputation for missing concentration data will be performed.  
The data analysis of serum ustekinumab concentrations includes the following: 
x 
Summary of serum ustekinumab concentrations at each visit by treatment group 
x 
Summary of serum ustekinumab concentrations at each visit by treatment group and body 
weight quartiles 
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x 
Summary of serum ustekinumab concentrations at each visit by treatment group and baseline 
MTX (Yes, No) 
x 
Summary of serum ustekinumab concentrations by CRP levels at baseline 
x 
Proportion of subjects without detectable serum ustekinumab concentration at each visit by 
treatment group 
x 
Median serum ustekinumab concentrations plotted over time by treatment group. 
In addition, the relationship between serum ustekinumab concentrations, and antibody to 
ustekinumab status, safety and efficacy may be explored. Median trough serum ustekinumab 
concentrations will be plotted.  Box plots of serum ustekinumab concentrations will be plotted by 
percentage subjects who achieved ASAS 20 and ASAS 40 responses. 
For summary statistics of serum ustekinumab concentrations, concentration values below the 
lower limit of quantification will be treated as zero. Once a subject meets one of the following dosing 
deviation criteria, the subject’s data will be excluded from the by-visit data analyses from that point 
onwards. 
Dosing deviation criteria: 
x 
Discontinue study agent administrations 
x 
Skipped an administration 
x 
Received an incorrect dose 
x 
Received an incorrect study agent 
x 
Received an additional dose 
In addition, if a subject has an administration more than 7 days earlier or later than the scheduled 
dosing date, the concentration data collected between such a dosing visit and the subsequent dosing 
visit will be excluded from the by-visit data analyses. For the Week 24 visit, if the PK sampling time 
deviates more than 3 days earlier or later than the scheduled date, the PK concentration at this visit will 
be excluded from the by-visit data analysis.  Additional exclusions for incongruous PK data to be 
implemented based on Janssen TV-SOP-11008v3.0. 
Population PK analyses will be performed to characterize the population PK parameters based on the 
available ustekinumab concentration data obtained through the Week 24 visit. The population 
pharmacokinetic approach will also be used to identify and quantify any significant covariates such 
as demographic characteristics (including but not limited to body weight, ethnic origin, sex, and age) 
and concomitant medications that have substantial impact on the population pharmacokinetics of 
ustekinumab in subjects with AS. A detailed analysis plan for population PK analysis will be 
developed separately, and a stand-alone technical report will be written to summarize the results of 
the population PK analysis. 
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PK  analyses  presentation 
PK analyses will be summarized through the following time periods: 
x 
Through Week 24 
x 
Through Week 52  
x 
Through Week 64 
For the analyses, a subject is included in one and only one treatment group on the basis of the 
treatment regimen followed. The descriptions of treatment groups for all reporting periods are as 
follows. 
7.1.1. 
PK Treatment Groups Through Week 24 
1. Ustekinumab 45 mg:  Subjects randomized to ustekinumab 45 mg and received 45 mg 
ustekinumab through Week 24. 
2. Ustekinumab 90 mg:  Subjects randomized to ustekinumab 90 mg and received 90 mg 
ustekinumab through Week 24. 
 
7.1.2. 
PK Treatment Groups Through Week 52 
1. Placebo ė Ustekinumab 45 mg:  Subjects randomized to placebo and were switched over to 
ustekinumab 45 mg at Week 24 and continue to receive ustekinumab 45 mg through Week 52. 
2. Ustekinumab 45 mg:  Subjects randomized to ustekinumab 45 mg and received 45 mg 
ustekinumab through Week 52. 
3. Placebo ė Ustekinumab 90 mg:  Subjects randomized to placebo and were switched over to 
ustekinumab 90 mg at Week 24 and continue to receive ustekinumab 90 mg through Week 52. 
4. Ustekinumab 90 mg:  Subjects randomized to ustekinumab 90 mg and received 90 mg 
ustekinumab through Week 52. 
7.1.3. 
PK Treatment Groups Through Week 64 
1. Placebo ė Ustekinumab 45 mg:  Subjects randomized to placebo and were switched over to 
ustekinumab 45 mg at Week 24 and continue to receive ustekinumab 45 mg through the end of 
the study. 
2. Ustekinumab 45 mg:  Subjects randomized to ustekinumab 45 mg and received 45 mg 
ustekinumab through the end of the study. 
3. Placebo ė Ustekinumab 90 mg:  Subjects randomized to placebo and were switched over to 
ustekinumab 90 mg at Week 24 and continue to receive ustekinumab 90 mg through the end of 
the study. 
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4. Ustekinumab 90 mg:  Subjects randomized to ustekinumab 90 mg and received 90 mg 
ustekinumab through the end of the study. 
 
