Clinical trial NCT04882072
Conditions: Takayasu Arteritis
Sponsor: Janssen Pharmaceutical K.K.
Start date: 2021-09-15; Completion date: 2023-05-25
Enrollment: 14 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy of ustekinumab compared to placebo, in combination with oral glucocorticoid (GC) taper regimen, in participants with relapsing Takayasu Arteritis (TAK).

Detailed description:

Arms: arm 1: Double-blind (DB) Period: Participants will receive weight-ranged based ustekinumab (6 milligrams/kilogram\[mg/kg\]) as IV infusion at Week 0 followed by ustekinumab 90mg injection SC 8 weeks after initial IV dose, then every 8 weeks (q8w) thereafter until the end of the DB period with starting the protocol defined oral GC taper regimen from Week 2 visit.

Open Label Extension (OLE) period: Participants will receive ustekinumab SC injection at Week OL-0, followed by ustekinumab 90mg SC injection with oral GC taper at investigator's discretion for 52 weeks (Week OL-52) or until 32 weeks from first SC administration after end of DB period whichever is later.

Long-term Extension (LTE) Period: Participants who completed OLE period may be eligible to enter LTE and continue to receive ustekinumab 90mg SC injection q8w. arm 2: DB period: Participants will receive placebo intravenous (IV) infusion at Week 0 followed by placebo subcutaneous (SC) injection administration, 8 weeks after the initial IV dose, then q8w thereafter until the end of DB period with starting the protocol defined oral GC taper regimen from Week 2 visit.

OLE period: Participants will receive ustekinumab SC at Week OL-0, followed by SC administration of ustekinumab with oral GC taper at investigator's discretion for 52 weeks (Week OL-52) or until 32 weeks from the first SC administration after the end of DB period, whichever is later.

LTE Period: Participants who complete their participation in OLE period may be eligible to enter the LTE and continue to receive 90 mg SC ustekinumab q8w.
Interventions: intervention 1: Ustekinumab intervention 2: Placebo intervention 3: Glucorticoid Taper Regimen
Intervention descriptions: intervention 1: Participants will receive IV infusion and SC injection of ustekinumab. intervention 2: Participants will receive IV infusion and SC injection of matching placebo. intervention 3: Glucocorticoid will be administered orally.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
1
Status: Approved,  Date:  15 August 2022
Janssen Pharmaceutical K.K.*
Clinical Protocol
Protocol Title
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group
Study of Ustekinumab in Participants With Takayasu Arteritis
Protocol CNTO1275TAT3001; Phase 3
AMENDMENT 2
CNTO1275 (Ustekinumab)
*This study is being conducted by Janssen Pharmaceutical K.K. in Japan. The term “sponsor” is used
throughout the protocol to represent Janssen Pharmaceutical K.K
Status: 
Approved
Date: 
15 August 2022
Prepared by: Janssen Pharmaceutical K.K.
EDMS number: 
EDMS-RIM-226774, 3.0
GCP Compliance:  This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory
requirements.
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or
otherwise.
NCT04882072


CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
2
Status: Approved,  Date:  15 August 2022
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 2 
15 August 2022
Amendment 1 
7 April 2021
Original Protocol 
12 Februar y 2021
Amendment 2 (15 August 2022)
Overall Rationale for the Amendment: To modify eligibility criteria to include a broader population of
Takayasu arteritis patients. Additional minor corrections and clarifying changes are also included in this
amendment.
The changes to the protocol are described in the table below. For select changes, additions to the text are
indicated by underline; deletion of text is shown in strikethrough.
Section Number 
and Name
Description of Change 
Brief Rationale
1.3. Schedule of
Activities
(SoA)
Footnotes o. in
Table 1
Relapse Confirmation Visit is the second relapse
assessment visit after participants meet the relapse
criteria once at scheduled visit or unscheduled visit
(This visit will be treated defined as “1st relapse
visit”). At Relapse Confirmation Visit, TAK
Disease Assessment S&S and CRP/ESR must be
performed and the other items are not needed to
perform if they already performed at “1st relapse
visit”. If participants are judged as relapse once at
“1st relapse visit” only, all the assessments at
Relapse Confirmation Visit should be performed.
For PK assessment, PK samples will be collected at
1st relapse visit defined above.
Text was revised to clarify the PK
sample collection at relapse.
1.3. Schedule of 
Activities 
(SoA) 
Footnotes j. in  
Table 2 
Relapse Confirmation Visit is the second relapse
assessment visit after participants meet the relapse
criteria for the first time once at scheduled visit or
unscheduled visit (This visit will be treated defined
as “1st relapse visit”). At Relapse Confirmation
Visit, TAK Disease Assessment S&S and
CRP/ESR must be performed and the other items
are not needed to perform if they already
performed at “1st relapse visit”. If participants are
judged as relapse at the first assessment only at “1st
relapse visit” only, all the assessments at Relapse
Confirmation Visit should be performed.
For PK assessment, PK samples will be collected at
1st relapse visit defined above.
Text was revised to clarify the PK
sample collection at relapse.
1.1. Synopsis 
This is a Phase 3, randomized, double-blind,
placebo-controlled, multicenter, interventional
study in participants ≥18 15 years and ≤75 years of
age with TAK to evaluate the efficacy, safety,
pharmacokinetic (PK), and immunogenicity of
intravenous (IV) and subcutaneous (SC)
ustekinumab.
Updated the inclusion criteria for
age to expand participant
population.
NCT04882072


CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
3
Status: Approved,  Date:  15 August 2022
Section Number 
and Name
Description of Change 
Brief Rationale
4.1. Overall Design 
This is a Phase 3, randomized, double-blind,
placebo-controlled, parallel, multicenter,
interventional study in participants ≥1815 years
and ≤75 years of age with TAK to evaluate the
efficacy, safety, PK, and immunogenicity of IV and
SC ustekinumab.
5.1. Inclusion 
Criteria 1.
Criterion modified per Amendment 2:
 
1.1   1815 to 75 years of age, inclusive, (at the time
of the first administration of study intervention
at Week 0). If participant’s disease onset of
TAK is over 50 years old, appropriate
evaluations should be made to distinguish
from giant cell arteritis (GCA).
5.1. Inclusion 
Criteria 19. 
Criterion modified per Amendment 2: 
 
19.1 Are considered eligible according to the
following TB screening criteria:
d. 
Within 6 weeks prior to the first
administration of the study intervention,
has a negative interferon gamma release
assays (IGRAs) result, or have a newly
identified positive IGRAs result in
which active TB has been ruled out and
for which appropriate treatment for
latent TB has been initiated at least 3
weeks prior to the first administration of
the study intervention. A participant
whose first IGRA result is indeterminate
should have the test repeated. In the
event that the second IGRA result is also
indeterminate, the participant should be
excluded from the study. 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 participant has no additional
risk factors for TB as determined by the
investigator. This determination must be
promptly reported to the sponsor and
recorded in the participant's source
documents and initialed by the
investigator.
 
Text was revised to clarify
the inclusion criteria for TB.
5.1. Inclusion 
Criteria 22. and 23. 
Criterion modified per Amendment 2: 
 
22.1 Must sign an ICF (or their legally 
acceptable representative must sign)
indicating that he or she understands the
purpose of, and procedures required for, the
study and is willing to participate in the
study. Parent(s) (preferabl y both if available
Text was added to clarify assent
form in the inclusion criteria for
informed consent process.
NCT04882072


CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
4
Status: Approved,  Date:  15 August 2022
Section Number 
and Name
Description of Change 
Brief Rationale
or as per local requirements) (or their
legally acceptable representative) must sign
an ICF indicating that they understand the
purpose of, and procedures required for, the
study and is/are willing to allow the child to
participate in the study. Assent is also
required of children capable of
understanding the nature of the study
(typically 7 years of age and older) as
described in Informed Consent Process and
Assent Form in Appendix 8: Regulatory,
Ethical, and Study Oversight
Considerations.
 
Criterion modified per Amendment 2:
 
23.1 Must sign a separate informed consent form
(or their legally-acceptable representative
must sign) if he or she agrees to provide an
optional (DNA) sample for research.
Refusal to give consent for the optional
DNA research sample does not exclude a
participant from participation in the study.
Parent(s) (preferably both if available or as
per local requirements) (or their legally
acceptable representative) must sign a
separate informed consent form if they
agree to the child providing an optional
DNA sample for research. Assent is also
required of children capable of
understanding the nature of the study
(typically 7 years of age and older) as
described in the Informed Consent Process
and Assent Form in Appendix 8:
Regulatory, Ethical, and Study Oversight
Considerations.
 
5.2. Exclusion 
Criteria 3. 
Criterion modified per Amendment 2: 
 
3.1  
Has received immunosuppressant (s) 
(including but not limited to MTX, AZA,
mycophenolate mofetil [(MMF)], oral TAC,
oral cyclosporine A) within 4 weeks of first
study intervention.
Text was added to clarify the
exclusion criteria for the previous
medical therapy.
5.2. Exclusion  
Criteria 8. 
Criterion modified per Amendment 2: 
 
8.1  
Has previously been treated with any  
immunomodulatory biologic agent not
described in this protocol within 5 half-lives
or 12 weeks, whichever is longer, before the
first administration of study intervention
(eg, abatacept, agents whose mechanism of
action targets B cell [eg, belimumab], IL-1
[eg, canakinumab], IL-2, IL-17 [eg,
Text was added to clarify the
exclusion criteria for the previous
medical therapy.
NCT04882072


CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
5
Status: Approved,  Date:  15 August 2022
Section Number 
and Name
Description of Change 
Brief Rationale
secukinumab, ixekizumab, brodalumab], or
IFN pathways).
 
5.2. Exclusion 
Criteria 10. 
Criterion modified per Amendment 2: 
 
10.1 Has previously failed to respond Janus 
kinase (JAK) inhibitor* for the treatment of
TAK (ie, lack of efficacy), including but not
limited to tofacitinib, baricitinib,
upadacitinib. Has received treatment with
JAK inhibitor within 5 half-lives before the
first administration of study intervention, if
discontinued by any reasons excepting lack
of efficacy.
 
*Failed response to JAK inhibitor is defined
for participants who have received at least
4 weeks treatment of JAK inhibitor and
signs and symptoms of TAK persisted for
2 weeks or more and were not able to taper
oral GC dose of 7.5 mg/day (prednisolone
or equivalent) or less due to recurrence of
disease activity of TAK based on clinical
judgment of a treating physician. These
signs and symptoms of TAK must have
occurred ≥2 weeks after receiving JAK
inhibitor.
Text was revised to clarify the
exclusion criteria for the previous
medical therapy.
6.8. Concomitant 
Therapy  
Oral NSAIDs 
 
Participants are permitted to receive stable doses
(≥2 weeks prior to first study intervention
administration) of oral NSAIDs treatment
according to the local practice at the discretion of
the investigator. Participants should not initiate oral
NSAIDs therapy during DB period, unless
discussed and agreed with the sponsor medical
monitor.
Text was revised to clarify how to
use NSAIDs.
6.8. Concomitant 
Therapy  
 
Prohibited Therapies 
Use of additional investigational or approved 
biologic or non-biologic immunosuppressant or 
immunomodulatory agents, other than those
explicitly allowed in the inclusion/exclusion
criteria, are prohibited until safety follow-up visit
including but not limited to, the following:
Text was added to clarify the
period of Prohibited Therapies.
7.1. Discontinuation  
of Study  
Intervention  
 The participant requires a prohibited therapy  
such as an immunomodulatory biologic, 
cyclophosphamide, or IV glucocorticoid (see 
Section 6.8).
Text was added to clarify the
discontinuation of study
intervention.
8. STUDY 
ASSESSMENTS  
AND  
PROCEDURES  
If multiple assessments are scheduled for the same 
timepoint, it is recommended that procedures be 
performed in the following sequence: patient-
reported outcome (PRO) assessments, ECG and
Text was revised to clarify the
sequence of study assessment.
NCT04882072


CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
6
Status: Approved,  Date:  15 August 2022
Section Number 
and Name
Description of Change 
Brief Rationale
 
Overview 
vital signs, patient reported outcome (PRO)
assessments, clinical safety laboratory assessments,
PK, immunogenicity, and biomarkers.
 
9.3. Populations for 
Analysis Sets 
Population 
Description 
Enrolled 
All participants who sign the
ICF.
Randomized 
All participants who were
randomized in the study.
FAS 
All randomized participants
who take at least 1 dose of
study intervention. Full
analysis set will be the
primary population for
efficac y analyses.
Per protocol 
All participants who take at
least 1 dose of study
intervention and have no
major protocol deviations.
More details will be provided
in the SAP.
Safety 
All participants who take at
least 1 dose of study
intervention.
PK 
All participants who take at
least 1 complete dose of
ustekinumab and have at
least 1 post-dose sample
collection.
Immunogenicity 
All participants who take at
least 1 dose of ustekinumab
and have at least 1 post-dose
sample collection.
 
Correction of error in writing
9.4.2. Primary 
Endpoint 
The Kaplan-Meier method will be used to estimate 
the distribution of time to relapse for each
treatment. One efficacy interim analysis is planned
and the type I error rate will be controlled at 5% (2-
sided). The significant level is to be determined
based on the O’Brien-Fleming alpha spending
function. Based on this approach, the interim
analysis will be performed at a significance level of
0.00280.0012 when exactly 15 of 35 events were
observed and if the study is not stopped, the final
analysis performed at the 0.04910.0496
significance level.
 
Correction of error in writing
9.5. Interim Analysis One efficacy interim analysis is planned after 15 
events have been occurred. The O’Brien-Fleming
alpha spending function as implemented by the
Lan-DeMets method will be used to determine the
statistical boundary for early success (2-sided p-
value ≤0.00280.0012 for the efficacy interim
analysis when exactly 15 of 35 events were
observed).
Correction of error in writing
NCT04882072


CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
7
Status: Approved,  Date:  15 August 2022
Section Number 
and Name
Description of Change 
Brief Rationale
10.5. Appendix 5: 
Definition of 
Inadequate Response 
or Intolerance to 
Biologics 
1. Inadequate response to current or prior therapy 
with TCZ or anti-TNF therapy 
 
b. Was not able to taper oral GC dose to 
7.5 mg/day (prednisolone or equivalent) or less
due to recurrence of disease activity of TAK
based on clinical judgment of a treating
physician.
 
The recurrence of disease activity of TAK must
have occurred persisted ≥2 weeks after
receiving one of the biologic treatments.
Text was revised to clarify the
definition of inadequate response
to biologics based on current
clinical practice.
10.8.6. Committees
Structure
One efficacy interim analysis is planned after 15
events have been occurred. The O’Brien-Fleming
alpha spending function as implemented by the
Lan-DeMets method will be used to determine the
statistical boundary for early success (2-sided p-
value ≤0.00280.0012 for the efficacy interim
analysis when exactly 15 of 35 events were
observed).
Correction of error in writing
Throughout the
protocol
Minor grammatical, formatting, and/or spelling
changes were made.
Minor errors were noted.
NCT04882072


CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
8
Status: Approved,  Date:  15 August 2022
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................. 2
TABLE OF CONTENTS .......................................................................................................................... 8
LIST OF IN-TEXT TABLES AND FIGURES .......................................................................................... 10
1. 
PROTOCOL SUMMARY .............................................................................................................. 11
1.1. 
Synopsis ................................................................................................................................... 11
1.2. 
Schema .................................................................................................................................... 17
1.3. 
Schedule of Activities ................................................................................................................ 18
2. 
INTRODUCTION .......................................................................................................................... 25
2.1. 
Study Rationale......................................................................................................................... 27
2.2. 
Background............................................................................................................................... 28
2.3. 
Benefit-risk Assessment ............................................................................................................ 29
2.3.1. 
Risks for Study Participation .................................................................................................. 29
2.3.2. 
Benefits for Study Participation .............................................................................................. 30
3. 
OBJECTIVES AND ENDPOINTS ................................................................................................. 30
4. 
STUDY DESIGN ........................................................................................................................... 33
4.1. 
Overall Design .......................................................................................................................... 33
4.2. 
Scientific Rationale for Study Design ......................................................................................... 35
4.2.1. 
Study-specific Ethical Design Considerations ......................................................................... 36
4.3. 
Justification for Dose ................................................................................................................. 37
4.4. 
End of Study Definition .............................................................................................................. 37
5. 
STUDY POPULATION ................................................................................................................. 38
5.1. 
Inclusion Criteria ....................................................................................................................... 38
5.2. 
Exclusion Criteria ...................................................................................................................... 43
5.3. 
Lifestyle Considerations ............................................................................................................ 48
5.4. 
Screen Failures ......................................................................................................................... 48
5.5. 
Criteria for Temporarily Delaying Enrollment, Randomization, and/or Administration of
Study Intervention ..................................................................................................................... 49
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY ......................................................... 49
6.1. 
Study Intervention Administered ................................................................................................ 49
6.2. 
Preparation/Handling/Storage/Accountability ............................................................................. 52
6.3. 
Measures to Minimize Bias: Randomization and Blinding .......................................................... 53
6.4. 
Study Intervention Compliance .................................................................................................. 54
6.5. 
Dose Modification ..................................................................................................................... 54
6.6. 
Continued Access to Study Intervention After the End of the Study............................................ 55
6.7. 
Treatment of Overdose ............................................................................................................. 55
6.8. 
Concomitant Therapy ................................................................................................................ 55
6.8.1. 
Rescue Medication ................................................................................................................ 59
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL ........................................................................................... 60
7.1. 
Discontinuation of Study Intervention ........................................................................................ 60
7.1.1. 
Liver Chemistry Stopping Criteria ........................................................................................... 61
7.2. 
Participant Discontinuation/Withdrawal From the Study ............................................................. 61
7.3. 
Lost to Follow-up ....................................................................................................................... 62
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................ 63
8.1. 
Efficacy and Immunogenicity Assessments ............................................................................... 64
8.1.1. 
TAK Disease Signs and Symptoms ........................................................................................ 64
8.1.2. 
Physician Global Activity-Visual Analog Scale (PhGA-VAS) ................................................... 65
NCT04882072


CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
9
Status: Approved,  Date:  15 August 2022
8.1.3. 
Imaging ................................................................................................................................. 65
8.1.4. 
Short Form 36 (SF-36) ........................................................................................................... 66
8.1.5. 
Patient Global Activity-Visual Analog Scale (PtGA-VAS) ........................................................ 66
8.1.6. 
Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue....................................... 66
8.1.7. 
Endpoint Definitions ............................................................................................................... 66
8.2. 
Safety Assessments .................................................................................................................. 67
8.2.1. 
Physical Examinations ........................................................................................................... 67
8.2.2. 
Vital Signs ............................................................................................................................. 68
8.2.3. 
Electrocardiograms ................................................................................................................ 68
8.2.4. 
Clinical Safety Laboratory Assessments ................................................................................. 68
8.2.5. 
Pregnancy Testing ................................................................................................................. 68
8.2.6. 
Infections ............................................................................................................................... 68
8.2.6.1. 
Tuberculosis ....................................................................................................................... 69
8.2.7. 
Infusion- or Injection-site Reactions........................................................................................ 69
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting...................................... 69
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information ............................................................................................................................ 69
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events ......................................... 70
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events ..................................................... 70
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events and Anticipated
Events ................................................................................................................................... 70
8.3.5. 
Pregnancy ............................................................................................................................. 71
8.3.6. 
Infections ............................................................................................................................... 71
8.3.7. 
Tuberculosis .......................................................................................................................... 71
8.3.8. 
Infusion- or Injection-site Reactions........................................................................................ 71
8.3.9. 
Events of Special Interest ...................................................................................................... 71
8.3.10. 
Disease-related Events and Disease-related Outcomes Not Qualifying as Adverse
Events or Serious Adverse Events ......................................................................................... 72
8.4. 
Pharmacokinetics ...................................................................................................................... 72
8.4.1. 
Evaluations ............................................................................................................................ 72
8.4.2. 
Analytical Procedures ............................................................................................................ 72
8.5. 
Genetics and Pharmacogenomics ............................................................................................. 72
8.6. 
Biomarkers ............................................................................................................................... 73
8.6.1. 
Pharmacodynamics ............................................................................................................... 73
8.6.2. 
Serum biomarkers ................................................................................................................. 73
8.6.3. 
Whole Blood Gene Expression Profile .................................................................................... 74
8.6.4. 
Peripheral Blood Mononuclear Cells ...................................................................................... 74
8.7. 
Immunogenicity Assessments ................................................................................................... 74
8.8. 
Medical Resource Utilization and Health Economics.................................................................. 75
9. 
STATISTICAL CONSIDERATIONS .............................................................................................. 75
9.1. 
Statistical Hypotheses ............................................................................................................... 75
9.2. 
Sample Size Determination ....................................................................................................... 75
9.3. 
Populations for Analysis Sets .................................................................................................... 75
9.4. 
Statistical Analyses ................................................................................................................... 76
9.4.1. 
Primary Estimand .................................................................................................................. 76
9.4.2. 
Primary Endpoint ................................................................................................................... 76
9.4.3. 
Secondary Endpoints ............................................................................................................. 76
9.4.4. 
Exploratory Endpoints ............................................................................................................ 77
9.4.5. 
Safety Analyses ..................................................................................................................... 77
9.4.6. 
Other Analyses ...................................................................................................................... 78
9.5. 
Interim Analysis......................................................................................................................... 80
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................... 81
10.1. 
Appendix 1: Abbreviations and Definitions ................................................................................. 81
10.2. 
Appendix 2: Diagnostic criteria for Takayasu arteritis according to JCS 2017 guideline on
management of vasculitis syndrome .......................................................................................... 83
10.3. 
Appendix 3: Definitions of relapse/remission of TAK .................................................................. 85
NCT04882072


CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
10
Status: Approved,  Date:  15 August 2022
10.4. 
Appendix 4: Relapse Judgement Flow....................................................................................... 89
10.5. 
Appendix 5: Definition of Inadequate Response or Intolerance to Biologics................................ 92
10.6. 
Appendix 6: Glucocorticoid Conversion Table............................................................................ 95
10.7. 
Appendix 7: Clinical Laboratory Tests........................................................................................ 96
10.8. 
Appendix 8: Regulatory, Ethical, and Study Oversight Considerations ....................................... 98
10.8.1. 
Regulatory and Ethical Considerations ................................................................................... 98
10.8.2. 
Financial Disclosure ............................................................................................................. 101
10.8.3. 
Informed Consent Process and Assent Form ....................................................................... 101
10.8.4. 
Data Protection .................................................................................................................... 102
10.8.5. 
Long-term Retention of Samples for Additional Future Research .......................................... 103
10.8.6. 
Committees Structure .......................................................................................................... 103
10.8.7. 
Publication Policy/Dissemination of Clinical Study Data ........................................................ 104
10.8.8. 
Data Quality Assurance ....................................................................................................... 105
10.8.9. 
Case Report Form Completion ............................................................................................. 105
10.8.10. Source Documents .............................................................................................................. 106
10.8.11. Monitoring............................................................................................................................ 107
10.8.12. On-site Audits ...................................................................................................................... 108
10.8.13. Record Retention ................................................................................................................. 108
10.8.14. Study and Site Start and Closure ......................................................................................... 109
10.9. 
Appendix 9: Adverse Events, Serious Adverse Events, Product Quality Complaints, and
Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up,
and Reporting ......................................................................................................................... 110
10.9.1. 
Adverse Event Definitions and Classifications ...................................................................... 110
10.9.2. 
Attribution Definitions ........................................................................................................... 111
10.9.3. 
Severity Criteria ................................................................................................................... 111
10.9.4. 
Special Reporting Situations ................................................................................................ 111
10.9.5. 
Procedures .......................................................................................................................... 112
10.9.6. 
Product Quality Complaint Handling ..................................................................................... 113
10.9.7. 
Contacting Sponsor Regarding Safety, Including Product Quality ......................................... 114
10.10. Appendix 10: Contraceptive and Barrier Guidance .................................................................. 115
10.11. Appendix 11: Liver Safety: Suggested Actions and Follow-up Assessments ............................ 117
10.12. Appendix 12: Guidance on study conduct during COVID-19 pandemic .................................... 119
10.13. Appendix 13: Hepatitis B Virus screening ................................................................................ 121
10.14. Appendix 14: Protocol Amendment History .............................................................................. 122
11. REFERENCES ........................................................................................................................... 126
INVESTIGATOR AGREEMENT .......................................................................................................... 128
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Schedule of Activities (Screening through the Double-Blind Period) ...................................... 18
Table 2: 
Schedule of Activities (Open-Label Extension Period) .......................................................... 22
Table 3: 
Study Intervention ................................................................................................................ 50
Table 4: 
Glucocorticoid dose requirements for each study period ....................................................... 56
Table 5: 
Glucocorticoid Taper Schedule (Daily Dose [mg] of Prednisolone or Equivalent) (Table
shows only up to Week 24) .................................................................................................. 57
FIGURES
Figure 1: Schematic Overview of the Study ......................................................................................... 17
Figure 2: Flow Chart For Relapse Judgement Process ........................................................................ 89
Figure 3: The flow of relapse judgement without adjudication .............................................................. 90
Figure 4: The flow of relapse judgement with adjudication ................................................................... 91
NCT04882072


CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
11
Status: Approved,  Date:  15 August 2022
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Study of
Ustekinumab in Participants With Takayasu Arteritis
STELARA® (ustekinumab) is a fully human immunoglobulin G1 kappa monoclonal antibody which binds
with high affinity to the p40 subunit common to both interleukin (IL)-12 and IL-23. This study is designed
to evaluate glucocorticoids (GC) sparing effect of ustekinumab in participants with Takayasu arteritis
(TAK). The mechanism of action of ustekinumab is prevention of IL-12/23p40 binding to the IL-12R1 cell
surface receptor shared by both cytokines. Through this mechanism of action, ustekinumab effectively
neutralizes IL-12 T helper (Th)1- and IL-23 Th17-mediated cellular responses and has the potential to offer
patients with relapsing TAK a safe and effective steroid sparing therapy.
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
 
To evaluate the efficacy of ustekinumab
compared to placebo, in combination with oral
GC taper regimen, in participants with relapsing
TAK
 
Time to relapse of TAK according to
protocol-defined criteria (see Section 8.1)
through the end of DB period
Secondary
 
To evaluate the safety of ustekinumab, in
combination with oral GC taper regimen, in
participants with relapsing TAK
 
Number/proportion of participants with
TEAEs through the end of study
 
Number/proportion of participants with
TEAEs by system organ class with a
frequency threshold of 5% or more through
the end of study
 
Number/proportion of participants with
treatment-emergent SAEs through the end
of study
 
To evaluate the efficacy of ustekinumab
compared to placebo, in combination with oral
GC taper regimen, in participants with relapsing
TAK as measured by alternative definitions of
relapse criteria, relapse rate, GC sparing effects,
and disease activity
 
Time to relapse of TAK according to
Kerr’s definition through the end of DB
period
 
Time to relapse of TAK based on clinical
symptoms only through the end of DB
period
 
Time to relapse of TAK in each of the
5 categories through the end of DB period
 
Relapse rate in each of the 5 categories
through the end of DB period
 
Cumulative oral GC dose (prednisolone or
equivalent) through the end of DB period
 
Change from baseline in oral GC dose
(prednisolone or equivalent) through the
end of DB period
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CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
12
Status: Approved,  Date:  15 August 2022
Objectives 
Endpoints
 
Number/proportion 
of 
participants
achieving oral GC dose of 5 mg/day or less
through the end of DB period
 
Change 
from 
baseline 
in 
imaging
evaluation through the end of DB period
 
Change from baseline in inflammatory
markers (CRP, ESR) through the end of
DB period
 
To evaluate the PK and immunogenicity of
ustekinumab, in combination with oral GC taper
regimen, in participants with relapsing TAK
 
Serum concentrations of ustekinumab in
participants 
receiving 
ustekinumab
through the end of study
 
Number/proportion of participants who are
positive for anti-ustekinumab antibodies in
participants 
receiving 
active 
study
intervention through the end of study
Exploratory
 
To explore changes in the PRO instruments and
the physician reported outcome
 
Changes from baseline PROs through the
end of study
 
SF-36
 
PtGA of disease activity on VAS
 
FACIT-Fatigue
 
Change from baseline on physician
reported outcome: PhGA through the end
of study
 
To explore the efficacy of ustekinumab in
combination with oral GC taper regimen, in
participants with relapsing TAK during OLE
period
 
Number/proportion of participants who
experience relapse of TAK according to
protocol-defined criteria during OLE
period
 
Number/proportion of participants who
experience relapse of TAK according to
Kerr’s definition during OLE period
 
Number/proportion of participants who
experience relapse of TAK based on
clinical symptoms only during OLE period
 
Number/proportion of participants who
experience relapse of TAK in each of the 5
categories during OLE period
 
Cumulative oral GC dose (prednisolone or
equivalent) during OLE period
 
Change from baseline in oral GC dose
(prednisolone or equivalent) during OLE
period
NCT04882072


CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
13
Status: Approved,  Date:  15 August 2022
 
Number/proportion 
of 
participants
achieving oral GC dose of 5 mg/day or less
during OLE period
 
Change 
from 
baseline 
in 
imaging
evaluation during OLE period
 
Change from baseline in inflammatory
markers (CRP, ESR) during OLE period
Abbreviations: CRP=C-reactive protein; DB=double-blind; ESR=erythrocyte sedimentation rate;
FACIT=Functional Assessment of Chronic Illness Therapy; GC=glucocorticoid; OLE=open-label extension;
PK=pharmacokinetic; PRO=patient reported outcome; PhGA=Physician’s Global Assessment of Disease Activity;
PtGA=Patient’s global assessment; TAK=Takayasu arteritis; SAE=serious adverse event; SF-36=short-form 36;
TEAE=treatment-emergent adverse event; VAS=visual analog scale
Hypothesis
The hypothesis is that ustekinumab will prolong time to relapse while attempting corticosteroids tapering
as compared with placebo in participants with TAK.
OVERALL DESIGN
This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter, interventional study in
participants ≥15 years and ≤75 years of age with TAK to evaluate the efficacy, safety, pharmacokinetic
(PK), and immunogenicity of intravenous (IV) and subcutaneous (SC) ustekinumab.
The total duration of the study will be approximately 2 years, consisting of (1) a ≤6-week screening period
in which a participant’s eligibility will be reviewed prior to administration of the first dose of study
intervention; (2) a double-blind (DB) period: up to participant’s relapse of TAK or end of the DB period (a
total of 35 relapse events occur), whichever is earlier; (3) an open-label extension (OLE) period: 52 weeks
or 32 weeks from the first SC administration after the end of DB period, whichever is later; and (4) a safety
follow-up period: 16 weeks.
Participants must have experienced TAK relapse within 12 weeks prior to administration of study
intervention and the relapse must have occurred at oral GC dose of at least 7.5 mg/day (prednisolone or
equivalent). The relapse must have been adequately treated with ≥15 mg/day of prednisone or equivalent
and participants must subsequently have achieved remission at least 1 week prior to the first administration
of the study intervention.
Approximately 50 participants will be randomized at Week 0 in a blind fashion to 1:1 ratio stratified by
oral GC dose at Week 0 (<0.5 mg/kg/day, ≥0.5 mg/kg/day of prednisolone or equivalent) and status of
previous biologic medication (bio-nonfailure or bio-failure) to receive either ustekinumab or matching
placebo with the following treatment regimens during the DB period until participants develop relapse or a
total of 35 relapse events have occurred.
Ustekinumab group: The participants will receive body weight-range based IV administration of
ustekinumab (~6 mg/kg) at Week 0 followed by ustekinumab 90 mg SC administered 8 weeks after the
initial IV dose and then every 8 weeks (q8w) thereafter.
Placebo group: The participants will receive IV administration of placebo at Week 0 followed by placebo
SC administered 8 weeks after the initial IV dose and then q8w thereafter.
During the DB period, participants will receive IV administration of study intervention followed by SC
administration of study intervention, with starting the protocol defined oral GC taper regimen from Week
2 visit (baseline oral GC dose will be stable until Week 2). Participants who develop relapse will receive
rescue medication of oral GC that is at least double the oral GC dose at the relapse. These participants will
NCT04882072


CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date:  15 August 2022
be assessed whether they achieve remission at the next scheduled administration visit from the relapse
(Week OL-0) to enter OLE phase as the Escape arm regardless of remission status, and then receive IV
administration of ustekinumab at Week OL-0 followed by ustekinumab 90 mg SC administered 8 weeks
after the initial IV dose, then q8w thereafter. Escape arm is identical to OLE period except participants in
Escape arm will receive IV ustekinumab at Week OL-0 instead of SC ustekinumab. Participants in Escape
arm may receive continuous administrations of IV ustekinumab with 8-week interval once in the study if
they relapse prior to Week 8.
When a total of 35 relapse events occur, the DB period will end and rest of the participants in the DB period
will enter OLE period except for participants who reach oral GC dose of 5 mg/day (prednisolone or
equivalent) or less in the placebo group to avoid unnecessary administration of ustekinumab for those who
are considered to be placebo responders. These participants will continue or switch (if participants receive
placebo in DB period) to receive SC ustekinumab administered q8w with maintaining the originally dosing
schedule. For these participants, the first dosing visit from the end of DB period will be regarded as Week
OL-0. In transition period from the end of DB period to completion of the database lock (DBL), participants
who reach oral GC dose of 5 mg/day (prednisolone or equivalent) or less at the end of DB period will
continue to receive study intervention assigned in DB period until completion of the DBL for DB period in
order to maintain the blind. The data occurred in the transition period will be handled as that of OLE period.
Participants assigned to the placebo group who reach oral GC dose of 5 mg/day (prednisolone or equivalent)
or less at the end of DB period will terminate the study intervention administration and conduct
early-termination (early-term) visit after completion of the DBL for DB period.
When 35 events occur, further recruitment will end.
During OLE period, participants will receive SC administration of ustekinumab at Week OL-0 and followed
by SC administration of ustekinumab with oral GC taper of investigator’s discretion for 52 weeks (Week
OL-52) or until 32 weeks from the first SC administration after the end of DB period, whichever is later.
Safety follow-up visit will be conducted 16 weeks after last SC ustekinumab administration.
A long-term extension (LTE) study to evaluate further long-term effects of ustekinumab may be conducted
if the sponsor deems that ustekinumab treatment is beneficial to study participants based on results of the
primary analysis. Participants who complete their participation in OLE period may be eligible to enter the
LTE and continue to receive 90 mg SC ustekinumab q8w. Details will be provided in a separate LTE
protocol or amendment of this protocol.
The efficacy interim analysis is planned to determine early success when relapse of TAK occurs in
15 events.
The primary efficacy analysis will be performed when relapse of TAK occurs in 35 events with additional
secondary endpoints to be analyzed.
A first DBL will occur after a total of 15 events in relapse of TAK occurred for an interim analysis. A
second DBL will occur after a total of 35 events in relapse of TAK occurred. A third DBL will occur
approximately 24 weeks after the second DBL. A fourth DBL will occur when all participants have either
completed their final study visit or terminated study participation prior to their final visit. Additional DBLs
other than the ones specified above may be performed.
Investigative study sites and participants will remain blinded to initial treatment assignment until the end
of the study, except the assignment for participants who reach oral GC dose of 5 mg/day (prednisolone or
equivalent) or less when a total of 35 relapse events occur will be revealed after the second DBL.
Identification of sponsor personnel who will have access to the unblinded participant data will be
documented prior to unblinding to the sponsor.
The primary endpoint of this study is the time taken to relapse of TAK according to protocol-defined criteria
through the end of DB period.
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CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date:  15 August 2022
An external Independent Data Monitoring Committee (IDMC) will be commissioned for this study to
ensure the continuous safety and well-being of the participants enrolled in this study.
An interim analysis will be implemented to evaluate early efficacy after 15 relapse events occurred. This
efficacy analysis is unblinding and IDMC recommend the continuation or early termination of the DB
period based on the results of interim analysis. The sponsor will decide the continuation and termination of
DB period based on the recommendation by IDMC. If the sponsor decides early termination of DB period,
all participants will be rolled over to the OLE period except for participants assigned to the placebo group
who reach oral GC dose of 5 mg/day (prednisolone or equivalent) or less at the end of DB period. In
transition period, follow the same process as 35 relapse events occurrence. The sponsor will continue to
enroll participants into OLE period until reaching a total of approximately 50 participants. Participants who
are eligible according to Inclusion/Exclusion criteria in this protocol will directly enter to OLE period to
receive body weight-range based IV administration of ustekinumab (~6 mg/kg) at Week OL-0 and followed
by ustekinumab 90 mg SC q8w with oral GC taper at investigator’s discretion for 52 weeks (Week OL-52).
Safety follow-up visit will be conducted 16 weeks after last SC ustekinumab administration.
NUMBER OF PARTICIPANTS
Approximately 50 participants will be enrolled in this study.
EFFICACY EVALUATIONS
TAK Disease Signs and Symptoms
Efficacy of ustekinumab in TAK will be assessed from the presence of TAK activity including investigator
assessment of signs and symptoms of TAK.
Physician Global Activity-Visual Analog Scale (PhGA-VAS)
Physician Global Activity is partially validated tool to measure the global evaluation by the physician of
the participant's overall disease activity at the time of assessment using a 10 cm VAS.
Imaging
In this study, imaging assessment will be performed using computed tomography angiography (CTA) or
magnetic resonance angiography (MRA), if CTA is not feasible, by the dedicated radiologist or physician
from study site (or designee) at specified time point in Schedule of Activities (Section 1.3). Imaging
assessment will include the aorta and its major branches from the terminal of the common carotid artery
(internal and external carotid branches) to the abdominal aortic terminal (common iliac artery branch) and
will be performed in multiple planes using contrast media agent. When imaging assessment has been
performed within 12 weeks prior to scheduled imaging assessment visit, imaging assessment may not be
performed and the prior results will be used for this scheduled assessment.
(1) Vessel involvement such as stenosis, obstruction, and aneurysm; (2) Arterial wall thickness; and (3)
The presence of mural contrast enhancement and oedema (MRA only) will be assessed for imaging
evaluation on disease activity of TAK. Study independent central imaging assessment will be used to
analyze all computed tomography or MRA scans included in this study. The central imaging assessment of
imaging will be blinded to the clinical data.
Short Form 36 (SF-36)
The SF-36 is a widely used tool that assesses the global medical quality of life, functional health, and
well-being of general and specific populations.
NCT04882072


CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date:  15 August 2022
Patient Global Activity-Visual Analog Scale (PtGA-VAS)
Patient Global Activity is partially validated tool to measure the global evaluation by the participant of the
participant's overall disease activity at the time of assessment using a 10 cm VAS.
Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue
The Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale version 4.0 is a 13-item
questionnaire formatted for self-administration that assesses patient- reported fatigue and its impact upon
daily activities and functions over the past 7 days.
PHARMACOKINETIC EVALUATIONS
Blood samples will be collected to evaluate the serum PK of ustekinumab as specified in Schedule of
Activities (Section 1.3). Serum samples will be analyzed to determine concentrations of ustekinumab using
a validated, specific, and sensitive immunoassay method by or under the supervision of the sponsor.
IMMUNOGENICITY EVALUATIONS
Serum samples will be evaluated for the presence of anti-ustekinumab antibodies and the titer according to
the Schedule of Activities (Section 1.3). Additionally, serum samples should be collected at the final visit
from participants who are discontinued from treatment or withdrawn from the study. Serum samples that
test positive for anti-ustekinumab antibodies will be further characterized to determine if anti-ustekinumab
antibodies could neutralize the biological effects of ustekinumab in vitro (ie, neutralizing antibodies to
ustekinumab). These samples will be tested by the sponsor or sponsor’s designee.
PHARMACODYNAMIC AND BIOMARKER EVALUATIONS
Assessments will be performed to identify biomarkers that are relevant to ustekinumab treatment and/or
TAK, where local regulations permit. These may include, but are not limited to, the evaluation of relevant
biomarkers in serum, whole blood, and peripheral blood mononuclear cells collected as specified in the
Schedule of Activities (Section 1.3).
PHARMACOGENOMIC (DNA) EVALUATIONS
A pharmacogenomic blood sample will be collected from participants who consent separately to this
component of the study to allow for pharmacogenomic research, where local regulations permit.
Participation in the pharmacogenomic research is optional.
Whole blood samples will be collected for genetic analyses at screening as specified in the Schedule of
Activities (Section 1.3) if within the maximum blood volume allowed.
SAFETY EVALUATIONS
Safety evaluations will include assessment of adverse events (AEs), concomitant medications, pregnancy
testing, administration reactions, chemistry and hematology laboratory tests, immunogenicity, vital signs,
and general physical examinations. In addition, electrocardiogram, chest x-ray, chest CT, human
immunodeficiency virus, hepatitis B, hepatitis C, and tuberculosis testing will be required at screening.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. Specific details of the
statistical methods to be used to analyze the efficacy and safety data will be provided in the statistical
analysis plan. For the primary endpoint of time to relapse, primary analysis will consist of test using a Cox
proportional hazard regression model for comparison between 2 treatment groups. The hazard ratio and its
2-sided 95% confidence intervals will be also presented. The Kaplan-Meier method will be used to estimate
the distribution of time to relapse for each treatment. All reported AEs with onset during treatment phase
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CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date:  15 August 2022
(ie, treatment adverse events [TEAEs] and AEs that have worsened since baseline) will be included in
analysis. For each AE, the percentage of participants who experience at least 1 AE will be summarized by
treatment group. Adverse events will also be summarized based on patient-year by treatment group.
Summaries, listings, or participants narratives may be provided, as appropriate, for those participants who
die, who discontinue treatment due to AE, or who experience a serious adverse event (SAE). Descriptive
statistics will be calculated for each laboratory analyte at baseline and for observed values and changes
from baseline at each scheduled time point. Clinically relevant abnormalities will be evaluated by frequency
tabulations. Descriptive statistics of weight, temperature, pulse/heart rate, respiratory rate, and blood
pressure (right and left hands separately) values and changes from baseline will be summarized at each
scheduled time point. Serum ustekinumab concentrations will be summarized with descriptive statistics at
each sampling time point. A listing of participants who are positive for anti-ustekinumab antibodies will be
provided.
1.2. 
Schema
Figure 1: 
Schematic Overview of the Study
Abbreviations: DB=double-blind; DBL=database lock; Early-Term=early-termination; GC=glucocorticoids;
IC=informed consent; IV=intravenous; OLE=open-label extension; UST=ustekinumab; PBO=placebo;
SC=subcutaneous; Scr=screening; US=ustekinumab; q8w=every 8 weeks.
* When a total of 35 relapse events occur, participants who reach oral GC dose of 5 mg/day (prednisolone or
equivalent) or less at the end of the DB period in the placebo group will terminate the study intervention
administration and conduct early-term visit.
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NCT04882072


CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date:  15 August 2022
d. 
Minimum criteria for the availability of documentation supporting the eligibility criteria will be described in the full protocol. Check clinical status again before
first dose of study intervention.
e. 
Imaging assessment will be performed during screening period, every 24 weeks from Week 0 (eg, Week 24, 48, 72), and Relapse Confirmation Visit using CTA or
MRA, if CTA is not feasible. When imaging assessment has been performed within 12 weeks prior to scheduled imaging assessment visit, imaging assessment
may not be performed, and the prior results will be used for this scheduled assessment. Imaging assessment for screening visit should be performed and the prior
imaging results for screening assessment will not be allowed. Additional imaging assessment may be performed if investigator deems a need for further evaluation
of participant’s disease activities. At Relapse Confirmation Visit, imaging assessment will be performed within 4 weeks after the investigator confirms participants
meets the relapse criteria and it is recommended to be performed prior to Week OL-0.
f. 
All PRO assessments should be conducted in the order listed in the above Schedule of Activities table. Whenever possible, PRO assessments should be conducted
before any tests, procedures, or other consultations for that visit to prevent influencing participants’ perceptions.
g. 
A 12-lead ECG will be performed locally. Participants should rest in a supine position for at least 5 minutes before ECG recording and should refrain from talking
or moving arms or legs.
h. 
Chest x-ray posterior/anterior and lateral views must be taken within 3 months prior to the first administration of study intervention for TB detection. If x-ray is not
feasible, Chest CT can be substituted for x-ray.
i. 
TB evaluation includes an assessment of recent exposure or risk of TB including new or chronic cough, fever, night sweats, unintentional weight loss or recent
contact with someone with active TB. If TB is suspected at any time during the study, a chest x-ray, chest HRCT, and T-SPOT.TB test or QFT should be
performed.
j. 
In addition to the urine screening evaluation, a serum pregnancy test may be conducted at any time at the discretion of Investigator or participant. Urine pregnancy
tests may be conducted more frequently (eg, monthly basis). Urine pregnancy tests may not be necessary if a participant is considered a postmenopausal state
defined as no menses for 12 months without an alternative medical cause and a high FSH level (>40 IU/L or mIU/mL) during the study.
k. 
Participants should be monitored for the occurrence of infusion reactions for at least 1 hour after IV infusion and injection-site reactions for at least 30 minutes
following SC injection.
l. 
See Section 6.8 for information on oral GC tapering.
m. The pharmacogenomic (DNA) sample should be collected at the specified time point; however, if necessary, it may be collected at a later time point without
constituting a protocol deviation.
n. 
After Week 24, participants will visit the study site every 4 weeks until they develop relapse or end of DB period, whichever is earlier. For Non-dosing Visit,
participants will visit the study site every 8 weeks from Week 28. For Dosing Visit, participants will visit the study site every 8 weeks for study intervention
administration from Week 32.
o. 
Relapse Confirmation Visit is the second relapse assessment visit after participants meet the relapse criteria once at scheduled visit or unscheduled visit (This visit
will be defined as “1st relapse visit”). At Relapse Confirmation Visit, TAK Disease Assessment S&S and CRP/ESR must be performed and the other items are not
needed to perform if they already performed at “1st relapse visit”. If participants are judged as relapse at “1st relapse visit” only, all the assessments at Relapse
Confirmation Visit should be performed.
For PK assessment, PK samples will be collected at 1st relapse visit defined above.
p. 
Participants, who permanently discontinue study intervention administrations before the end of DB period or their relapse, must undergo procedures for early
termination and return approximately 16 weeks after last study intervention administration to undergo procedures for safety F/U visits.
q. 
At Week 0, 2 separate samples for serum ustekinumab concentrations (indicated by “2X” in the Schedule above) will be collected (1 sample will be collected prior
to IV infusion and the other collected 1 hour after the end of the infusion) for all participants.
NOTE
* Participants who do not experience relapse at the end of DB period will enter OLE period at the participants’ next dosing visit regarded as Week OL-0.
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CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date:  15 August 2022
assessment will not be performed and the prior results will be used for this scheduled assessment. At Relapse Confirmation Visit, imaging assessment will be
performed within 4 weeks after the investigator confirms participant meets the relapse criteria.
c. 
All PRO assessments should be conducted in the order listed in the above Schedule of Activities table. Whenever possible, PRO assessments should be conducted
before any tests, procedures, or other consultations for that visit to prevent influencing participants’ perceptions.
d. 
A 12-lead ECG will be performed locally. Participants should rest in a supine position for at least 5 minutes before ECG recording and should refrain from talking
or moving arms or legs.
e. 
TB evaluation includes an assessment of recent exposure or risk of TB including new or chronic cough, fever, night sweats, unintentional weight loss or recent
contact with someone with active TB. If TB is suspected at any time during the study, a chest x-ray, chest HRCT, and T-SPOT.TB test or QFT should be
performed.
f. 
In addition to the urine screening evaluation, a serum pregnancy test may be conducted at any time at the discretion of Investigator or participant. Urine pregnancy
tests may be conducted more frequently (eg, monthly basis). Urine pregnancy tests may not be necessary if a participant is considered a postmenopausal state
defined as no menses for 12 months without an alternative medical cause and a high FSH level (>40 IU/L or mIU/mL) during the study.
g. 
Participants should be monitored for the occurrence of infusion reactions for at least 1 hour after IV infusion and injection-site reactions for at least 30 minutes
following SC injection.
h. 
See Section 6.8 for information on oral GC tapering.
i. 
Week OL-0 is the participant’s next dosing visit from  Relapse Confirmation Visit or the end of DB period.
j. 
Relapse Confirmation Visit is the second relapse assessment visit after participants meet the relapse criteria once at scheduled visit or unscheduled visit (This visit
will be defined as “1st relapse visit”). At Relapse Confirmation Visit, TAK Disease Assessment S&S and CRP/ESR must be performed and the other items are not
needed to perform if they already performed at “1st relapse visit”. If participants are judged as relapse at “1st relapse visit” only, all the assessments at Relapse
Confirmation Visit should be performed.
For PK assessment, PK samples will be collected at 1st relapse visit defined above.
k. 
Participants, who permanently discontinue study intervention administrations before Week OL-52, must undergo procedures for early termination and return
approximately 16 weeks after last study intervention administration to undergo procedures for safety F/U visits.
l. 
OLE period continues through Week OL-52 or until 32 weeks from the first SC administration after the end of DB period , whichever is later. If participants
complete Week OL-52 visit earlier than 32 weeks from the first SC administration after the end of DB period, they will be continuing to visit the study site every 8
weeks from Week OL-56 until the end of OLE period.
m. Participants who are in escape arm will receive IV ustekinumab. Participants who are rolled over from DB period will receive SC ustekinumab.
n. 
At early-termination visit, GC tapering is not needed.
o. 
At Week OL-0, 2 separate samples for serum ustekinumab concentrations (indicated by “2X” in the Schedule above) will be collected (1 sample will be collected
prior to IV infusion and the other collected 1 hour after the end of the infusion) for all participants. For participants who receive SC administration at Week OL-0,
a single blood sample at predose will be collected.
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CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
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Status: Approved,  Date:  15 August 2022
2. 
INTRODUCTION
STELARA® (ustekinumab) is a fully human immunoglobulin G1 kappa monoclonal antibody
which binds with high affinity to the p40 subunit common to both interleukin (IL)-12 and IL-23.
The mechanism of action of ustekinumab is prevention of IL-12/23p40 binding to the IL-12R1
cell surface receptor shared by both cytokines. Through this mechanism of action, ustekinumab
effectively neutralizes IL-12 T helper (Th)1- and IL-23 Th17-mediated cellular responses.
Ustekinumab (subcutaneous [SC] formulation) has been approved globally for the treatment of
psoriasis in adults and pediatric and for psoriatic arthritis (PsA) in adults. Ustekinumab has also
been approved for the treatment of Crohn’s disease (CD) and ulcerative colitis (UC) in adults using
intravenous (IV) induction dosing followed by SC maintenance dosing.
Takayasu arteritis is a rare, chronic large vessel vasculitis that affects the aorta and its primary
branches, coronary arteries, and pulmonary arteries. Its principal manifestations are systemic
inflammation, pain due to vasculitis, vascular stenosis, occlusion, dilatation, and poses problems
including disorders of various organs due to disturbance of the blood flow and aneurysms even
after remission of inflammation. The symptoms are not only diverse but also often non-specific
and many cases are still considered to be left undiagnosed. Frequently observed symptoms include
signs of ischemia of the upper limbs such as a difference in blood pressure between the left and
right arms and the absence of pulses in the upper limb, fever, malaise, neck pain, pain in various
regions, and dizziness. In refractory cases, vascular remodeling progresses and leads to serious
outcomes. Complications vary widely including those caused by stenotic lesions and dilated
lesions such as aortic insufficiency, aortic aneurysm, aortic dissection, ischemic attacks of the
brain, pulmonary infarction, angina pectoris, subclavian steal syndrome, atypical coarctation of
the aorta, and renovascular hypertension and tend to occur in large numbers.
Takayasu arteritis is considered to be caused by destruction of elastic arteries, particularly aorta,
by autoimmune mechanisms triggered by environmental factors including infection based on
genetic factors. Human leucocyte antigen (HLA)-B52 has been reported to be related to the
pathogenesis of this disease (Isohisa 1978; Kimura 1996). In addition, one genome-wide
association study identified a locus near the IL-12B gene (lead variant rs6871626) was
significantly associated with disease susceptibility for TAK (Terao 2013). This lead variant is
within a poorly characterized long non-coding ribonucleic acid (RNA) gene (69 KB) close to the
IL-12B gene. No functional data is available to link this single nucleotide polymorphisms (SNP)
directly to IL-12B; however, the same lead SNP has been reported to be associated with
inflammatory bowel disease (IBD), UC, and ankylosing spondylitis. Thus, although the role of the
IL-12/23 pathway in TAK pathophysiology has been suggested, more data is needed to understand
the link between the genetic signal and the IL-12B gene.
Additionally, inflammatory cells, particularly Th17 and Th1 cells and cytokines, including IL-6
(Alibaz 2015; Park 2006), IL-8 (Alibaz 2015), IL-12 (Verma 2005), IL-18 (Alibaz 2015;
Park 2006), IL-23 (Misra 2016), and tumor necrosis factor (TNF)-α (Park 2006) are elevated in
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patients with TAK (Alibaz 2015; Verma 2005; Misra 2016). Furthermore, IL-6, IL-12, IL-17, and
interferon (IFN)-γ are highly expressed in the aortic tissues in patients with TAK (Kong 2016).
There are strong associations between TAK and IBD. Several case series reported that TAK
patients also have IBD, and frequency of IBD in TAK patients was reported to be between 6.3%
and 9.3% (Kilic 2016). This co-existence of these 2 diseases cannot be accepted as incidental
considering prevalence of these 2 diseases. In addition, 1 literature review identified 144 patients
with large vessel vasculitis and IBD, of which 133 patients were with TAK and IBD (Sy 2016).
TAK and IBD have many common characteristics, including the age of onset, female
predominance, granulomatous inflammation, and benefit from anti-TNF treatment. HLA-B52,
HLA-DR2, and IL-12B were suggested to be the genetic determinants for both UC and TAK
(Morita 1996; Terao 2015). Furthermore, recently autoantibodies specific to TAK have been
identified among autoimmune rheumatic diseases (autoantibodies against endothelial protein C
receptor [EPCR] and scavenger receptor class B type 1 [SR-B1]), and each accounted for one-third
of the patients with TAK. Surprisingly, 68.6% of 35 primary UC patients had anti-EPCR
autoantibodies, suggesting common pathophysiology among TAK and UC (Mutoh 2020).
IL-12/23 inhibition has been shown to be effective in UC and CD thus supporting a potential case
for its investigation in TAK.
TAK is prevalent in Asia and Middle East and females tend to be more often affected in both
regions.
In Japan, approximately 4,433 patients with this disease have been registered (Japan Intractable
Disease Information Center). The male/female ratio is about 1:9 and the age of onset in women
peaks around 20 years.
Glucocorticoids are used empirically as the first-line treatment to induce remission in TAK,
however, due to the known increased risk with long term use of GC (eg, cataracts, osteoporosis,
infection, adrenal insufficiency) forces to taper GC dose to at least physiological level (7.5 mg/day
[prednisolone or equivalent]) with maintaining remission.
It is reported that supraphysiological doses of GC (above 7.5 mg/day [prednisolone or equivalent])
increases the 10-year risk of some complications (Dora 2013). High relapse rate has been reported
during GC taper in TAK. Immunosuppressants such as methotrexate, azathioprine (AZA),
tacrolimus (TAC), cyclosporine A, and mycophenolate mofetil has been used as a concomitant
therapy to enhance or spare GC effects in TAK, but evidence of their GC sparing effects is limited.
To date, tocilizumab (TCZ) has been the only approved biologic agent demonstrating a trend of
its GC sparing effects in patients with TAK in Japan while attempting GC taper. However,
treatment with TCZ is still insufficient as a GC sparing agent in TAK since 49.4% of the subjects
relapsed at Week 24 during GC taper in the TAKT trial (Nakaoka 2018). A combination therapy
of GC and TCZ notably increased the risk of infections, which requires careful attention to
potential infections during TCZ treatment in TAK (Common Technical Document Module 2). In
addition, bowel perforation, laboratory abnormalities in liver function, lipids, and other parameters
are often associated with TCZ treatments, which would limit a wide usage of TCZ in TAK
management. Furthermore, IL-6 receptor blockade with TCZ abrogates the hepatic synthesis of
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acute-phase reactants and renders C-reactive protein (CRP) and erythrocyte sedimentation rate
(ESR) measurement unreliable for the purpose of monitoring disease activity in TAK. Considering
that TAK often affects relatively younger women, less frequent dosing would be preferred to the
currently approved weekly SC administration with TCZ in terms of convenience as well as work
productivity.
Taken together, significant unmet medical needs still exist for the development of new treatment
options for TAK that provide higher GC sparing effect with favorable safety profiles.
There have been several reports that ustekinumab was investigated in TAK. Small case series
suggested a potential therapeutic effect of ustekinumab: 1 pilot study in 3 Japanese patients with
refractory TAK showed all patients responded to ustekinumab 45 mg SC administered at Days 0
and 28, of which 2 patients with elevated acute-phase reactants at baseline showed significantly
decreased levels of CRP and ESR, and the other patients with symptomatic burdens showed
considerable symptomatic relief. Despite the response to ustekinumab, vascular imaging
performed on Day 84 did not observe any change in vascular wall enhancement (Terao 2016); a
Caucasian patient with GC-, immunosuppressant-, and biologics-resistant TAK was successfully
treated with ustekinumab 90 mg SC administered at Weeks 1 and 4. Three months later, her
symptoms resolved and acute-phase reactants normalized. Her daily GC requirements were
significantly reduced and a repeat CT angiogram showed full resolution of wall thickening and
re-establishment of the normal smooth contours of the aorta (Yachoui 2018).
In summary, several lines of evidence suggest pathogenic association between IL-12/23 and
clinical manifestation of TAK, although data demonstrating causal role of IL-12/23 pathway in
disease pathogenesis are still lacking. Given the totality of available scientific evidence and
favorable safety and efficacy profile established in other indications, ustekinumab has the potential
to offer patients with relapsing TAK a safe and effective steroid sparing therapy.
For the most comprehensive nonclinical and clinical information regarding ustekinumab, refer to
the latest version of the Investigator's Brochure (IB) (IB Ustekinumab 2020) and Addenda for
ustekinumab.
The term “study intervention” throughout the protocol, refers to treatment with active drug or
placebo.
The term "sponsor" used throughout this document refers to the entities listed in the Contact
Protocol Supplementary Information, which will be provided as a separate document.
The term "participant" throughout the protocol refers to the common term "subject".
2.1. 
Study Rationale
This is double-blind, placebo-controlled, multicenter trial, designed to evaluate GC sparing effect
of ustekinumab in participants with TAK. Participants must have experienced TAK relapse within
12 weeks prior to administration of study intervention and the relapse must have occurred at a dose
of at least 7.5 mg/day (prednisolone or equivalent). The relapse must have been adequately treated
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with ≥15 mg/day of prednisone or equivalent and participants must subsequently have achieved
remission 1 week prior to the first administration of study intervention to ensure that GC sparing
effects of ustekinumab can be reliably investigated.
Time to TAK relapse is selected as the primary endpoint because this is a sensitive parameter to
distinguish GC sparing effects between ustekinumab and placebo while attempting GC taper. The
DB phase will complete once a total of 35 TAK relapses occur allowing relatively faster study
conclusion while securing sufficient statistical power. Participants who experience TAK relapse
will be rescued with increased GC and be rolled over to the escape arm to receive ustekinumab.
Participants who do not experience TAK relapse at the end of DB period, except for participants
who reach GC dose of 5 mg/day or less in the placebo group at which 35 relapse events occur, will
be rolled over to the OLE period and receive ustekinumab at least 52 weeks in order to investigate
long-term safety and efficacy of ustekinumab in TAK participants.
2.2. 
Background
Human Pharmacokinetics and Immunogenicity
The pharmacokinetic (PK) of ustekinumab has been evaluated in healthy participants and in
Phase 1, Phase 2, and Phase 3 studies that included adult participants with psoriasis, PsA, multiple
sclerosis, CD, UC, primary biliary cirrhosis, sarcoidosis, and rheumatoid arthritis. The PK of
ustekinumab has also been evaluated in Asian studies (Japanese, Chinese, Korean, and Taiwanese)
with psoriasis and Japanese participants with atopic dermatitis. In addition, the PK of ustekinumab
has been evaluated in a Phase 3 study in pediatric participants (≥6 to <18 years of age) with
moderate to severe plaque psoriasis.
The PK of ustekinumab was generally comparable across different disease indications when
consideration was given to differences in participant body weight.
Immunogenicity data from the completed studies show a generally low incidence of antibodies to
ustekinumab. In most of these studies, the majority of participants who were positive for antibodies
had neutralizing antibodies, however, the presence of antibodies did not preclude clinical response.
Participants who were positive for antibodies to ustekinumab generally had lower serum
concentrations of ustekinumab than those participants who were negative for antibodies to
ustekinumab.
Efficacy/Safety Studies
The efficacy of ustekinumab has been evaluated for psoriasis, PsA, CD, and UC. Most of these
studies showed superiority over placebo in achieving primary endpoints.
In all the studies conducted so far, the safety was comparable across ustekinumab and placebo.
For the most comprehensive nonclinical and clinical information regarding ustekinumab, refer to
the latest version of the IB for ustekinumab.
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2.3. 
Benefit-risk Assessment
More detailed information about the known and expected benefits and risks of ustekinumab may
be found in the IB.
2.3.1. 
Risks for Study Participation
Potential Risks of Clinical 
Significance 
Summary of Data/
Rationale for Risk 
Mitigation Strategy
Risks Due to Study Intervention (Ustekinumab)
Serious infections  
Ustekinumab is a selective 
immunosuppressant and may have 
the potential to increase the risk of 
infections and reactivate latent 
infections. 
 Participants with a history of,
or ongoing, chronic, or
recurrent infectious disease,
including HIV, HBV, or HCV
will be excluded from the
study. Similarly, participants
with evidence of active or
untreated latent TB will be
excluded from the study
(Section 5.2).
 Throughout the protocol,
participants will be monitored
for signs and symptoms of
infection, including, but not
limited to, TB, sepsis, and
pneumonia.
 Live viral or live bacterial
vaccinations will be restricted
during the study as described
in Section 5.2.
Hypersensitivity reactions, 
including serious 
hypersensitivity reactions 
Serious hypersensitivity reactions, 
including anaphylaxis and 
angioedema have been reported in 
post-marketing experience with 
ustekinumab.  
 Participants with known
allergy, hypersensitivity, or
intolerance to ustekinumab or
its excipients will be excluded
from the study. Any participant
who develops a serious
hypersensitivity reaction such
as anaphylaxis must
discontinue study intervention
(Section 7.1).
 For injections that occur at the
site, appropriately trained
personnel and medications
must be available to treat
hypersensitivity reactions,
including anaphylaxis.
Malignancy 
Ustekinumab is a selective 
immunosuppressant. 
Immunosuppressive agents have 
 Participants who have the
presence or history of any
malignancy including
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Potential Risks of Clinical 
Significance 
Summary of Data/
Rationale for Risk 
Mitigation Strategy
the potential to increase the risk of 
malignancy. Some participants 
who received ustekinumab in 
clinical studies developed 
cutaneous and non-cutaneous 
malignancies 
lymphoproliferative disease
including lymphoma, or signs
and symptoms suggestive of
possible lymphoproliferative
disease, such as
lymphadenopathy of unusual
size or location, and
monoclonal gammopathy of
undetermined significance, or
clinically significant
hepatomegaly or splenomegaly
will be excluded from the
study (Section 5.2).
 Participants who develop a
malignancy during the study
(with the exception of
≤2 localized basal cell skin
cancers that are treated with no
evidence of recurrence or
residual disease) will be
discontinued from study
intervention (Section 7.1).
Abbreviations: HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency syndrome;
PK=pharmacokinetic; TB=tuberculosis.
2.3.2. 
Benefits for Study Participation
Clinical data of ustekinumab supports the notion that it will provide clinical benefits to TAK
participants with manageable safety profile.
More detailed information about the known and expected benefits and risks of ustekinumab may
be found in the IB.
3. 
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary 
 To evaluate the efficacy of ustekinumab compared to
placebo, in combination with oral GC taper regimen, in
participants with relapsing TAK
 Time to relapse of TAK according to
protocol-defined criteria through the
end of DB period
Secondary
 To evaluate the safety of ustekinumab in combination
with oral GC taper regimen, in participants with
relapsing TAK
 Number/proportion of participants
with TEAEs through the end of study
 Number/proportion of participants
with TEAEs by system organ class
with a frequency threshold of 5% or
more through the end of study
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Objectives 
Endpoints
 Number/proportion of participants
with treatment-emergent SAEs
through the end of study
 To evaluate the efficacy of ustekinumab compared to
placebo, in combination with oral GC taper regimen, in
participants with relapsing TAK as measured by
alternative definitions of relapse criteria, relapse rate,
GC sparing effects, and disease activity
 Time to relapse of TAK according to
Kerr’s definition through the end of
DB period
 Time to relapse of TAK based on
clinical symptoms only through the
end of DB period
 Time to relapse of TAK in each of the
5 categories through the end of DB
period
 Relapse rate in each of the
5 categories through the end of DB
period
 Cumulative oral GC dose
(prednisolone or equivalent) through
the end of DB period
 Change from baseline in oral GC dose
(prednisolone or equivalent) through
the end of DB period
 Number/proportion of participants
achieving GC dose of 5 mg/day or
less through the end of DB period
 Change from baseline in imaging
evaluation through the end of DB
period
 Change from baseline in
inflammatory markers (CRP, ESR)
through the end of DB period
 To evaluate the PK and immunogenicity of
ustekinumab in combination with oral GC taper
regimen, in participants with relapsing TAK
 Serum concentrations of ustekinumab
in participants receiving ustekinumab
through the end of study
 Number/proportion of participants
who are positive for anti-ustekinumab
antibodies in participants receiving
ustekinumab through the end of study
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Objectives 
Endpoints
Exploratory
 To explore changes in the PRO instruments and the 
physician reported outcome 
 Changes from baseline on PROs
through the end of study
 SF-36
 PtGA of disease activity on VAS
 FACIT-Fatigue
 Change from baseline on physician
reported outcome: PhGA through the
end of study
 To explore the efficacy of ustekinumab in combination  
with oral GC taper regimen, in participants with  
relapsing TAK during OLE period 
 Number/proportion of participants
who experience relapse of TAK
according to protocol-defined criteria
during OLE period
 Number/proportion of participants
who experience relapse of TAK
according to Kerr’s definition during
OLE period
 Number/proportion of participants
who experience relapse of TAK based
on clinical symptoms only during
OLE period
 Number/proportion of participants
who experience relapse of TAK in
each of the 5 categories during OLE
period
 Cumulative oral GC dose
(prednisolone or equivalent) during
OLE period
 Change from baseline in oral GC dose
(prednisolone or equivalent) during
OLE period
 Number/proportion of participants
achieving GC dose of 5 mg/day or
less during OLE period
 Change from baseline in imaging
evaluation during OLE period
 Change from baseline in
inflammatory markers (CRP, ESR)
during OLE period
Abbreviations: CRP=C-reactive protein; DB=double-blind; ESR=erythrocyte sedimentation rate;
FACIT=Functional Assessment of Chronic Illness Therapy; GC=glucocorticoid; OLE=open-label extension;
PK=pharmacokinetic; PRO=patient reported outcome; PhGA= Physician’s Global Assessment of Disease
Activity; PtGA=Patient’s global assessment; TAK=Takayasu arteritis; SAE=serious adverse event;
SF-36=short-form-36; TEAE=treatment-emergent adverse event; VAS=visual analog scale.
Refer to Section 8, STUDY ASSESSMENTS AND PROCEDURES for evaluations related to endpoints.
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HYPOTHESIS
Efficacy:
The clinical cure rate with ustekinumab is superior to a regimen of placebo for participants with
relapsing TAK with effective steroid sparing property.
The primary hypothesis of this study is that ustekinumab took more time to relapse of TAK
according to protocol-defined criteria through the end of DB period.
Safety:
The safety of intervention with ustekinumab is similar to a regimen of placebo in TAK participants.
Benefit-risk:
The ustekinumab is safe and tolerated for participants with relapsing TAK with effective steroid
sparing property.
4. 
STUDY DESIGN
4.1. 
Overall Design
This is a Phase 3, randomized, double-blind, placebo-controlled, parallel, multicenter,
interventional study in participants ≥15 years and ≤75 years of age with TAK to evaluate the
efficacy, safety, PK, and immunogenicity of IV and SC ustekinumab.
Participants must have experienced TAK relapse within 12 weeks prior to administration of study
intervention and the relapse must have occurred at oral GC dose of at least 7.5 mg/day
(prednisolone or equivalent).
A target of approximately 50 participants will be randomized at Week 0 in a blind fashion to 1:1
ratio stratified by oral GC dose at Week 0 (<0.5 mg/kg/day, ≥0.5 mg/kg/day of prednisolone or
equivalent) and status of previous biologic medication (bio-nonfailure or bio-failure) to receive
either ustekinumab or matching placebo with the following treatment regimens during the DB
period until participants develop relapse or a total of 35 relapse events have occurred.
Ustekinumab group: Body weight-range based IV administration of ustekinumab (~6 mg/kg) at
Week 0 followed by ustekinumab 90 mg SC administered 8 weeks after the initial IV dose, then
every 8 weeks (q8w) thereafter.
Placebo group: IV administration of placebo at Week 0 followed by placebo SC administered
8 weeks after the initial IV dose, then q8w thereafter.
Before randomization, participants must have experienced TAK relapse within 12 weeks prior to
administration of study intervention and the relapse must have occurred at oral GC dose of at least
7.5 mg/day (prednisolone or equivalent). The relapse must have been adequately treated with
≥15 mg/day of prednisone or equivalent and participants must subsequently have achieved
remission at least 1 week prior to the first administration of study intervention.
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During the DB period, participants will receive IV administration of study intervention followed
by SC administration of study intervention, with starting the protocol defined oral GC taper
regimen from Week 2 visit (baseline oral GC dose will be stable until Week 2). Participants who
develop relapse will receive rescue medication of oral GC that is at least doubling the oral GC
dose at the relapse. These participants will be assessed whether they achieve remission at the next
scheduled administration visit from the relapse (Week OL-0) to enter OLE phase as the Escape
arm regardless of remission status, and then receive IV administration of ustekinumab at Week
OL-0 followed by ustekinumab 90 mg SC administered 8 weeks after the initial IV dose, then q8w
thereafter. Escape arm is identical to OLE period except participants in Escape arm will receive
IV ustekinumab at Week OL-0 instead of SC ustekinumab. Participants in Escape arm may receive
continuous administrations of IV ustekinumab with 8-week interval once in the study if they
relapse prior to Week 8.
When a total of 35 relapse events occur, the DB period will end and rest of the participants in the
DB period will enter OLE period except for participants who reach oral GC dose of 5 mg/day
(prednisolone or equivalent) or less in the placebo group to avoid unnecessary administration of
ustekinumab for those who are considered to be placebo responders. These participants will
continue or switch (if participants receive placebo in DB period) to receive SC ustekinumab
administered q8w with maintaining the originally dosing schedule. For these participants, the first
dosing visit from the end of DB period will be regarded as Week OL-0. In transition period from
the end of DB period to completion of the DBL, participants who reach to oral GC 5 mg/day
(prednisolone or equivalent) or less at the end of DB period will continue to receive study
intervention assigned in DB period until completion of the DBL for DB period in order to maintain
the blind. Participants assigned to the placebo group who reach oral GC dose of 5 mg/day
(prednisolone or equivalent) or less at the end of DB period will terminate the study intervention
administration and conduct early-term visit after completion of the DBL for DB period.
When 35 events occur, further recruitment will end.
During OLE period, participants will receive SC administration of ustekinumab at Week OL-0,
and followed by SC administration of ustekinumab with oral GC taper at investigator’s discretion
for 52 weeks (Week OL-52) or until 32 weeks from the first SC administration after the end of DB
period, whichever is later. Safety follow-up visit will be conducted 16 weeks after last SC
ustekinumab administration.
A long-term extension (LTE) study to evaluate further long-term effects of ustekinumab may be
conducted if the sponsor deems that ustekinumab treatment is beneficial to study participants based
on results of the primary analysis. Participants who complete their participation in OLE period
may be eligible to enter the LTE and continue to receive 90 mg SC ustekinumab q8w. Details will
be provided in a separate LTE protocol or amendment of this protocol.
The efficacy interim analysis is planned to determine early success when relapse of TAK occurs
in 15 events.
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The primary efficacy analysis will be performed when relapse of TAK occurs in 35 events with
additional secondary endpoints to be analyzed.
A first DBL will occur after a total of 15 events in relapse of TAK occurred for an interim analysis.
A second DBL will occur after a total of 35 events in relapse of TAK occurred. A third DBL will
occur approximately 24 weeks after the second DBL. A fourth DBL will occur when all
participants have either completed their final study visit or terminated study participation prior to
their final visit. Additional DBLs other than the ones specified above may be performed.
Investigative study sites and participants will remain blinded to initial treatment assignment until
the end of the study, except the assignment for participants who reach oral GC dose of 5 mg/day
(prednisolone or equivalent) or less when a total of 35 relapse events occur will be revealed after
the second DBL. Identification of sponsor personnel who will have access to the unblinded
participant data will be documented prior to unblinding to the sponsor.
An external, independent data monitoring committee (IDMC) will be commissioned for this study
to ensure the continuous safety and well-being of the participants enrolled in this study. Refer to
Committees Structure in Section 10.8, Appendix 8: Regulatory, Ethical, and Study Oversight
Considerations for details.
An interim analysis will be implemented to evaluate early efficacy after 15 relapse events occurred.
This efficacy analysis is unblinding and IDMC recommend the continuation or early termination
of the DB period based on the results of interim analysis. The sponsor will decide the continuation
and termination of DB period based on the recommendation by IDMC. If the sponsor decides early
termination of DB period, all participants will be rolled over to the OLE period except for
participants assigned to the placebo group who reach oral GC dose of 5 mg/day (prednisolone or
equivalent) or less at the end of DB period. In transition period, follow the same process as 35
relapse events occurrence. The sponsor continues to enroll participants into OLE period until
reaching a total of approximately 50 participants. Participants who are eligible according to
Inclusion/Exclusion criteria in this protocol will directly enter to OLE period to receive body
weight-range based IV administration of ustekinumab (~6 mg/kg) at Week OL-0 and followed by
ustekinumab 90 mg SC q8w with GC taper of investigator’s discretion for 52 weeks (Week OL-
52). Safety follow-up visit will be conducted 16 weeks after last SC ustekinumab administration.
A diagram of the study design is provided in Section 1.2, Schema.
4.2. 
Scientific Rationale for Study Design
Blinding, Control, Study Phase/Periods, Intervention 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 intervention. Randomization will be used to
minimize bias in the assignment of participants to intervention sequence groups, to increase the
likelihood that known and unknown participant attributes (eg, demographic and baseline
characteristics) are evenly balanced across intervention sequence groups, and to enhance the
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validity of statistical comparisons across intervention groups. Blinded intervention will be used to
reduce potential bias during data collection and evaluation of clinical endpoints.
DNA and Biomarker Collection
Optional pharmacogenomic samples may be obtained from participants only when specific consent
is provided by signing the optional genetic research informed consent form /assent form (ICF). It
is recognized that genetic variation can be an important contributory factor to interindividual
differences in intervention distribution and response and can also serve as a marker for disease
susceptibility and prognosis. Pharmacogenomic research may help to explain interindividual
variability in clinical outcomes and may help to identify population subgroups that respond
differently to an intervention. The goal of the pharmacogenomic component is to collect
deoxyribonucleic acid (DNA) to allow the identification of genetic factors that may influence the
PK, pharmacodynamics (PD), efficacy, safety, or tolerability of ustekinumab and to identify
genetic factors associated with TAK.
Biomarker samples will be collected to evaluate the mechanism of action of ustekinumab or help
to explain interindividual variability in clinical outcomes or may help to identify population
subgroups that respond differently to an intervention. The goal of the biomarker analyses is to
evaluate the PD of ustekinumab and aid in evaluating the intervention-clinical response
relationship.
DNA and biomarker samples may be used to help address emerging issues and to enable the
development of safer, more effective, and ultimately individualized therapies.
4.2.1. 
Study-specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study and, during
the study, participants 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 participants who are fully able to understand the risks, benefits,
and potential adverse events (AEs) of the study and provide their consent voluntarily will be enrolled.
When referring to the signing of the ICF, the terms legal guardian and legally acceptable
representative refer to the legally appointed guardian of the child with authority to authorize
participation in research. For each participant, his or her parent(s) (preferably both parents, if
available) or legally acceptable representative(s), as required by local regulations, must give written
consent (permission) according to local requirements after the nature of the study has been fully
explained and before the performance of any study-related assessments. Assent must be obtained
from children (minors) capable of understanding the nature of the study, typically participants 7
years of age and older, depending on the institutional policies. For the purposes of this study, all
references to participants who have provided consent (and assent as applicable) refers to the
participants and his or her parent(s) or the participant's legal guardian(s) or legally acceptable
representative(s) who have provided consent according to this process. Minors who assent to a study
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Status: Approved,  Date:  15 August 2022
and later withdraw that assent must not be maintained in the study against their will, even if their
parent(s) still want them to participate.
The total blood volume to be collected is considered to be an acceptable amount of blood to be
collected over this time period from the population in this study based upon the standard of the
Japanese Red Cross blood donation.
4.3. 
Justification for Dose
The proposed dose regimen is a body weight-range based IV administration of ustekinumab
(~6 mg/kg) at Week 0 followed by ustekinumab 90 mg SC administered 8 weeks after the initial
IV dose, then q8w thereafter.
The ustekinumab dose regimen for this Phase 3 study was selected based on the approved posology
in IBD (CD and UC) in which strong association with TAK is suggested and the investigating
posology in polymyositis (PM) and dermatomyositis (DM), which can maximize efficacy of
ustekinumab possible for treatment of TAK.
The proposed choice of IV administration of ustekinumab at Week 0 followed by ustekinumab SC
administered q8w follows the approved dose regimen in inflammatory diseases with target tissue
that is more difficult to penetrate (eg, CD). The proposed dose regimen is the highest approved
dose with substantial safety and tolerability data available. Evaluating this dose regimen optimizes
probability of demonstrating efficacy with an acceptable safety profile. As TAK causes irreversible
fibrosis of vascular intima and adventitia due to inflammation of aorta and potentially results in
serious complications observed in organs other than large blood vessel, it is important that
ustekinumab treatment should rapidly and sufficiently suppress inflammation in large blood vessel
to prevent relapse and consequent serious complications.
The proposed dose regimen has been studied in IBD patients with an established favorable safety
profile and is being further investigated in ongoing clinical trials with PM/DM.
Given the favorable safety and efficacy profile of ustekinumab established in other indications and
several lines of evidence suggesting pathogenic association between IL-12/23 and clinical
manifestation of TAK and reported genetic and clinical links between TAK and IBD, ustekinumab
has the potential to offer participants with relapsing TAK a safe and effective steroid sparing
therapy with a single IV induction dose followed by maintenance SC dosing.
4.4. 
End of Study Definition
End of Study Definition
The end of study is considered as the last safety follow-up assessment visit shown in the Schedule
of Activities (Section 1.3) for the last participant in the study. The final data from the study site
will be sent to the sponsor (or designee) after completion of the final participant safety follow-up
assessment visit at that study site, in the time frame specified in the clinical trial agreement.
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Status: Approved,  Date:  15 August 2022
Study Completion Definition
A participant will be considered to have completed the study if he or she has completed
assessments at Week 16 of the safety follow-up phase.
Participants who prematurely discontinue study intervention for any reason before completion of
the DB phase will not be considered to have completed the study.
5. 
STUDY POPULATION
Screening for eligible participants will be performed within 42 days before administration of the
study intervention. Refer to Section 5.4, Screen Failures for conditions under which the repeat of
any screening procedures is allowed.
The inclusion and exclusion criteria for enrolling participants in this study are described below. If
there is a question about these criteria, the investigator must consult with the appropriate sponsor
representative and resolve any issues before enrolling a participant in the study. Waivers are not
allowed.
For a discussion of the statistical considerations of participant selection, refer to Section 9.2,
Sample Size Determination.
5.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
Age
1. 
Criterion modified per Amendment 2:
1.1 15 to 75 years of age, inclusive, (at the time of the first administration of study
intervention at Week 0). If participant’s disease onset of TAK is over 50 years old,
appropriate evaluations should be made to distinguish from giant cell arteritis
(GCA).
Type of Participant and Disease Characteristic
2. 
Must be medically stable on the basis of physical examination, medical history, vital
signs, and 12-lead ECG performed at screening. Any abnormalities, must be consistent
with the underlying illness in the study population and this determination must be
recorded in the participant's source documents and initialed by the investigator.
3. 
Must be medically stable on the basis of clinical laboratory tests performed at screening.
If the results of the serum chemistry panel including liver enzymes, other specific tests,
blood coagulation, hematology, or urinalysis are outside the normal reference ranges,
the participant may be included only if the investigator judges the abnormalities or
deviations from normal to be not clinically significant or to be appropriate and
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Status: Approved,  Date:  15 August 2022
reasonable for the population under study. This determination must be recorded in the
participant's source documents and initialed by the investigator.
4. 
Must have a diagnosis of TAK made or confirmed by a physician (such as a
rheumatologist or cardiovascular specialist) experienced in treatment of TAK.
5. 
Must have a documented medical history that participant met the diagnostic criteria of
definite TAK according to JCS 2017 Guidelines on Management of Vasculitis
Syndrome (Section 10.2, Appendix 2: Diagnostic criteria for Takayasu arteritis
according to JCS 2017 guideline on management of vasculitis syndrome) before
signature on an ICF.
6. 
Must have developed a relapse of TAK within 12 weeks prior to administration of study
intervention and the relapse must have occurred at a dose of at least 7.5 mg/day
(prednisolone or equivalent).
7. 
Must have achieved remission* with an oral GC treatment at least 1 week prior to the
first administration of study intervention and maintain remission of clinical
symptoms** at the first administration of study intervention.
*Remission is defined as assessment of ‘absence of any of the signs and symptoms’ as
judged by the investigator for 5 following categories: objective systemic symptoms;
subjective systemic symptoms; elevated inflammation markers; vascular signs and
symptoms; ischemic symptoms (Section 10.3, Appendix 3: Definitions of
relapse/remission of TAK).
**Remission of clinical symptoms is defined as assessment of ‘absence of any of the
signs and symptoms’ as judged by the investigator for 4 following categories: objective
systemic symptoms; subjective systemic symptoms; vascular signs and symptoms;
ischemic symptoms (Section 10.3, Appendix 3: Definitions of relapse/remission of
TAK).
Allowed concomitant or previous medical therapies for TAK
8. 
Must be receiving oral GC treatment of ≥15 mg/day (prednisolone or equivalent),
inclusive for the treatment of relapsing TAK and be on a stable dose for at least 2 weeks
prior to the first administration of study intervention.
9. 
Criterion modified per Amendment 1
9.1  If receiving an oral anti-platelet therapy (including but not limited to aspirin,
clopidogrel, ticlopidine) or anti-coagulation therapy (including but not limited to
warfarin) for treatment of TAK, the dose must have been stable for at least 2 weeks
prior to first administration of the study intervention. In terms of warfarin, the dose
should be controlled 1-5mg/day to maintain PT-INR target range between 2.0-3.0
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(if participants are over 70 years old, PT-INR target range should be between 1.6-
2.6).
10. 
Criterion modified per Amendment 1
10.1 If receiving topical medication such as non-steroidal anti-inflammatory
interventions (NSAIDs), GC to treat skin lesions of TAK, the dose must have
been stable for ≥2 weeks prior to first administration of the study intervention.
11. 
If receiving an oral anti-hypertensive therapy for treatment of TAK, the dose must have
been stable for at least 2 weeks prior to first administration of the study intervention.
12. 
If receiving an oral NSAIDs therapy for treatment of TAK or other pain (including
menstrual pain and migraine), the dose must have been stable for at least 2 weeks prior
to first administration of the study intervention.
Sex and Contraceptive/Barrier Requirements
13. 
Male or female
 
A woman must be (as defined in Section 10.10, Appendix 10: Contraceptive and Barrier
Guidance),
a. Not of childbearing potential
b. Of childbearing potential and
o 
Practicing a highly effective method of contraception (failure rate of <1%
per year when used consistently and correctly) and agrees to remain on a
highly effective method throughout the study and for at least 16 weeks
after the last dose of the study intervention- the end of relevant systemic
exposure after the last dose - the end of relevant systemic exposure. The
investigator should evaluate the potential for contraceptive method failure
(eg, noncompliance, recently initiated) in relationship to the first dose of
study intervention. Examples of highly effective methods of
contraception are located in Section 10.10, Appendix 10: Contraceptive
and Barrier Guidance.
o 
Pregnancy testing (serum or urine) at the end of study intervention.
Note: If childbearing potential changes after start of the study (eg, a woman who is not
heterosexually active becomes active or a premenarchal woman experiences menarche)
a woman must begin a highly effective method of birth control, as described above.
14. 
A woman of childbearing potential must have a negative highly sensitive serum
(-human chorionic gonadotropin [-hCG]) at screening and then have a negative urine
pregnancy test at Week 0 prior to study intervention administration.
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Status: Approved,  Date:  15 August 2022
15. 
A woman using oral contraceptives must use an additional contraceptive method (above
that required in Inclusion Criterion #13).
16. 
A woman must agree not to donate eggs (ova, oocytes) or freeze for future use for the
purposes of assisted reproduction during the study and for a period of 4 months.
17. 
A male participant must wear a condom when engaging in any activity that allows for
passage of ejaculate to another person and a man who has not had a vasectomy, he 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. Male
participants should also be advised of the benefit for a female partner to use a highly
effective method of contraception as condom may break or leak.
18. 
A male participant must agree not to donate sperm for the purpose of reproduction
during the study and for a minimum 20 weeks after receiving the last dose of study
intervention.
Tuberculosis
19. 
Criterion modified per Amendment 2:
19.1 
Are considered eligible according to the following TB screening criteria:
a. Have no history of latent or active TB prior to screening. An exception is made
for participants who have a history of latent TB and are currently receiving
treatment for latent TB, will initiate treatment for latent TB at least 3 weeks
prior to the first administration of the study intervention, or have
documentation of having completed appropriate treatment for latent TB within
3 years prior to the first administration of the study intervention. It is the
responsibility of the investigator to verify the adequacy of previous
antituberculous 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 at least 3 weeks prior to the first administration of the study
intervention.
d. Within 6 weeks prior to the first administration of the study intervention, has
a negative interferon gamma release assays (IGRAs) result, or have a newly
identified positive IGRAs result in which active TB has been ruled out and for
which appropriate treatment for latent TB has been initiated at least 3 weeks
prior to the first administration of the study intervention. A participant whose
first IGRA result is indeterminate should have the test repeated. In the event
that the second IGRA result is also indeterminate, the participant may be
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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 participant has no additional risk factors for TB as determined by the
investigator. This determination must be promptly reported to the sponsor and
recorded in the participant's source documents and initialed by the
investigator.
NOTE: IGRA is not required at screening for participants with a history of latent TB
and ongoing treatment for latent TB or documentation of having completed adequate
treatment as described above. Participants with documentation of having completed
adequate treatment as described above are not required to initiate additional treatment
for latent TB.
e. Have a chest radiograph (both posterior-anterior and lateral views) or chest
CT, taken within 3 months prior to the first administration of the study
intervention and read by a radiologist or pulmonologist, with no evidence of
current, active TB or old, inactive TB.
Screening laboratory tests
20. 
Have screening laboratory test results within the following parameters. If 1 or more of the
laboratory parameters is out of range, a single retest of laboratory values is permitted during
6-week screening period:
a) Hemoglobin           ≥8.0 g/dL (International System of Units [ISI]: ≥80 g/L)
b) White blood cells   ≥3.0×103/μL (ISI: ≥3.0 GI/L)
c) Lymphocytes         ≥0.5×103/μL (ISI: ≥0.5 GI/L)
d) Neutrophils            ≥1.5×103/μL (ISI: ≥1.5 GI/L)
e) Platelets                 ≥100×103/μL (ISI: ≥75 GI/L)
f) Serum creatinine   ≤1.8 mg/dL (ISI: ≤170 μmol/L)
A one-time repeat of these screening laboratory tests (ie, hemoglobin, white blood cells,
lymphocytes, neutrophils, platelets, serum creatinine) is allowed during the 6-week
screening period and the investigator may consider the participant eligible if the
previously abnormal laboratory test result is within an acceptable range on repeat
testing at the central laboratory. A screening laboratory test analyzed by the central
laboratory may be repeated more than once in the event of suspected error in sample
collection or analysis as long as the result is obtained within the 6-week screening
period.
21. 
Participants with other marked disease-associated laboratory abnormalities may be
included only if the investigator judges the abnormalities or deviations from normal to be
not clinically significant or to be appropriate and reasonable for the population under study.
This determination must be recorded in the participant’s source documents and initialed by
the investigator. Participants with Common Terminology Criteria for Adverse Events
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(CTCAE) Grade 3 or Grade 4 laboratory abnormalities must be discussed with the sponsor
to determine eligibility for enrollment.
Informed Consent
22. 
Criterion modified per Amendment 2:
22.1 Must sign an ICF (or their legally acceptable representative must sign) indicating
that he or she understands the purpose of, and procedures required for, the study
and is willing to participate in the study. Parent(s) (preferably both if available or
as per local requirements) (or their legally acceptable representative) must sign an
ICF indicating that they understand the purpose of, and procedures required for,
the study and is/are willing to allow the child to participate in the study. Assent is
also required of children capable of understanding the nature of the study
(typically 7 years of age and older) as described in Informed Consent Process and
Assent Form in Appendix 8: Regulatory, Ethical, and Study Oversight
Considerations.
23. 
Criterion modified per Amendment 2:
23.1 Must sign a separate informed consent form (or their legally-acceptable
representative must sign) if he or she agrees to provide an optional (DNA) sample
for research. Refusal to give consent for the optional DNA research sample does
not exclude a participant from participation in the study. Parent(s) (preferably
both if available or as per local requirements) (or their legally acceptable
representative) must sign a separate informed consent form if they agree to the
child providing an optional DNA sample for research. Assent is also required of
children capable of understanding the nature of the study (typically 7 years of
age and older) as described in the Informed Consent Process and Assent Form in
Appendix 8: Regulatory, Ethical, and Study Oversight Considerations.
24. 
Be willing and able to adhere to the lifestyle restrictions specified in this protocol.
5.2. 
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from
participating in the study:
TAK Diagnosis and Status:
1. 
Has currently any known severe or uncontrolled TAK complications (eg, hypertension
not responding to adequate treatment, aortic incompetence with cardiac insufficiency,
progressing aortic aneurysm, coronary artery lesions with severe stenosis).
2. 
Has any other active rheumatic disease other than TAK including but not limited to
granulomatosis with polyangiitis (Wegener's), rheumatoid arthritis, systemic lupus
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erythematosus, and Behcet’s disease that could interfere with assessment of TAK. GCA
and polymyalgia rheumatica are not eligible to participate to the study.
Concomitant or previous medical therapies received:
3. 
Criterion modified per Amendment 2:
3.1 Has received immunosuppressant (s) (including but not limited to MTX, AZA,
mycophenolate mofetil [MMF], oral TAC, oral cyclosporine A) within 4 weeks of
first study intervention.
4. 
Has received oral cyclophosphamide within 12 weeks or IV cyclophosphamide within
24 weeks prior to the first dose of the study intervention.
5. 
Has previously received ustekinumab, guselkumab, risankizumab, and agents whose
mechanism of action targets IL-23.
6. 
Has received treatment with an anti-TNF agent: (including but not limited to infliximab,
etanercept, adalimumab, golimumab, certolizumab pegol) within 8 weeks before the
first administration of study intervention.
7. 
Has received treatment with an IL-6 inhibitor (including but not limited to TCZ,
sarilumab) within 6 weeks before the first dose of study intervention.
8. 
Criterion modified per Amendment 2:
8.1 Has previously been treated with any immunomodulatory biologic agent not
described in this protocol within 5 half-lives or 12 weeks, whichever is longer,
before the first administration of study intervention (eg, abatacept, agents whose
mechanism of action targets B cell [eg, belimumab], IL-1 [eg, canakinumab], IL-
2, IL-17 [eg, secukinumab, ixekizumab, brodalumab], or IFN pathways).
9. 
Has received rituximab or B cell depletion treatment within 24 weeks before the first
administration of the study intervention.
10. 
Criterion modified per Amendment 2:
10.1 
Has previously failed to respond Janus kinase (JAK) inhibitor* for the treatment
of TAK (ie, lack of efficacy), including but not limited to tofacitinib, baricitinib,
upadacitinib. Has received treatment with JAK inhibitor within 5 half-lives
before the first administration of study intervention, if discontinued by any
reasons excepting lack of efficacy.
*Failed response to JAK inhibitor is defined for participants who have received
at least 4 weeks treatment of JAK inhibitor and signs and symptoms of TAK
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persisted for 2 weeks or more and were not able to taper oral GC dose of
7.5 mg/day (prednisolone or equivalent) or less.
11. 
Use of apheresis therapy (including but not limited to plasmapheresis, photopheresis,
leukocytapheresis) or immunoadsorption is prohibited within 2 weeks prior to the first
administration of the study intervention.
12. 
Having a condition that is steroid dependent (eg, steroid dependent asthma, chronic
obstructive pulmonary disease, etc) that is not amenable to tapering oral GC.
13. 
Has received an investigational intervention (including investigational vaccines) within
5 half-lives or 12 weeks before (whichever is longer) the planned first dose of study
intervention or is currently enrolled in an investigational study.
14. 
Taken any disallowed therapies as noted in Section 6.8, Concomitant Therapy before
the planned first dose of study intervention.
Infections or predisposition to infections:
15. 
Has had a Bacille Calmette-Guérin (BCG) vaccination within 12 months of screening.
16. 
Has received a live virus or live bacterial vaccination within 16 weeks prior to the first
administration of the study intervention.
17. 
Has a history of active granulomatous infection, including but not limited to
histoplasmosis or coccidioidomycosis.
18. 
Has a chest radiograph or chest high-resolution computer tomography (HRCT) within
3 months prior to the first administration of the study intervention that shows an
abnormality suggestive of a malignancy or current active infection, including TB.
Radiographic findings such as pulmonary nodules should be evaluated by an
experienced radiologist and/or pulmonologist to determine whether the presentation is
suggestive of infection or active malignancy and final assessment documented by the
investigator prior to randomization.
19. 
Has had a nontuberculous mycobacterial infection or opportunistic infection (eg,
cytomegalovirus, pneumocystosis, aspergillosis).
20. 
Has a history of, or ongoing, chronic or recurrent infectious disease, including but not
limited to, chronic renal infection, chronic chest infection (eg, bronchiectasis), chronic
infectious sinusitis, recurrent urinary tract infection (eg, recurrent pyelonephritis), an
open, draining, or infected skin wound or ulcer.
21. 
Has a history of HIV antibody positive or tests positive for HIV at screening.
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Status: Approved,  Date:  15 August 2022
22. 
Has a hepatitis B infection. Participants must undergo screening for hepatitis B virus
(HBV). At a minimum, this includes testing for HBV surface antigen (HBsAg), HBV
surface antibody (anti-HBs), and HBV core antibody total (anti-HBc total).
23. 
Is seropositive for antibodies to HCV, unless has 2 negative HCV ribonucleic acid
(RNA) test results 6 months apart prior to screening and has a third negative HCV RNA
test result at screening.
24. 
Has experienced a recent single dermatomal herpes zoster eruption within the past
4 months. Has ever had multi-dermatomal herpes zoster (defined as appearance of
lesion outside the primary or adjacent dermatome) or central nervous system zoster
infection prior to the first administration of the study intervention.
25. 
Within 8 weeks prior to the first administration of the study intervention, has had a
serious infection (eg, pneumonia, sepsis, or pyelonephritis), or has been hospitalized for
an infection, or has been treated with IV antibiotics for an infection. Less serious
infections (eg, acute upper respiratory tract infection, simple urinary tract infection)
need not be considered exclusionary at the discretion of the investigator.
26. 
Is a potential participant with the following features will be excluded from participating
in the study:
During the 6 weeks prior to baseline, have had ANY of the following:
a. confirmed severe acute respiratory syndrome-corona virus-2 (SARS-CoV)-2
corona virus disease (COVID-19) infection (test positive), OR
b. suspected SARS-CoV-2 infection (clinical features [eg, symptoms] without
documented test results), OR
c. close contact with a person with known or suspected SARS-CoV-2 infection
Exception: may be included with a documented negative result for a validated
SARS-CoV-2 test:
o 
If obtained at least 2 weeks after conditions (a), (b), (c) above (timed from
resolution of key clinical features if present, eg, fever, cough, dyspnea)
AND
o 
With absence of ALL conditions (a), (b), (c) above during the period
between the negative test result and the baseline study visit.
Concurrent medical conditions or past medical history and procedures:
27. 
Has known allergies, hypersensitivity, or intolerance to ustekinumab or its excipients
(see the ustekinumab IB).
28. 
Any major illness/condition or evidence of an unstable clinical condition (eg, history of
liver or renal insufficiency (estimated creatinine clearance below 60 mL/min);
significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic,
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hematologic, rheumatologic, psychiatric, or metabolic disturbances), disease of any
organ system or active acute or chronic infection/infectious illness that, in the
investigator’s judgment, will substantially increase the risk to the participant if he or she
participates in the study.
29. 
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 participant is expected to participate in the study or within 1 month after the last
dose of study intervention administration.
Note: Participants with planned surgical procedures to be conducted under local
anesthesia may participate after discussion with the sponsor.
30. 
Has a transplanted organ (except for a corneal transplant performed >3 months prior to
the first administration of the study intervention).
31. 
Has or has had a substance abuse (intervention or alcohol) problem within the previous
3 years.
32. 
Is unwilling or unable to undergo multiple venipunctures because of poor tolerability or
lack of easy venous access.
Malignancy or increased potential for malignancy:
33. 
Presence or history of malignancy within 5 years before screening (exceptions are
squamous and basal cell carcinomas of the skin that has been treated with no evidence
of recurrence for at least 3 months before the first study drug administration and
carcinoma in situ of the cervix that has been documented to be surgically cured).
34. 
Has 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,
history of splenectomy, or history of monoclonal gammopathy of undetermined
significance.
Others
35. 
Is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this
study or within 4 months after the last dose of study intervention.
36. 
Is 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.
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37. 
Any condition for which, in the opinion of the investigator, participation would not be
in the best interest of the participant (eg, compromise the well-being) or that could
prevent, limit, or confound the protocol-specified assessments.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening.
If a participant's clinical status changes (including any available laboratory results or receipt of
additional medical records) after screening but before the first dose of study intervention is given
such that he or she no longer meets all eligibility criteria, then the participant should be excluded
from participation in the study. Section 5.4, Screen Failures, describes options for retesting. The
required source documentation to support meeting the enrollment criteria are noted in Section 10.8,
Appendix 8: Regulatory, Ethical, and Study Oversight Considerations.
5.3. 
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions
during the course of the study to be eligible for participation:
1. 
Refer to Section 6.8, Concomitant Therapy for details regarding prohibited and
restricted therapy during the study.
2. 
Agree to follow all requirements that must be met during the study as noted in the
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
3. 
Must agree not to receive a live virus or live bacterial vaccination during the study.
Participants must also agree not to receive BCG vaccination for 12 months after last
dose of study agent, or any other live vaccine for 3 months after receiving the last
administration of study agent.
5.4. 
Screen Failures
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy
identification of each participant during and after the study. This document will be reviewed by
the sponsor study site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed
by the investigator in the study file. To ensure participant confidentiality, no copy will be made.
All reports and communications relating to the study will identify participants by participant
identification and age at initial informed consent/assent. In cases where the participant is not
randomized into the study, the date seen and age at initial informed consent/assent will be used.
If, during the screening period, a participant has not met all inclusion criteria or has met any
exclusion criteria or is unable or unwilling to adhere to the lifestyle considerations of the study,
the participant is considered to be a screen failure and is not eligible to be enrolled in the study.
NCT04882072


CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
49
Status: Approved,  Date:  15 August 2022
In general, if a participant is a screen failure, but at some timepoint in the future meets all of the
participant eligibility criteria, the participant may be rescreened after a new informed
consent/assent has been obtained. Participants who are rescreened should be assigned a new
participant number and will restart a new screening period.
Completion of screening and randomization procedures must occur within the specified screening
window of 6 weeks.
If any delay leads to the expiration of time-specific assessments (eg, TB, chest radiograph), further
discussion with the sponsor should occur before the participant is considered for rescreening. The
participant will be considered a screen failure because he/she will not meet eligibility criteria and
the expired assessments (along with the non-time-specific laboratory tests) will have to be repeated
on rescreening.
Additional criteria for retesting and rescreening are outlined below.
Retesting
Retesting of abnormal laboratory values that may lead to exclusion will be allowed once. Retesting
can occur at an unscheduled visit during the screening period, as long as this is done within the
specified screening window of 6 weeks.
Rescreening
Participants who do not meet the criteria for participation in this study (screen failure) may be
rescreened 1 time and only after consultation with the sponsor. Participants who are rescreened
will be assigned a new participant number, undergo the informed consent/assent process, and then
start a new screening period.
5.5. 
Criteria for Temporarily Delaying Enrollment, Randomization, and/or
Administration of Study Intervention
Additional information for delayed enrollment randomization and/or administration of study
intervention will be considered on a case-by-case basis after consultation with the sponsor.
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY
6.1. 
Study Intervention Administered
Study intervention administration must be captured in the source documents and the electronic
case report form (eCRF).
Ustekinumab will be manufactured and provided under the responsibility of the sponsor. Refer to
the IB for a list of excipients.
For details on rescue medications, refer to Section 6.8.1, Rescue Medication. For a definition of
study intervention overdose, refer to Section 6.7, Treatment of Overdose.
NCT04882072


CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
50
Status: Approved,  Date:  15 August 2022
Description of Interventions
Table 3: 
Study Intervention
☒ Intervention(s)
Arm Name 
Ustekinumab Group 
Placebo Group 
Ustekinumab Group/ Placebo Group
Period 
DB 
OLE / Escape arm**
Intervention Name 
Ustekinumab 
Ustekinumab 
Placebo 
Placebo 
Ustekinumab 
Ustekinumab
Type 
INTERVENTION: INCLUDING PLACEBO
Dose Formulation 
Unit Dose 
Strength(s) 
A single-use, sterile 
solution in 30 mL 
vials with 1 dose 
strength (ie, 130 mg 
in 26 mL nominal 
volume) 
A single-use PFS  
in a strength of 
90 mg in 1 mL 
nominal volume for 
SC administration 
A single-use, sterile 
solution in 30 mL 
vials with a 26 mL 
nominal volume 
A single-use PFS 
for SC 
administration 
  
A single-use, sterile 
solution in 30 mL 
vials with 1 dose 
strength (ie, 130 mg 
in 26 mL nominal 
volume)
A single-use PFS
in a strength of
90 mg in 1 mL
nominal volume for
SC administration
Dosage Level(s) 
and Frequency 
At Week 0  
 
Body weight-range 
based IV dosing* 
At Week 8 and q8w 
until developing 
relapse or end of DB 
period  
 
90 mg 
At Week 0 
 
Body weight-range 
based IV dosing* 
At Week 8 and q8w 
until developing 
relapse or end of DB 
period
 
At Week OL-0 after 
developing relapse 
only 
 
 
Body weight-range 
based IV dosing* 
At Week OL-0 after
the end of DB
period.
 
At Week OL-8 and
q8w until Week
OL-48, or 32 weeks
from the first SC
administration after
the end of DB
period, whichever is
later.
 
90 mg
Route of 
Administration
IV infusion 
SC injection 
IV infusion 
SC injection 
IV infusion 
SC injection
Dosing instructions 
*The body weight-range based doses are based on the following:
Body weight ≤55 kg: 260 mg ustekinumab (2 vials)
Body weight ˃55 kg and ≤85 kg: 390 mg ustekinumab (3 vials)
Bod y weight ˃85 kg: 520 m  g ustekinumab (4 vials)
Use 
Experimental 
Experimental 
Placebo comparator 
Placebo comparator 
Experimental 
Experimental
Investigational 
Medicinal Product
(IMP)
☒ Yes 
☐ No 
☒ Yes 
☐ No 
☒ Yes 
☐ No 
☒ Yes 
☐ No 
☒ Yes 
☐ No 
☒ Yes 
☐ No
NCT04882072


CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
51
Status: Approved,  Date:  15 August 2022
Abbreviations: DB=double blind; IV=intravenous; OLE=open-label extension; PFS=prefilled syringe; SC=subcutaneous.
**Participants who experienced relapse in DB period and entered in Escape arm will receive IV infusion at Week OL-0, while participants who didn’t experience
relapse in DB period and entered in OLE period will receive SC administration at Week OL-0.
NCT04882072


CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
52
Status: Approved,  Date:  15 August 2022
6.2. 
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
All study intervention must be stored at controlled temperatures ranging from 36°F to 46°F (2°C
to 8°C), not frozen, and protected from light.
Vigorous shaking of product should be avoided. The formulation does not contain preservatives.
Ustekinumab can be administered either by SC route (without dilution) or IV route after being
diluted to an appropriate concentration using an appropriate diluent. Prior to administration, the
solution should be visually inspected for particulate matter or discoloration prior to SC
administration. The solution is clear to slightly opalescent, colorless to light yellow, and may
contain a few small translucent particles of protein. This appearance is not unusual for
proteinaceous solutions. The medicinal product should not be used if the solution is discolored or
cloudy or if foreign particulate matter is present.
The needle cover on the prefilled syringe contains dry natural rubber (a derivative of latex), which
may cause allergic reactions in individuals sensitive to latex.
For SC administration, the liquid intervention is supplied with 90 mg/1 mL PFS.
For IV administration, ustekinumab 5 mg/mL LIV can be administered after being diluted to an
appropriate concentration using an appropriate diluent. Aseptic procedures must be used during
the preparation and administration of the study material. Exposure to direct sunlight should be
avoided during preparation and administration.
Refer to the pharmacy manual/study site investigational product and procedures manual for
additional guidance on study intervention preparation, handling, and storage.
Accountability
The investigator is responsible for ensuring that all study intervention received at the site is
inventoried and accounted for throughout the study. The study intervention administered to the
participant must be documented on the intervention accountability form. All study intervention
will be stored and disposed of according to the sponsor's instructions. Study site personnel must
not combine contents of the study intervention containers.
Study intervention 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 intervention and study intervention returned by the
participant, 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 intervention or used returned study
intervention for destruction, will be documented on the intervention return form. When the study
site is an authorized destruction unit and study intervention supplies are destroyed on-site, this
must also be documented on the intervention return form.
NCT04882072


CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
53
Status: Approved,  Date:  15 August 2022
Potentially hazardous materials containing hazardous liquids, such as used ampules, needles,
syringes, and vials should be disposed of immediately in a safe manner and therefore will not be
retained for intervention accountability purposes.
Study intervention 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 intervention will be
supplied only to participants participating in the study. Returned study intervention must not be
dispensed again, even to the same participant. Whenever a participant brings his or her study
intervention to the study site for pill count, this is not seen as a return of supplies. Study
intervention may not be relabeled or reassigned for use by other participants. The investigator
agrees neither to dispense the study intervention from, nor store it at, any site other than the study
sites agreed upon with the sponsor. Further guidance and information for the final disposition of
unused study interventions are provided in the study reference manual.
6.3. 
Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Participants will be randomly assigned
to 1 of study intervention sequence groups based on a computer-generated randomization schedule
prepared before the study by or under the supervision of the sponsor. The randomization will be
balanced by using randomly permuted and will be stratified by GC dose at Week 0
(<0.5 mg/kg/day, ≥0.5 mg/kg/day of prednisolone or equivalent) and status of previous biologic
medication (bio-nonfailure or bio-failure). The interactive web response system (IWRS) will
assign a unique intervention code, which will dictate the intervention assignment and matching
study intervention kit for the participant. The requestor must use his or her own user identification
and personal identification number when contacting the IWRS and will then give the relevant
participant details to uniquely identify the participant.
Blinding
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 participant.
Data that may potentially unblind the intervention assignment (ie, study intervention serum
concentrations, anti-ustekinumab antibodies, study intervention preparation/accountability data,
intervention allocation, biomarker or other specific laboratory data) 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 participants have completed
DB period of the study and the database is finalized. The investigator may in an emergency
determine the identity of the intervention by contacting the IWRS. While the responsibility to
NCT04882072


CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
54
Status: Approved,  Date:  15 August 2022
break the intervention code in emergency situations resides solely with the investigator, 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, time, and reason for the unblinding must be
documented by the IWRS, 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
participant's source documents in a secure manner.
Participants who have had their intervention assignment unblinded will not be eligible to receive
further study intervention but should complete evaluations specified in the appropriate Schedule
of Activities (Section 1.3) for participants who discontinue study intervention.
In this study, 4 DBLs are planned. A first DBL will occur after a total of 15 events in relapse of
TAK occurred. A second DBL will occur after a total of 35 events in relapse of TAK occurred. A
third DBL will occur approximately 24 weeks after the second DBL. A fourth DBL will occur
when all participants have either completed their final study visit or terminated study participation
prior to their final visit. Additional DBLs other than the ones specified above may be performed.
Investigative study sites and participants will remain blinded to initial treatment assignment until
after the fourth DBL, except for participants who can taper oral GC dose to 5 mg/day (prednisolone
or equivalent) or less at which 35 relapse events occur. After the first DBL, the data will be
unblinded to IDMC for analysis while participants are still participating in the study. Identification
of sponsor personnel who will have access to the unblinded participant data will be documented
prior to unblinding to sponsor.
6.4. 
Study Intervention Compliance
Ustekinumab will be administered as an IV and SC injection.
The details of each study intervention administration will be recorded in the eCRF, including date
and time of IV and SC injection.
All visits will occur within a range of ±4 days of the scheduled visit through Week 4 and then
±7 days of the scheduled visit until safety follow-up (Section 1.3). Any visits outside of these
ranges should be discussed with the sponsor and should be documented in the eCRF.
Study-site personnel will maintain a log of all study intervention administered. Study intervention
supplies for each participant will be inventoried and accounted for. Information regarding study
intervention administrations that are administered outside of the scheduled windows or missed will
be recorded. Participant charts and worksheets may be reviewed and compared with the data
entries on the eCRFs to ensure accuracy. Although it is understood that treatment may be
interrupted for many reasons, compliance with the treatment schedule is strongly encouraged.
6.5. 
Dose Modification
This section is not applicable.
NCT04882072


CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
55
Status: Approved,  Date:  15 August 2022
6.6. 
Continued Access to Study Intervention After the End of the Study
Long-term extension study to evaluate further long-term effects of ustekinumab may be conducted
if the sponsor deems that ustekinumab treatment is beneficial to study participants based on results
of the primary analysis. Participants who complete their participation in OLE period may be
eligible to enter the LTE and continue to receive 90 mg SC ustekinumab q8w. Details will be
provided in a separate LTE protocol or amendment of this protocol.
6.7. 
Treatment of Overdose
For this study, any dose of ustekinumab greater than the highest dosing visit at a single dosing visit
specified in this protocol will be considered an overdose. The sponsor does not recommend
specific treatment for an overdose.
In the event of an overdose, the investigator or treating physician should:
 
Contact the medical monitor immediately.
 