7.2. 
Immune Response  
Blood samples will be collected to examine the formation of antibodies to ustekinumab at the 
specified visits as shown in the schedule of events of the protocol (Weeks 0, 4, 8, 12, 24, 40, 52, 
and 64).  For subjects who discontinue study agent administrations, samples will be collected at their 
final safety visit, 12 weeks after the last study agent administration. 
The data analysis of antibodies to ustekinumab includes the following will be provided: 
x 
The summary of subjects’ antibody status (positive, negative) by ustekinumab treatment 
groups  
x 
A listing of subjects who are positive for antibodies to ustekinumab.   
x 
A summary of subject’s neutralizing antibody status (positive, negative) by ustekinumab 
treatment groups. 
x 
For subjects who discontinue study agent administrations, a listing of their antibody status will be 
presented. 
x 
The relationship between antibody to ustekinumab status and efficacy and safety at major 
assessment time points (Week 24, 52); ASAS 20 and ASAS 40 responses by antibody to 
ustekinumab status and treatment group (additionally at Week 16 which is the trough 
concentration for ustekinumab with Week 24 ASAS 20/ASAS 40 responses); injection-site 
reactions by antibody to ustekinumab status and treatment group; hypersensitivity by antibody to 
ustekinumab status and treatment group 
x 
The relationship between antibody to ustekinumab status at Week 24 and antibody to 
ustekinumab status at Week 52 will be explored.   
x 
The summary of onset and duration of antibody formation 
x 
Figure of serum ustekinumab concentrations by treatment group and by antibody to ustekinumab 
status and summary of PK concentration by treatment group and by antibody to ustekinumab 
status 
 
The descriptions of treatment groups for all reporting periods are as follows. 
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7.2.1. 
Immunogenicity Treatment Groups Through Week 24 
1. Ustekinumab 45 mg:  Subjects randomized to ustekinumab 45 mg and received 45 mg 
ustekinumab through Week 24. 
2. Ustekinumab 90 mg:  Subjects randomized to ustekinumab 90 mg and received 90 mg 
ustekinumab through Week 24. 
3. Total: subjects are in one of above groups 1and 2. 
 
7.2.2. 
Immunogenicity Treatment Groups Through Week 52  
1. Placebo ĺ Ustekinumab 45 mg:  Subjects randomized to placebo and were switched over to 
ustekinumab 45 mg at Week 24 and continue to receive ustekinumab 45 mg through Week 52. 
2. Ustekinumab 45 mg:  Subjects randomized to ustekinumab 45 mg and received 45 mg 
ustekinumab through Week 52. 
3. Combined Ustekinumab 45 mg: Subjects are in one of above groups 1 and 2. 
4. Placebo ĺ Ustekinumab 90 mg:  Subjects randomized to placebo and were switched over to 
ustekinumab 90 mg at Week 24 and continue to receive ustekinumab 90 mg through Week 52. 
5. Ustekinumab 90 mg:  Subjects randomized to ustekinumab 90 mg and received 90 mg 
ustekinumab through Week 52. 
6. Combined Ustekinumab 90 mg: Subjects are in one of above groups 4 and 5. 
7. Total: Subjects are in one of above groups 1,2, 4, and 5. 
7.3. 
Pharmacodynamics 
Pharmacodynamics biomarkers are collected at Weeks 0, 24, and 52.  The analyses results will be 
provided in an independent technical report. 
7.4. 
Pharmacokinetic/Pharmacodynamic Relationships  
The relationship between serum ustekinumab concentrations and pharmacodynamics markers may be 
explored and results will be reported in an independent technical report. 
7.5. 
Microbiome Substudy  
Approximately 100 subjects will be asked to provide stool samples for a fecal microbiome substudy. 
The samples will be collected at baseline, Weeks 4, 24, and 52, and analyses resultswill be provided 
in an independent technical report. 
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7.6. 
Pharmacogenomics  
In addition to HLA-B27 genotyping prior to study agent administration, 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, ie, 
modifications in DNA characteristics other than its sequence. Only DNA research related to 
ustekinumab or to the pathobiology of AxSpA will be performed in consenting subjects only.  The 
analyses results will be provided in an independent technical report. 
8. 
HEALTH ECONOMICS  
8.1. 
Definition  
8.1.1. 
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.  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. 
8.2. 
Analysis Methods 
Unless otherwise specified, the analysis population will be the FAS defined in Section 2.3.1. The change 
from baseline in 4 WPAI scores will be summarized over time by treatment groups. The 4 WPAI scores 
are: 
1. Percent work time missed due to AS.  This score is defined by [Q2/(Q2+Q4)]x100; 
2. Percent Impairment while Working due to AS.  This score is defined by (Q5/10)x100; 
3. Percent overall Work Impairment due to AS.  This score is defined by {Q2/(Q2+Q4)+[(1-
(Q2/(Q2+Q4)))x(Q5/10)]}x100; 
4. Percent activity impairment due to AS. This score is defined by (Q6/10)x100. 
 
Simple descriptive summary statistics, such as n, mean, SD, median, IQ range, minimum, and 
maximum will be provided.  
Nominal p-values will be provided at Week 16 and at Week 24. 
A Mixed Model for Repeated Measures (MMRM) will be used. 
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The independent variables for this model are treatment group, region (North America, Latin 
America, Western Europe, Europe, and Asia Pacific), baseline score, visit week, and an interaction of 
treatment and visit week.  An unstructured (UN) variance-covariance matrix for repeated measures 
within a subject will be used unless there are issues related to convergence. 
Data handling rule: 
Subjects with no observed data at all will be excluded from the analysis. Subjects with no value at 
baseline are excluded from the analysis. Early escape rules will be applied on Week 24 data.  After 
Week 24, no treatment failure rule and no missing data imputation rules will be applied.  All early 
escaped subjects will be excluded in the analyses at Week 52.  
 
NCT02438787


STELARA® (ustekinumab) 
Statistical Analysis Plan CNTO1275AKS3002  
14 April 2017 48 
Approved Date: 14 April 2017  
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PharmaSUG - Paper SP04 
NCT02438787