Evaluate the participant to determine, in consultation with the medical monitor, whether study
intervention should be interrupted or whether the dose should be reduced.
 
Closely monitor the participant for AE/serious adverse event (SAE) and laboratory
abnormalities.
 
Document the quantity of the excess dose as well as the duration of the overdosing in the
eCRF.
6.8. 
Concomitant Therapy
Prestudy therapies administered up to 12 weeks before having obtained the consent/assent must be
recorded at screening.
Concomitant therapies must be recorded throughout the study beginning with start of the screening
process and through final safety visit in the eCRF. Concomitant therapies should also be recorded
beyond the final safety follow-up visit only in conjunction with serious adverse events (SAEs) that
meet the criteria outlined in Section 8.3.1, for Collecting Adverse Event and Serious Adverse
Event Information.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special
diets, exercise regimens, or other specific categories of interest) different from the study
intervention must be recorded in the eCRF. Medications given for imaging such as contrast media
agent must also be recorded. Recorded information will include a description of the type of therapy,
duration of use, dosing regimen, route of administration, and indication. Modification of an
effective preexisting therapy should not be made for the explicit purpose of entering a participant
into the study.
Every reasonable effort should be made to keep doses of concomitant medications stable through
the end of DB period unless otherwise specified in the following sections.
NCT04882072


CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
56
Status: Approved,  Date:  15 August 2022
If necessary, a concomitant medication may be reduced or temporarily discontinued because of
abnormal laboratory values, safety and tolerability issues, concurrent illness, or the performance
of a surgical procedure, but the change and reason for the medication change should be clearly
documented in the participant’s medical record. Adjustments in permitted therapies (anti-platelet
or anti-coagulation therapy, anti-hypertensive therapy, NSAIDs, and topical medications) that do
not comply with the study protocol should not be allowed through the end of DB period except for
reduction of the concomitant therapies due to improvement of the symptoms and safety
considerations. During OLE, adjustments in concomitant therapies are allowed based on the
discretion of the investigator.
If protocol-prohibited immunosuppressants, biologics (such as TCZ), cytotoxic agents (such as
cyclophosphamide) or IV GC are initiated for severe, progressive, or unstable TAK disease activity,
the participant should be discontinued from the study.
Any questions or concerns with the use of concomitant therapies should be discussed with the
study sponsor and/or medical monitor. The sponsor must be notified in advance (or as soon as
possible thereafter) of any instances in which prohibited therapies are administered.
Permitted Therapy
Oral Glucocorticoid and Protocol-defined Taper for TAK
Table 4 outlines oral glucocorticoid dose requirements prior to randomization and throughout the
study.
Table 4: 
Glucocorticoid dose requirements for each study period
Study period 
Allowable dose
Before randomization 
Daily dose must be ≥15 mg/day of prednisolone or equivalent at randomization with
stable dosin  g ≥2 weeks prior to the first stud y intervention administration.
Week 0 through 
Week 2
No adjustments in GC dose are permitted.
Week 2 through 
participant’s relapse 
or end of DB period  
GC tapering will start from Week 2 based on defined GC taper schedule (See Table 5).
If current daily prednisolone or equivalent dose is ≥30 mg/day, GC dose will be tapered
by 5 mg/week.
If current prednisolone or equivalent dose is <30 mg/day and >20 mg/day, GC dose will
be tapered by 2.5 mg/week.
If current prednisolone or equivalent dose is ≤20 mg/day and ≥5 mg/day, GC dose will
be tapered by 10%/week according to the below formula.
Dose* of Week N=Dose of Week “N-1” ×0.9
*Should be rounded decimals to the nearest whole number.
 
Once the daily prednisolone dose (or equivalent) reaches 5 mg/day, while GC taper by
1 mg/4-8 weeks is encouraged to achieve GC-free remission, GC taper regimen is
ultimately at discretion of investigator at 5 mg or less based on disease activities of TAK
in participants.
 
OLE period including 
Escape arm 
GC taper regimen is at the investigator’s discretion and is encouraged to achieve GC-free
remission.
Abbreviations: GC=glucocorticoid; OLE=open-label extension; TAK=Takayasu arteritis.
NCT04882072


CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
57
Status: Approved,  Date:  15 August 2022
Table 5: 
Glucocorticoid Taper Schedule (Daily Dose [mg] of Prednisolone or Equivalent) (Table shows only up to Week 24)
 
Week
Baseline 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24
60 
60 
60 
55 
50 
45 
40 
35 
30 
25 
22.5 
20 
18 
16 
14 
13 
12 
11 
10 
9 
8 
7 
6 
5* 
5* 
5*
50 
50 
50 
45 
40 
35 
30 
25 
22.5 
20 
18 
16 
14 
13 
12 
11 
10 
9 
8 
7 
6 
5* 
5* 
5* 
5* 
5*
40 
40 
40 
35 
30 
25 
22.5 
20 
18 
16 
14 
13 
12 
11 
10 
9 
8 
7 
6 
5* 
5* 
5* 
5* 
5* 
5* 
5*
35 
35 
35 
30 
25 
22.5 
20 
18 
16 
14 
13 
12 
11 
10 
9 
8 
7 
6 
5* 
5* 
5* 
5* 
5* 
5* 
5* 
5*
30 
30 
30 
25 
22.5 
20 
18 
16 
14 
13 
12 
11 
10 
9 
8 
7 
6 
5* 
5* 
5* 
5* 
5* 
5* 
5* 
5* 
5*
25 
25 
25 
22.5 
20 
18 
16 
14 
13 
12 
11 
10 
9 
8 
7 
6 
5* 
5* 
5* 
5* 
5* 
5* 
5* 
5* 
5* 
5*
20 
20 
20 
18 
16 
14 
13 
12 
11 
10 
9 
8 
7 
6 
5* 
5* 
5* 
5* 
5* 
5* 
5* 
5* 
5* 
5* 
5* 
5*
15 
15 
15 
14 
13 
12 
11 
10 
9 
8 
7 
6 
5* 
5* 
5* 
5* 
5* 
5* 
5* 
5* 
5* 
5* 
5* 
5* 
5* 
5*
 
* Once the daily prednisolone dose (or equivalent) reaches 5 mg/day, while GC taper by 1 mg/4-8 weeks is encouraged to achieve GC-free remission,
GC taper regimen is ultimately at discretion of investigator based on disease activities of TAK in participants.
NCT04882072


CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
58
Status: Approved,  Date:  15 August 2022
Participants that are on GC other than prednisolone during screening should preferably be switched
to prednisolone to follow the GC taper in Table 5. If the participant continues on GC other than
prednisolone, the investigator should contact the sponsor to ensure that the taper is appropriately
adjusted for the GC equivalency compared with prednisolone (Refer to Section 10.6, Appendix 6:
Glucocorticoid Conversion Table). If participants have GC-induced side effects such as
osteoporosis and hyperglycemia, appropriate treatment must be given in the judgment of the
investigator.
Additional consideration of oral GC use during the study is as follow:
 
It is recommended that participants be educated about and monitored for symptoms of GC
adrenal insufficiency/deficiency (eg, Addisonian symptoms such as fatigue, muscle weakness,
decreased appetite, nausea, vomiting, joint and muscle pain) by study staff during periods of
GC tapering, as appropriate. Investigators should monitor participants at the regular study
visits for any signs and symptoms of Addisonian crisis.
Anti-platelet or Anti-coagulation Therapy
Participants are permitted to receive stable doses (≥2 weeks prior to first study intervention
administration) of anti-platelet therapy (including but not limited to aspirin, clopidogrel,
ticlopidine) or anti-coagulation therapy (including but not limited to warfarin) according to the
local practice at the discretion of the investigator. In terms of warfarin, the dose should be
controlled 1-5mg/day in order to maintain PT-INR target range between 2.0-3.0 (if participants are
over 70 years old, PT-INR target range should be between 1.6-2.6). Participants should not initiate
anti-platelet or anti-coagulation  therapy during DB period, unless discussed and agreed with the
sponsor medical monitor.
Anti-hypertensive Therapy
Participants are permitted to receive stable doses (≥2 weeks prior to first study intervention
administration) of anti-hypertensive treatment according to the local practice at the discretion of
the investigator. Participants should not initiate anti-hypertensive therapy during DB period, unless
discussed and agreed with the sponsor medical monitor.
NSAIDs
Participants are permitted to receive stable doses (≥2 weeks prior to first study intervention
administration) of NSAIDs treatment according to the local practice at the discretion of the
investigator. Participants should not initiate NSAIDs therapy during DB period, unless discussed
and agreed with the sponsor medical monitor.
Topical Medications
Participants are permitted to receive stable doses (≥2 weeks prior to first study intervention
administration) of topical medications according to the local practice at the discretion of the
investigator. Participants should not initiate topical medications during DB period, unless
discussed and agreed with the sponsor medical monitor.
NCT04882072


CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date:  15 August 2022
Prohibited Therapies
Use of additional investigational or approved biologic or non-biologic immunosuppressant or
immunomodulatory agents, other than those explicitly allowed in the inclusion/exclusion criteria,
are prohibited until safety follow-up visit including but not limited to, the following:
 
Anti-IL-6 (eg, actemra), anti-TNF therapy (eg, remicade, humira)
 
Anti-IL-23, anti- IL-12/23 p40, anti-IL-17 therapy
 
JAK inhibitors (eg, tofacitinib, upadacitinib)
 
Cell-depleting therapies (eg, abatacept, rituximab, alemtuzumab)
 
Cytotoxic akylating agents (eg, chlorambucil, cyclophosphamide)
 
Immunosuppressant (eg, MTX, AZA, MMF, TAC, cyclosporine)
 
Intra-muscular, intra-articular, intra-bursal, epidural, intra-lesional or IV GC
 
Other investigational agents
Oral Glucocorticoids
Oral GCs other than for the protocol-define taper, are prohibited during the study, with the
exception of use for GC rescue therapy. The use of oral GCs (or other systemic GCs) for
indications other than TAK during the study should be limited to only situations for which, in the
opinion of the treating physician, there are no adequate alternatives. This should be discussed with
the medical monitor or designee prior to providing these and may require discontinuation of study
intervention.
Intra-muscular, Intra-articular, Intra-bursal, Epidural, Intra-lesional, or IV
Glucocorticoids
Intra-muscular, intra-articular, intra-bursal, epidural, intra-lesional, or IV GCs are prohibited
within 6 weeks prior to first study intervention and during the study.
6.8.1. 
Rescue Medication
The study site will supply rescue medication that will be obtained locally.
Glucocorticoid rescue therapy is defined as a GC therapy for participants who meet the criteria of
protocol-defined relapse.
During the DB period, participants who develop a TAK relapse should stop GC taper and be treated
with GC rescue therapy that is at least double the dose at the relapse by discretion of the
investigator. When considering use of GC rescue therapy, a careful assessment should be made by
the investigator whether the symptoms are related to a TAK relapse or are more likely due to
non-inflammatory symptoms which could represent adrenal insufficiency or other comorbidities.
After receiving a GC rescue therapy, the participant will enter Escape arm to receive IV
ustekinumab at next study intervention administration visit and followed by SC ustekinumab
NCT04882072


CNTO1275  (Ustekinumab)  
Clinical Protocol CNTO1275TAT3001 Amendment 2
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date:  15 August 2022
administered 8 weeks after the IV dose, then q8w thereafter. If the participant will not be able to
receive IV ustekinumab at next study administration visit due to any reasons including his/her
disease activity and logistical reasons, the participant should be rearranged the visit within the
allowance if feasible. If it’s not feasible, the investigator should discuss with the sponsor. During
Escape arm, GC taper regimen is at the investigator’s discretion.
During the OLE period, participants who develop a TAK relapse will be treated GC rescue at
discretion of the investigator.
Oral NSAIDs rescue therapy for treatment of TAK in addition to GC rescue therapy is also allowed
as needed.
The date and time of rescue medication administration as well as the name and dosage regimen of
the rescue medication must be recorded.
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
7.1. 
Discontinuation of Study Intervention
A participant's study intervention must be discontinued if:
 
The participant withdraws consent or assent (or the participant’s parent/legal representative)
to receive study intervention
 
The investigator believes that for safety reasons or tolerability reasons (eg, AE) it is in the
best interest of the participant to discontinue study intervention
 
The participant becomes pregnant
 
Noncompliance with study intervention administration defined as multiple episodes of
missing the window in which to receive study intervention
 
The participant experiences an AE temporally associated with study intervention infusion or
injection, resulting in bronchospasm with wheezing and/or dyspnea requiring ventilatory
support or symptomatic hypotension with a greater than 40 mmHg decrease in systolic blood
pressure
 
The participant develops study intervention hypersensitivity (eg, anaphylaxis, angioedema)
reaction that is reported as serious or severe
 
The participant is deemed ineligible according to the following TB criteria:
 
A diagnosis of active TB is made.
 
A participant has symptoms suggestive of active TB based on follow-up assessment
questions and/or physical examination or has had recent close contact with a person with
active TB and cannot or will not continue to undergo additional evaluation.
 
A participant undergoing evaluation has a chest radiograph with evidence of current
active TB and/or a positive IGRA result, unless active TB can be ruled out and appropriate
treatment for latent TB can be initiated prior to the next administration of study
intervention and continued to completion. Indeterminate IGRA results should be handled
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as in Section 10.7, Appendix 7: Clinical Laboratory Tests. Participants with persistently
indeterminate IGRA 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 participant has no additional risk factors for TB as determined by
the investigator. This determination must be promptly reported to the sponsor and
recorded in the participant's source documents and initialed by the investigator.
 
A participant receiving treatment for latent TB discontinues this treatment prematurely 
or is noncompliant with the therapy.
 
The participant develops a serious opportunistic infection.
 
The participant has a malignancy including squamous cell skin cancer. Consideration may be
given to allowing participants who develop ≤2 basal cell skin cancers that are adequately
treated with no evidence of residual disease to continue to receive study intervention.
 
The participant who reaches oral GC dose of 5 mg/day (prednisolone or equivalent) or less in
the placebo group when a total of 35 relapse events occurs.
 
The participant requires a prohibited therapy such as an immunomodulatory biologic,
cyclophosphamide, or IV glucocorticoid (see Section 6.8).
Note: Any serious infection should be discussed with the medical monitor or designee and study
intervention should be withheld until the clinical assessment is complete.
If a participant discontinues study intervention for any reason before the end of the DB phase, then
the end-of-treatment assessments should be obtained and scheduled assessments of study
intervention should be continued.
7.1.1. 
Liver Chemistry Stopping Criteria
Discontinuation of study intervention for abnormal liver tests is required by the investigator when
a participant meets one of the conditions outlined in Section 10.11, Appendix 11: Liver Safety:
Suggested Actions and Follow-up Assessments and Study Intervention Rechallenge Guidelines or
in the presence of abnormal liver chemistries not meeting protocol-specified stopping rules if the
investigator believes that it is in best interest of the participant.
7.2. 
Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons:
 
Lost to follow-up
 
Withdrawal of consent or assent
 
Death
 
Other
When a participant withdraws before study completion, the reason for withdrawal is to be
documented in the eCRF and in the source document. If the reason for withdrawal from the study
is withdrawal of consent or assent, then no additional assessments are allowed.
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Withdrawal of Consent
A participant declining to return for scheduled visits does not necessarily constitute withdrawal of
consent. Alternate follow-up mechanisms that the participant agreed to when signing the
consent/assent form apply (eg, consult with family members, contacting the participant’s other
physicians, medical records, database searches, and use of locator agencies at study completion)
as local regulations permit.
7.3. 
Lost to Follow-up
To reduce the chances of a participant being deemed lost to follow-up, prior to randomization
attempts should be made to obtain contact information from each participant, eg, home, work, and
mobile telephone numbers and email addresses for both the participant as well as appropriate
family members.
A participant will be considered lost to follow-up if he or she repeatedly fails to return for
scheduled visits and is unable to be contacted by the study site. A participant cannot be deemed
lost to follow-up until all reasonable efforts made by the study site personnel to contact the
participant are deemed futile. The following actions must be taken if a participant fails to return to
the study site for a required study visit:
 
The study site personnel must attempt to contact the participant to reschedule the missed visit
as soon as possible, to counsel the participant on the importance of maintaining the assigned
visit schedule, to ascertain whether the participant wishes to or should continue in the study.
 
Before a participant is deemed lost to follow up, the investigator or designee must make every
reasonable effort to regain contact with the participant (where possible, 3 telephone calls,
e-mails, fax, and, if necessary, a certified letter to the participant’s last known mailing address,
or local equivalent methods). These contact attempts should be documented in the
participant’s medical records.
 
Should the participant continue to be unreachable, they will be considered to have withdrawn
from the study.
 
Site personnel, or an independent third party, will attempt to collect the vital status of the
participant within legal and ethical boundaries for all participants randomized, including those
who did not get study intervention. Public sources may be searched for vital status information.
If vital status is determined as deceased, this will be documented and the participant will not
be considered lost to follow-up. Sponsor personnel will not be involved in any attempts to
collect vital status information.
Should a study site close, eg, for operational, financial, or other reasons and the investigator cannot
reach the participant to inform them, their contact information will be transferred to another study
site.
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8. 
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedule of Activities (Section 1.3) summarizes the frequency and timing of efficacy, PK,
immunogenicity, PD, biomarker, pharmacogenomic, and safety measurements applicable to this
study.
If multiple assessments are scheduled for the same timepoint, it is recommended that procedures
be performed in the following sequence: patient-reported outcome (PRO) assessments, ECG and
vital signs, clinical safety laboratory assessments, PK, immunogenicity, and biomarkers. Urine
and blood collections for PK and PD assessments should be kept as close to the specified time as
possible. Other measurements may be done earlier than specified timepoints if needed. Actual
dates and times of assessments will be recorded in the source documentation and eCRF.
Guidelines for handling of assessments affected by the COVID-19 pandemic are found in
(Section 10.12, Appendix 12: Guidance on study conduct during COVID-19 pandemic).
Blood Sample Collection
As this study is event driven design and DB period for each participant depends on when they
relapse, the total blood volume will differ.
The total blood volume for the study is approximately 570 mL for participants who go through DB
period for 24 weeks and OLE period for 52 weeks.
The estimated maximum amount of blood drawn from each participant in this study will not exceed
850 mL for patients who go through the estimated longest DB period (Assuming 104 weeks) and
OLE period for 52 weeks.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the
samples.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory
requisition form. If blood samples are collected via an indwelling cannula, an appropriate amount
(1 mL) of serosanguineous fluid slightly greater than the dead space volume of the lock will be
removed from the cannula and discarded before each blood sample is taken. After blood sample
collection, the cannula will be flushed with 0.9% sodium chloride, United States Pharmacopeia
(USP) (or equivalent) sodium heparin of 10 U/mL and charged with a volume equal to the dead
space volume of the lock. If a mandarin (obturator) is used, blood loss due to discard is not
expected.
Refer to the Schedule of Activities (Section 1.3) for the timing and frequency of all sample
collections.
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Instructions for the collection, handling, storage, and shipment of samples are found in the
laboratory manuals 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 laboratory manuals.
Study-specific Materials
The investigator will be provided with the following supplies:
 
Ustekinumab IB
 
Pharmacy manual/study site investigational product and procedures manual
 
Laboratory manual
 
National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE)
version 5
 
IWRS Manual
 
Electronic data capture (eDC) Manual
 
Sample ICF
 
Participant diaries
8.1. 
Efficacy and Immunogenicity Assessments
The Schedule of Activities (Section 1.3) summarizes the frequency and timing of efficacy
measurements applicable to this study.
8.1.1. 
TAK Disease Signs and Symptoms
Efficacy of ustekinumab in TAK will be assessed from the presence of TAK activity including
investigator assessment of signs and symptoms of TAK.
Clinical signs and symptoms will be evaluated in the following items to assess if participants meet
the criteria of protocol-defined relapse by investigator or designee at specified time points in the
Schedule of Activities (Section 1.3). When 2 or more categories meets the criteria, participants
will be judged as relapse. Even if signs of relapse are not present in 2 of 5 categories, participants
will be judged as relapse if emergent hospitalization caused by worsening of TAK and GC
treatment required or if severe aortic valve incompetence accompanied by symptoms of cardiac
failure occurs under ‘vascular signs and symptoms’ or if CTCAE grade 2 or higher (grade ≥3 for
myocardial infarction) occurs under ‘ischaemic symptoms’. Definition of relapse are described in
Section 10.3, Appendix 3: Definitions of relapse/remission of TAK.
 
Systemic symptoms (objective assessment).
 
Systemic symptoms (subjective assessment).
 
Elevated inflammation markers (CRP, ESR).
 
Vascular signs and symptoms.
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 
Ischemic symptoms.
In assessment of disease activities of TAK, cause of relapse will be confirmed by eliminating other
causes such as infections, allergic disorders, and unexplained physical symptoms. Even
participants meet the definition of relapse once, they will not receive a GC rescue therapy and
continue to receive protocol-defined GC taper regimen except for the following cases. In the
following cases, participants will be judged as relapse once.
 
Emergent hospitalization caused by worsening of TAK and GC treatment required
 
Severe aortic valve incompetence accompanied by symptoms of cardiac failure occurs under
‘vascular signs and symptoms’
 
CTCAE grade 2 or higher (grade ≥3 for myocardial infarction) occurs under ‘ischemic
symptoms’
 
Both categories ‘vascular signs and symptoms’ and ‘ischemic symptoms’ meet the criteria
Except for above cases, the investigators will reconfirm whether the participant meets definition
of relapse including the same items of the first assessment at least and the relapse was caused by
worsening of TAK to make a final judgement of the relapse at Relapse Confirmation Visit.
Completion of confirmation for relapse must occur within the allowed window of 2 weeks (Refer
to Section 10.4, Appendix 4: Relapse Judgement Flow). After completion of confirmation, the first
relapse visit date will be regarded as relapse date.
In addition, if participants meet the definition of relapse by having only non-specific signs and
symptoms once, clinical and laboratory evidence (and imaging results if available) of the
non-specific signs and symptoms will be adjudicated by the blinded sponsor medical monitor to
verify that these are derived by worsening of TAK prior to the investigator’s final judgement of
the relapse. The sponsor’s medical monitor may request additional information as necessary.
Definition of relapse by having non-specific symptoms are described in Section 10.3, Appendix 3:
Definitions of relapse/remission of TAK.
8.1.2. 
Physician Global Activity-Visual Analog Scale (PhGA-VAS)
Physician Global Activity is partially validated tool to measure the global evaluation by the
physician of the participant's overall disease activity at the time of assessment using a 10 cm VAS.
8.1.3. 
Imaging
Computed tomography angiography (CTA) and magnetic resonance angiography (MRA) are
imaging modalities of choice for the assessment of the vessels’ lumen in terms of caliber
irregularities or stenosis, the vessels’ wall in terms of thickening and contrast enhancement, and
assessment of the surrounding tissue, using a venous contrast phase (Dejaco 2018). CT is suitable
for detecting structural lesions and wall inflammation with a higher resolution and shorter
procedural time than magnetic resonance imaging (MRI), however it entails radiation exposure
(Lariviere 2016).
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In this study, imaging assessment will be performed using CTA or MRA, if CTA is not feasible,
by the dedicated radiologist or physician from study site (or designee) at specified time point in
Schedule of Activities (Section 1.3). The same imaging modality will be used for the same
participant throughout the study. Imaging assessment will include the aorta and its major branches
from the terminal of the common carotid artery (internal and external carotid branches) to the
abdominal aortic terminal (common iliac artery branch) and will be performed in multiple planes
using contrast media agent. When imaging assessment has been performed within 12 weeks prior
to scheduled imaging assessment visit, imaging assessment may not be performed, and the prior
results will be used for this scheduled assessment. Imaging assessment for screening visit should
be performed and the prior imaging results for screening assessment will not be allowed.
(1) Vessel involvement such as stenosis, obstruction, and aneurysm; (2) Arterial wall thickness;
and (3) The presence of mural contrast enhancement and oedema (MRA only) will be assessed for
imaging evaluation on disease activity of TAK. Study independent central imaging assessment
will be used to analyze all computed tomography or MRA scans included in this study. The central
imaging assessment of imaging will be blinded to the clinical data. Procedural details are described
in a separate manual.
8.1.4. 
Short Form 36 (SF-36)
The SF-36 is a widely used tool that assesses the global medical quality of life, functional health,
and well-being of general and specific populations. It has shown evidence of content, concurrent,
criterion, construct, and predictive validity in many different chronic diseases and extensive
normative data are available.
8.1.5. 
Patient Global Activity-Visual Analog Scale (PtGA-VAS)
Patient Global Activity is partially validated tool to measure the global evaluation by the
participant of the patient's overall disease activity at the time of assessment using a 10 cm VAS.
8.1.6. 
Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue
The FACIT-Fatigue version 4.0 is a 13-item questionnaire formatted for self-administration that
assesses patient-reported fatigue and its impact upon daily activities and function over the past
7 days. Participants will be asked to answer each question using a 5-point Likert-type scale (0 Not
at all; 1 A little bit; 2 Somewhat; 3 Quite a bit; and 4 Very Much). The interpretation of
FACIT-Fatigue scores is such that a higher score indicates less fatigue, with a range of possible
scores of 0-52, with 0 being the worst possible score and 52 the best.
8.1.7. 
Endpoint Definitions
Time to relapse of TAK for primary endpoint is defined as assessment of ‘signs of relapse present’
as judged by the investigator for at least 2 of 5 categories: objective systemic symptoms, subjective
systemic symptoms, elevated inflammation markers, vascular signs and symptoms, or ischemic
symptoms.
Time to relapse of TAK according to Kerr’s definition (Kerr 1994) is defined as assessment of
‘signs of relapse present’ as judged by the investigator for at least 2 of 4 categories: systemic
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symptoms (objective or subjective), elevated inflammation markers, vascular signs, and symptoms
and ischemic symptoms.
8.2. 
Safety Assessments
Safety evaluations will include assessment of AEs, concomitant medications, pregnancy testing,
administration reactions, chemistry and hematology laboratory tests, immunogenicity, vital signs,
and general physical examinations. In addition, ECG, chest x-ray, chest CT, HIV, hepatitis B,
hepatitis C, and TB testing will be required at screening.
Adverse events will be reported and followed by the investigator as specified in Section 10.9,
Appendix 9: Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and
Reporting.
Any clinically relevant changes occurring during the study must be recorded on the AE section of
the eCRF.
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 condition is reached.
The study will include the following evaluations of safety and tolerability according to the time
points provided in the Schedule of Activities (Section 1.3).
8.2.1. 
Physical Examinations
Physical Examinations
Physical examinations will be performed by the investigator or designated physician, nurse
practitioner, or physician assistant as specified in the Schedule of Activities (Section 1.3). Any
new, clinically significant finding (in the opinion of the investigator) must be captured as an AE.
In addition, resolution of any abnormal findings during the study will be noted in the source
document.
The full physical examination will be performed including: the head and neck, chest, abdomen,
and extremities, as well as including examinations based on the individual’s medical history and
manifestations of TAK. Specific assessment of TAK related signs and symptoms will be
performed by a clinical assessor as described in Section 10.2, Appendix 2: Diagnostic criteria for
Takayasu arteritis according to JCS 2017 guideline on management of vasculitis syndrome, and at
time points specified in the Schedule of Activities (Section 1.3).
Assessment of the participants for safety may require some physical examination by an
investigator.
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Height and Weight
Height and weight will be measured as specified in the Schedule of Activities (Section 1.3).
Participants will be instructed to remove shoes and outdoor apparel and gear prior to this
measurement.
8.2.2. 
Vital Signs
Weight, temperature, pulse/heart rate, respiratory rate, blood pressure (right and left hands
separately) will be assessed.
Blood pressure and pulse/heart rate measurements will be assessed with a completely automated
device. Manual techniques will be used only if an automated device is not available.
Blood pressure and pulse/heart rate measurements should be preceded by at least 5 minutes of rest
in a quiet setting without distractions (eg, television, cell phones).
8.2.3. 
Electrocardiograms
During the collection of ECGs, participants should be in a quiet setting without distractions (eg,
television, cell phones). Participants should rest in a supine position for at least 5 minutes before
ECG collection and should refrain from talking or moving arms or legs. If blood sampling or vital
sign measurement is scheduled for the same time point as ECG recording, the procedure should
be performed as in the following order: ECG(s), vital signs, blood draw.
8.2.4. 
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry and hematology will be collected as noted in Section 10.7,
Appendix 7: Clinical Laboratory Tests. The investigator must review the laboratory results,
document this review, and record any clinically relevant changes occurring during the study in the
AE section of the eCRF. The laboratory reports must be filed with the source documents.
With prior sponsor approval, local laboratories may be used in the event of a safety concern or if
initiation of treatment is critical and the central laboratory results are not expected to be available
before the need to provide study intervention or take action to ensure participant safety.
8.2.5. 
Pregnancy Testing
Additional 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
participation in the study.
8.2.6. 
Infections
Participants will be counseled on the signs and symptoms of infections and will be instructed to
contact the site between scheduled visits should any signs and symptoms occur. At each site visit,
investigators or other site personnel are required to evaluate participants for any signs or symptoms
of infection and ask about symptoms of infection or other AEs that may have occurred between
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site visits. Investigators need to consider additional laboratory examination (such as test for fungal
or viral antigen) based on each participant’s risk of opportunistic infection.
8.2.6.1. 
Tuberculosis
In addition to general evaluation for infection, monitoring for TB will be performed with chest
x-ray or chest HRCT and IGRAs as scheduled in Schedule of Activities (Section 1.3).
8.2.7. 
Infusion- or Injection-site Reactions
Participants should be monitored for the occurrence of infusion reactions for at least 1 hour after
IV infusion and injection-site reactions for at least 30 minutes following SC injection.
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting
Timely, accurate, and complete reporting and analysis of safety information, including AEs, SAEs,
and product quality control (PQC), from clinical studies are crucial for the protection of
participants, investigators, and the sponsor and are mandated by regulatory agencies worldwide.
The sponsor has established standard operating procedures in conformity with regulatory
requirements worldwide to ensure appropriate reporting of safety information; all clinical studies
conducted by the sponsor or its affiliates will be conducted in accordance with those procedures.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate,
or the participant's legally acceptable representative) for the duration of the study.
Further details on AEs, SAEs, and PQC can be found in Section 10.9, Appendix 9: Adverse Events,
Serious Adverse Events, Product Quality Complaints, and Other Safety Reporting: Definitions and
Procedures for Recording, Evaluating, Follow-up, and Reporting.
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information
All Adverse Events
All AEs and special reporting situations, whether serious or non-serious, will be reported from the
time a signed and dated ICF is obtained until completion of the participant's last study-related
procedure, which may include contact for follow-up of safety.
Serious Adverse Events
All SAEs, as well as PQC, 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.
Serious adverse events, including those spontaneously reported to the investigator within 16 weeks
after the last dose of study intervention, must be reported. The sponsor will evaluate any safety
information that is spontaneously reported by an investigator beyond the time frame specified in
the protocol.
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Information regarding SAEs will be transmitted to the sponsor using the SAE Form, which must
be completed and signed by a physician from the study site and transmitted to the sponsor within
24 hours. The initial and follow-up reports of an SAE should be made by facsimile (fax).
Telephone reporting should be the exception and the reporter should be asked to complete the
appropriate form(s) first.
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and nonleading
verbal questioning of the participant is the preferred method to inquire about AE occurrence.
Solicited Adverse Events
Solicited AEs are predefined local (at the infusion or injection site) and systemic events for which
the participant is specifically questioned and which are noted by participants in their diary (see
Section 8, STUDY ASSESSMENTS AND PROCEDURES).
Unsolicited Adverse Events
Unsolicited AEs are all AEs for which the participant is not specifically questioned in the
participant diary.
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events
The investigator is obligated to perform or arrange for the conduct of supplemental measurements
and evaluations as medically indicated to elucidate the nature and causality of the AE, SAE, or
PQC as fully as possible. This may include additional laboratory tests or investigations,
histopathological examinations, or consultation with other health care professionals.
Adverse events, including pregnancy, will be followed by the investigator as specified in
Section 10.9, Appendix 9: Adverse Events, Serious Adverse Events, Product Quality Complaints,
and Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up,
and Reporting.
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events and
Anticipated Events
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities.
The sponsor will also report to the investigator (and the head of the investigational institute where
required) all suspected unexpected serious adverse reactions (SUSARs). The investigator (or
sponsor where required) must report SUSARs to the appropriate Independent Ethics
Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless otherwise
required and documented by the IEC/IRB. A SUSAR will be reported to regulatory authorities
unblinded. Participating investigators and IEC/IRB will receive a blinded SUSAR summary,
unless otherwise specified.
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8.3.5. 
Pregnancy
All initial reports of pregnancy in female participants or partners of male participants must be
reported to the sponsor by the study site personnel within 24 hours of their knowledge of the event
using the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg,
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are
considered SAEs and must be reported using an SAE reporting form. Any participant who becomes
pregnant during the study must be promptly withdrawn from the study and discontinue further
study intervention.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the
infant will be required.
8.3.6. 
Infections
The study intervention should not be administered to a participant with a clinically important,
active infection. Treatment with the study intervention should be withheld until serious and/or
severe infections are completely resolved. If a participant develops a serious or severe infection,
including but not limited to sepsis or pneumonia, discontinuation of the study intervention must
be considered. Treatment must be permanently discontinued for participants who develop a serious
opportunistic infection. This should be discussed with the sponsor. For active varicella zoster
infection or a significant exposure to varicella zoster infection in a participant without history of
chickenpox, the participant should be evaluated for symptoms of infection and if the participant
has received appropriate treatment and/or recovered or has no symptoms of infection, he/she may
continue the study intervention after discussion with the sponsor.
8.3.7. 
Tuberculosis
Any newly identified case of active TB occurring after the first administration of the study
intervention in participants participating in this study must be reported by the investigator
according to the local procedures. These events are to be considered serious only if they meet the
definition of an SAE. Treatment must be permanently discontinued for participants with active TB.
8.3.8. 
Infusion- or Injection-site Reactions
An infusion reaction is defined as an AE that occurs during or within 1 hour following the infusion
of the study intervention, excluding laboratory abnormalities. Permanent discontinuation of the
study intervention must be considered for participants who experience an AE of infusion reaction
that is considered serious or severe by the investigator.
8.3.9. 
Events of Special Interest
Adverse events of special interest: opportunistic infection (ie, infection by an organism that
normally is not pathogenic or does not cause invasive infection in immunocompetent hosts), case
of active TB, or malignancy occurring after the first administration of study intervention in
participants in this study must be reported by the investigator following procedures. Investigators
are also advised that active TB is considered a reportable disease required by local regulations.
These events are to be considered serious only if they meet the definition of an SAE as shown in
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Section 10.9, Appendix 9: Adverse Events, Serious Adverse Events, Product Quality Complaints,
and Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up,
and Reporting.
8.3.10. 
Disease-related Events and Disease-related Outcomes Not Qualifying
as Adverse Events or Serious Adverse Events
All events that meet the definition of an SAE will be reported as SAEs, regardless of whether they
are protocol-specific assessments.
8.4. 
Pharmacokinetics
Serum samples will be used to evaluate the PK of ustekinumab. Serum collected for PK 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. Participant
confidentiality will be maintained.
8.4.1. 
Evaluations
At visit for measurement of ustekinumab concentrations in PK only evaluations (ie, no
anti-ustekinumab antibodies will be evaluated), venous blood samples of 5 mL should be collected
and each sample will be divided into 2 aliquots (1 for serum ustekinumab concentration and 1 for
back-up). At visit for serum concentration of PK and immunogenicity, venous blood samples of
7.5 mL should be collected, and each sample will be divided into 3 aliquots (1 each for serum
concentration of ustekinumab, for anti-ustekinumab antibodies, and for back-up). Additional
information about the collection, handling, and shipment of biological samples can be found in the
laboratory manual.
8.4.2. 
Analytical Procedures
Pharmacokinetics
Blood samples will be collected to evaluate the serum PK of ustekinumab as specified in Schedule
of Activities (Section 1.3). Serum samples will be analyzed to determine concentrations of
ustekinumab using a validated, specific, and sensitive method by or under the supervision of the
sponsor.
8.5. 
Genetics and Pharmacogenomics
Pharmacogenomics
A pharmacogenomic blood sample will be collected from participants who consent separately to
this component of the study to allow for pharmacogenomic research, as necessary. Participant
participation in pharmacogenomic research is optional.
HLA-B and IL-12B genotype
The genotypes of the HLA-B and IL-12B genes will be tested for participants who consent
separately to this component of the study. The genotyping tests may include, but are not limited
to, the presence of HLA-B*52:01 allele (for HLA-B) and rs6871626 polymorphism (for IL-12B).
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Genetic (DNA) variation may be an important contributory factor to interindividual variability in
drug response and associated clinical outcomes. Genetic factors may also serve as markers for
disease susceptibility and prognosis and may identify population subgroups that respond
differently to an intervention.
DNA samples may be analyzed for identification of genetic and epigenetic factors that may be
associated with the disease and/or the responses to the treatment. This research may consist of the
analysis of 1 or more candidate genes, or the analysis of genetic and epigenetic markers throughout
the genome, or analysis of the entire genome (as appropriate) in relation to ustekinumab
intervention and/or TAK. Whole blood samples will be collected for genetic analyses at screening
as specified in the Schedule of Activities (Section 1.3) if within the maximum blood volume
allowed.
8.6. 
Biomarkers
Biomarker assessments will be performed to identify biomarkers that are relevant to ustekinumab
treatment and/or TAK. These may include, but are not limited to, the evaluation of relevant
biomarkers in serum, whole blood, and peripheral blood mononuclear cell (PBMC) samples
collected as specified in the Schedule of Activities (Section 1.3). Data collected from these samples
will be used for exploratory research that will include the following objectives:
 
To understand the molecular effects of ustekinumab.
 
 To understand TAK pathogenesis.
 
To understand why individual participants may respond differently to ustekinumab.
 
To understand the impact of treatment with ustekinumab on vascular or systemic
inflammation.
Stopping Analysis
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and
clinical response rates. Biomarker analysis may be deferred or not performed, during or at the end
of the study, if it becomes clear that the analysis will not have sufficient scientific value for
biomarker evaluation or if there are not enough samples or responders to allow for adequate
biomarker evaluation. In the event the study is terminated early or shows poor clinical efficacy,
completion of biomarker assessments will be based on justification and intended utility of the data.
8.6.1. 
Pharmacodynamics
Samples for the analysis of pharmacodynamic biomarkers will be collected from all participants.
Serum level of IL-12, IL-23, IL-17A, IL-17F, and IL-22 may be measured to assess the
pharmacodynamic effect of ustekinumab.
8.6.2. 
Serum biomarkers
Blood samples will be collected from all participants for serum-based biomarker analyses, where
local regulations permit. Serum may be analyzed for levels of specific proteins, autoantibodies,
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other inflammation-related molecules, and/or broad panel of analytes relevant to TAK
pathogenesis and ustekinumab treatment.
8.6.3. 
Whole Blood Gene Expression Profile
Whole blood will be collected by venipuncture from participants for RNA expression analysis,
where local regulations permit. Total RNA will be isolated and used for differential gene
expression analyses to identify gene expression patterns that are relevant to ustekinumab treatment
and/or TAK and to evaluate markers that can predict clinical response. Transcriptomic studies may
be conducted using microarray and/or alternative equivalent technologies, which facilitate the
simultaneous measurement of the relative abundances of multiple RNA species resulting in a
transcriptome profile for each blood sample. The samples may also be used for targeted assessment
of genes relevant to the disease and/or the treatment. These analyses may be used to evaluate the
changes in gene expression profiles that may correlate with biologic response relating to TAK
and/or the action of ustekinumab and may also be used to identify population subgroups that
respond differently to an intervention.
8.6.4. 
Peripheral Blood Mononuclear Cells
Whole blood will also be collected and processed for peripheral blood mononuclear cells (PBMC)
isolation and cryopreserved for later analysis. Analysis may include but is not limited to flow
cytometric assessment of cell populations, single cell transcriptomics, or functional assessment of
cells in response to ustekinumab treatment and/or related to TAK pathogenesis. These analyses
may not be performed if cryopreserved PBMC samples do not meet the quality or quantity standard
required for the assessments.
8.7. 
Immunogenicity Assessments
Anti-ustekinumab antibodies will be evaluated in serum samples collected from all participants
according to the Schedule of Activities (Section 1.3). Additionally, serum samples should also be
collected at the safety follow-up visit from participants who discontinued study intervention or
were withdrawn from the study. These samples will be tested by the sponsor or sponsor's designee.
Serum samples will be screened for antibodies binding to ustekinumab and the titer of confirmed
positive samples will be reported. Serum samples that test positive for anti-ustekinumab antibodies
will be further characterized to determine if anti-ustekinumab antibodies could neutralize the
biological effects of ustekinumab in vitro (ie, neutralizing antibodies [NAbs] to ustekinumab).
Other analyses may be performed to verify the stability of antibodies to ustekinumab and/or further
characterize the immunogenicity of ustekinumab.
Samples collected for 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. Participant confidentiality will be maintained.
Analytical Procedures
The detection and characterization of anti-ustekinumab antibodies will be performed using a
validated assay method by or under the supervision of the sponsor. All samples collected for
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detection of anti-ustekinumab antibodies will also be evaluated for ustekinumab serum
concentration to enable interpretation of the antibody data. Antibodies may be further
characterized and/or evaluated for their ability to neutralize the activity of the study intervention(s).
Samples may be stored up to 15 years (or according to local regulations) following the last
participant’s last visit for the study at a facility selected by the sponsor to enable further analysis
of immune responses to ustekinumab.
8.8. 
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics parameters are not evaluated in this study.
9. 
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general
description of the statistical methods to be used to analyze the efficacy and safety data is outlined
below. Specific details will be provided in the statistical analysis plan (SAP).
9.1. 
Statistical Hypotheses
The hypothesis is that ustekinumab will prolong time to relapse while attempting corticosteroids
tapering as compared with placebo in participants with TAK.
9.2. 
Sample Size Determination
Thirty-five events of relapse will have a power of 80% to detect a hazard ratio of 0.371 at a 2-sided
alpha level of 0.05 (fixed design with no interim analysis is assumed) assuming a relapse-free rate
of 55% in ustekinumab group and 20% in placebo group at Week 24. The assumptions of
relapse-free rate at Week 24 is based on the results of clinical trial of TCZ showing trend of its
steroid sparing effects in moderate to severe TAK participants. Total sample size is approximately
50 (25/treatment group) participants with which 35 events will occur 105 weeks after the first
participant was enrolled. Regarding study duration, enrollment speed is assumed uniform every
6 months for 2 years; 5 participants for the first 6 months, 12 participants for the next 6 months,
18 participants for the next 6 months, and 15 participants for the last 6 months. Relapse free rate
will carefully be monitored by using blind data during DB period and the actual number of
participants enrolled in this study will be flexibly determined through the trial.
9.3. 
Populations for Analysis Sets
For purposes of analysis, the following populations are defined:
Population 
Description
Enrolled 
All participants who sign the ICF.
Randomized 
All participants who were randomized in the study.
FAS 
All randomized participants who take at least 1 dose of study intervention. Full analysis set
will be the primar y population for efficac y analyses.
Safety 
All participants who take at least 1 dose of stud y intervention.
PK 
All participants who take at least 1 complete dose of ustekinumab and have at least 1
post-dose sample collection.
Immunogenicity 
All participants who take at least 1 dose of ustekinumab and have at least 1 post-dose sample
collection.
Abbreviations: FAS=full analysis set; ICF=informed consent form; PK=pharmacokinetic
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9.4. 
Statistical Analyses
The SAP will be finalized prior to DBL and it will include a more technical and detailed description
of the statistical analyses described in this section. This section is a summary of the planned
statistical analyses of the most important endpoints including primary and key secondary endpoints.
9.4.1. 
Primary Estimand
The primary estimand, the main clinical quantity of interest to be estimated in this study, is defined
by the following 5 components:
 
Population: Participants with TAK who have not adequately responded to conventional
therapy
 
Endpoint: Time from randomization to relapse
 
Treatment: Stelara versus placebo
 
Intercurrent Events (ICE)
 
Death or treatment discontinuation: Use time to ICE (While on treatment strategy)
 
Major protocol deviation: Use time to relapse regardless of the occurrence of major
protocol deviations (Treatment policy strategy)
 
Population level summary: Hazard ratio for time to relapse
9.4.2. 
Primary Endpoint
Primary analysis will be performed after 35 events of relapse occurred. For the primary endpoint
of time to relapse, primary analysis will consist of test using a Cox proportional hazard regression
model for comparison between 2 treatment groups. GC dose at Week 0 and the status of previous
biologic medication will be considered as stratification factors. The hazard ratio and its 2-sided
95% confidence intervals will be also presented. The Kaplan-Meier method will be used to
estimate the distribution of time to relapse for each treatment. One efficacy interim analysis is
planned and the type I error rate will be controlled at 5% (2-sided). The significant level is to be
determined based on the O’Brien-Fleming alpha spending function. Based on this approach, the
interim analysis will be performed at a significance level of 0.0012 when exactly 15 of 35 events
were observed and if the study is not stopped, the final analysis performed at the 0.0496
significance level.
9.4.3. 
Secondary Endpoints
Other time-to-event efficacy endpoints
Time-to-relapse using other definitions such as Kerr’s definition, based on clinical symptoms only
and each of 5 categories will be estimated by Kaplan-Meier method. The hazard ratio and its
2-sided 95% confidence intervals will be estimated using Cox proportional hazard regression
model. GC dose at Week 0 and the status of previous biologic medication will be considered as
stratification factors. Proportion of number of relapsed participants through treatment period will
be also summarized by each definition of relapse.
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GC tapering
Prednisolone dose will be descriptively summarized including cumulative dose and change from
baseline through the end of DB period. Proportion of participants who achieved GC dose of
5mg/day or less will be also summarized.
Imaging
Change from baseline in imaging evaluation through the end of DB period will be calculated.
Inflammatory makers
Change from baseline in inflammatory markers (CRP and ESR) through the end of DB period will
be descriptively summarized.
9.4.4. 
Exploratory Endpoints
For exploratory endpoints, the continuous variables will be summarized by intervention group and
week using descriptive statistics, which will include the number of participants (N), mean, standard
deviation (SD), median, minimum, and maximum. The categorical variables will be summarized
by intervention group and week using frequencies and percentages. The further details will be
described in SAP.
Exploratory endpoints are as follows:
 
Proportion of participants who experienced relapse using each definition such as
protocol-defined criteria, Kerr’s definition, based on clinical symptoms only and each of five
categories during OLE period.
 
Changes from baseline on PROs through the end of study (SF-36, PtGA of disease activity on
VAS, FACIT-Fatigue) through the end of study.
 
Change from baseline PhGA through the end of study.
 
Cumulative oral GC dose during OLE period.
 
Change from baseline in oral GC dose during OLE period.
 
Proportion of participants achieving oral GC dose of 5 mg/day or less during OLE period.
 
Change from baseline in imaging evaluation during OLE period.
 
Change from baseline in inflammatory markers (CRP, ESR) during OLE period.
For continuous variables of patient reported outcomes, descriptive analysis followed by mixed
model repeated measures will be used. No adjustment for multiple comparison will be made.
9.4.5. 
Safety Analyses
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the
Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent AEs are AEs with
onset during the treatment phase or that are a consequence of a preexisting condition that has
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worsened since baseline. All reported AEs with onset during treatment phase (ie, TEAEs and AEs
that have worsened since baseline) will be included in the analysis. For each AE, the percentage
of participants who experience at least 1 occurrence of the given event will be summarized by
intervention group.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those
participants who die, who discontinue intervention due to an AE, or who experience a severe or an
SAE.
All safety analyses will be performed on the safety population.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly
abnormal results (specified in the SAP) will be used in the summary of laboratory data. Descriptive
statistics will be calculated for each laboratory analyte at baseline and for observed values and
changes from baseline at each scheduled time point. Frequency tabulations of the changes from
baseline will be presented in pre- versus post-intervention cross-tabulations (with classes for below,
within, and above normal ranges). Frequency tabulations of the laboratory abnormalities will be
made. A listing of participants with any laboratory results outside the reference ranges will be
provided. A listing of participants with any markedly abnormal laboratory results will also be
provided.
Electrocardiogram
Clinically relevant abnormalities will be evaluated by frequency tabulations.
Vital Signs
Vital signs including descriptive statistics of weight, temperature, pulse/heart rate, respiratory rate,
and blood pressure (right and left hands separately, systolic and diastolic) values and changes from
baseline will be summarized over time at each scheduled time point, using descriptive statistics
and/or graphically. The percentage of participants with values beyond clinically important limits
will be summarized.
Physical Examinations
Descriptive statistics of changes from baseline will be summarized at each scheduled time point.
Physical examination findings will be summarized at each scheduled time point. Descriptive
statistics will be calculated at baseline and for observed values and changes from baseline at each
scheduled time point. Frequency tabulations of the abnormalities will be made.
9.4.6. 
Other Analyses
Pharmacokinetics analysis
Pharmacokinetic analyses for ustekinumab will be performed on the PK analysis population.
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Serum ustekinumab concentrations will be summarized with descriptive statistics, including
arithmetic mean, SD, coefficient of variation%, median, interquartile range, minimum, and
maximum at each nominal sampling timepoint. All concentrations below the lowest quantifiable
sample concentration of the assay or missing data will be labeled as such in the concentration data
listing or statistical analysis system dataset. Below the lowest quantifiable concentrations will be
treated as zero in the summary statistics.
Detailed rules for the analysis including exclusion from the PK analyses will be specified in the
SAP. If feasible, population PK analysis of ustekinumab may be performed using nonlinear
mixed-effect modeling. Further details will be provided in a population PK analysis plan and the
results will be provided in a separate report.
Immunogenicity Analyses
Anti-ustekinumab antibodies will be analyzed on the immunogenicity analysis population.
A listing of participants who are positive for anti-ustekinumab antibodies will be provided. The
maximum titers of anti-ustekinumab antibodies will be summarized for participants who are
positive for anti-ustekinumab antibodies. The incidence of NAbs to ustekinumab will be
summarized for participants who are positive for anti-ustekinumab antibodies and have samples
evaluable for NAbs to ustekinumab.
Pharmacodynamic and Biomarker Analyses
The biomarker analyses will be used to understand TAK, characterize the effects of ustekinumab,
to identify PD markers and biomarkers relevant to treatment, and to determine if these markers
can predict response to ustekinumab. The biomarker analyses may include but are not limited to
serum cytokines, inflammatory markers, whole blood RNA profile, and other categories of
biomarkers potentially involved in the development and the progression of TAK.
Changes in biomarkers over time may be summarized by treatment group. Associations between
baseline levels and changes from baseline in selected markers and clinical response may be
explored. Results of biomarker analyses may be presented in a separate technical report.
Planned biomarker analyses may be deferred if emerging study data show no likelihood of
providing useful scientific information or insufficient number of samples are available for analyses.
Any biomarker samples received by the contract vendor or sponsor after the cutoff date will not
be analyzed and therefore, excluded from the biomarker analysis.
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Pharmacokinetic/Pharmacodynamic Analyses
If data permit, the relationship between serum ustekinumab concentration and efficacy/safety
measures, biomarkers, and immunogenicity will be analyzed graphically. In addition, PK/PD
modeling may be performed to characterize the relationship between serum ustekinumab exposure
and efficacy/safety measures. Analyses plan and results may be provided in a separate report.
Pharmacogenomic Analyses
Genetic (DNA) analyses may be conducted only in participants who sign the consent/assent form
to participate in the pharmacogenomic sampling. These analyses are considered exploratory. DNA
samples may be used for research related to ustekinumab or TAK. They may also be used to
develop tests/assays related to ustekinumab and TAK. Pharmacogenomic research may consist of
the analysis of one or more candidate genes or of the analysis of genetic markers throughout the
genome or analysis of the entire genome (as appropriate) in relation to ustekinumab TAK clinical
endpoints. Analyses results may be summarized in a separate technical report.
9.5. 
Interim Analysis
An IDMC will be established to monitor data on an ongoing basis to ensure the continuous safety
and well-being of the participants enrolled in this study. The committee will meet periodically to
review safety data and provide recommendation to the sponsor on continuing the trial. The IDMC
responsibilities, authorities, and procedures will be documented in the IDMC charter.
One efficacy interim analysis is planned after 15 events have been occurred. The O’Brien-Fleming
alpha spending function as implemented by the Lan-DeMets method will be used to determine the
statistical boundary for early success (2-sided p-value ≤0.0012 for the efficacy interim analysis
when exactly 15 of 35 events were observed). Specific details will be provided in the IDMC
Charter and IDMC SAP.
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. 
Appendix 1: Abbreviations and Definitions
AE 
Adverse event
anti-HBc total 
HBV core antibod y total
anti-HBs 
HBV surface antibody 
Aza 
Azathioprine
-hCG 
-human chorionic gonadotrophin
CD 
Crohn’s disease
COVID-19 
Coronavirus Disease 2019
CRP 
CTCAE 
C-reactive protein
Common Terminology Criteria for Adverse Events
CTA 
Computed tomograph  y angiography 
CT 
Computed tomography 
DB 
Double-blind
DBL 
database lock
DM 
dermatomyositis
DNA 
deoxyribonucleic acid
ECG 
electrocardiogram
EPCR 
endothelial protein C receptor
ESR 
erythrocyte sedimentation rate
eCRF 
electronic case report forms
eDC 
electronic data capture
FACIT 
The Functional Assessment of Chronic Illness Therapy 
FSH 
Follicle stimulatin  g hormone
GC 
glucocorticoid
GCA 
Giant Cell Arteritis
GCP 
Good Clinical Practice
HBsAg 
HBV surface antigen
HBV 
hepatitis B virus
HCV 
hepatitis C virus
HIV 
human immunodeficienc y virus
HLA 
Human leucocyte antigen
HRCT 
high-resolution computer tomography 
IB 
Investigator's Brochure
IBD 
inflammator y bowel disease
ICE 
Intercurrent events
ICF 
informed consent form/assent form
ICH 
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals
for Human Use
IDMC 
Independent data monitorin  g committee
IDMJE 
International Committee of Medical Journal Editors
IEC 
International ethics committee
IFN 
Interferon
Ig 
Immunoglobulin
IGRA 
interferon gamma release assay 
IL 
Interleukin
INR 
international normalized ratio
IRB 
Institutional Review Board
ISI 
International System of Units
IV 
Intravenous
IWRS 
JAK 
interactive web response system
Janus kinase
LIV 
liquid in vial
LTE 
Long-term extension
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria for Adverse Events
NSAID 
non-steroidal anti-inflammator y drug
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MedDRA 
Medical Dictionar y for Regulator y Activities
MMF 
mycophenolate mofetil
MRA 
Magnetic resonance angiography 
MRI 
Magnetic resonance imaging
MTX 
methotrexate
NAbs 
neutralizin  g antibodies
OLE 
open-label extension
PBMC 
peripheral blood mononuclear cell
PD 
Pharmacodynamic
PFS 
prefilled syringe
PK 
Pharmacokinetic
PM 
polymyositis
PQC 
product qualit y complaint
PRO 
patient-reported outcome
PsA 
PtGA 
psoriatic arthritis
Patient’s global assessment
QFT 
QuantiFERON-TB Gold
Q8W 
Ever y 8 weeks
RA 
rheumatoid arthritis
RNA 
ribonucleic acid
SAE 
serious adverse event
SAP 
statistical analysis plan
SARS-CoV-2 
Severe acute respirator y syndrome-corona virus
SC 
Subcutaneous
SD 
standard deviation
SF-36 
Short form-36
SI 
International System of Units
SLE 
systemic lupus erythematosus
SNPs 
single nucleotide polymorphisms
SR-B1 
scavenger receptor class B type 1
SUSAR 
suspected unexpected serious adverse reactions
TAC 
Tacrolimus
TAK 
Takayasu arteritis
TB 
Tuberculosis
TCZ 
tocilizumab
TEAE 
treatment-emergent adverse events
TNF 
Tumor necrosis factor
UC 
ulcerative colitis
ULN 
upper limit of normal
VAS 
visual analo g scale
WBC 
white blood cell
Definitions of Terms
COA 
An umbrella term encompassin  g different types of outcomes assessments
Electronic source 
system 
Contains data traditionally maintained in a hospital or clinic record to document medical
care or data recorded in a eCRF as determined by the protocol. Data in this system may
be considered source documentation.
PRO 
Reports directl y from the participant without interpretation b y clinician or anyone else
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10.2. 
Appendix 2: Diagnostic criteria for Takayasu arteritis according to JCS
2017 guideline on management of vasculitis syndrome
The diagnostic criteria of definite is at least 1 of the items in A+ any of the conditions in B are
observed, and conditions in C can be excluded.
A. Signs and symptoms
 Systemic signs and symptoms: Fever, generalized malaise, easy fatigability, lymphadenopathy
(cervical), hypertension in younger patients (≥140/90 mmHg)
 Pain: Carotidynia, chest pain, back pain, lower back pain, shoulder pain, upper limb pain, lower
limb pain
 Visual signs and symptoms: Transient or persistent visual impairment, preocular bright or dark
sensation, loss of vision, fundus changes (hypotensive changes, hypertensive changes)
 Head and neck signs and symptoms: Headache, toothache, jaw claudication,*a dizziness, hearing
impairment, tinnitus, syncope, cervical vascular murmurs, hemiplegia
 Upper limb signs and symptoms: Numbness, cold sensation, difficulty in arm raising,
claudication,*b abnormal pulse and blood pressure (weakness or loss of radial artery pulse or left-
right difference of ≥10 mmHg), increased pulse pressure (related to aortic insufficiency)
 Lower limb signs and symptoms: Numbness, cold sensation, weakness, claudication, abnormal
pulse and blood pressure (augmented or weakened pulse of lower limb arteries, reduced blood
pressure, blood pressure difference between upper and lower limbs*c)
 Chest symptoms: Shortness of breath, palpitation, dyspnea, bloody sputum, sensation of chest
compression, anginal symptoms, arrhythmia, cardiac murmur, back vascular murmur
 Abdominal signs and symptoms: Abdominal vascular murmur, complication by ulcerative colitis
 Skin signs and symptoms: Erythema nodosum
*a. Intermittent mastication due to pain caused by mastication
*b. Intermittent exertion of the upper limbs due to pain and weakness caused by exertion
*c. Instances other than “10–30 mmHg higher in the lower limb than upper limb”
B. Examination findings
Imaging examination findings: In the aorta or its primary branches*a or both, multiple*b or diffuse
hypertrophic lesions,*c stenotic lesions (including occlusions),*d or dilated lesions (including
aneurysms)*d detected.
*a. The aorta and its primary branches corresond to the aorta (ascending, arch, thoracic
descending, abdominal descending), primary branches of the aorta (including the coronary
artery), and pulmonary artery.
*b. Multiple lesions are defined as those that involve two or more of the above arteries or sites or
two or more segments of the aorta.
*c. Hypertrophic lesions are detected by ultrasonography (macaroni sign of the common carotid
artery), contrast-enhanced CT, contrast-enhanced MRI (circumferential contrast enhancement
of the arterial wall), and PET-CT (circumferential FDG uptake of the arterial wall).
*d. Stenotic lesions and dilated lesions are detected by chest radiography (wave-like deformation
of the descending aorta), CT angiography, MR angiography, echocardiography (aortic
insufficiency), and angiography. They are accompanied by dilatation of the ascending aorta
and frequently also by aortic insufficiency. In the chronic stage, circumferential calcification of
the arterial wall is visualized by CT, and the development of collateral circulation is detected
by CT angiography and MR angiography
 
Points of attention in imaging diagnosis: Contrast-enhanced CT is performed in the late phase of
contrast enhancement. CT angiography is performed in the early phase of contrast enhancement with 3-
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dimensional image processing. Angiography is usually performed when other procedures such as
endovascular treatment and coronary artery angiography or left ventriculography are simultaneously
intended.
C. Conditions to be included in the differential diagnoses of Takayasu arteritis
Arteriosclerosis, congenital vascular anomaly, inflammatory abdominal aortic aneurysm, infectious
aneurysm, syphilitic mesaortitis, giant cell arteritis (temporal arteritis), vascular Behçet’s disease,
IgG4-related diseases.
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10.3. 
Appendix 3: Definitions of relapse/remission of TAK
Definitions of relapse of TAK (Inclusion criteria definition/Efficacy evaluation definition)
Category 
Inclusion criteria definition
When 2 or more categories in the
following 5 categories meet the criteria,
participants will be judged as relapse.
Efficacy evaluation definition
When 2 or more categories in the
following 5 categories meet the criteria,
participants will be judged as relapse.
Even if signs of relapse were not present
in 2 of 5 categories, relapse was
considered to have occurred if emergent
hospitalization caused by worsening of
TAK and GC treatment required or if
severe aortic valve incompetence
accompanied by symptoms of cardiac
failure occurred under ‘vascular signs
and symptoms’ or if CTCAE grade 2 or
higher (grade ≥3 for myocardial
infarction) occurred under ‘ischaemic
symptoms’.
1. Systemic
symptoms
(objective
assessment)
An assessment of ‘signs of relapse
present’ should be made for this category
if any of the following are observed;
 Fever: body temperature ≥38.0°C
 Weight loss: weight loss >2 kg in
4 weeks
 Arthritis: joint symptoms in ≥2 joints
(arthralgia, swelling and tenderness in
joints)
An assessment of ‘signs of relapse
present’ should be made for this
category if any of the following are
observed;
 Fever: body temperature ≥38.0°C
 Weight loss: weight loss >2 kg since
the previous measurement
 Arthritis: joint symptoms in ≥2 joints
(arthralgia, swelling, and tenderness
in joints)
2. Systemic
symptoms
(subjective
assessment)
An assessment of ‘signs of relapse
present’ should be made for this category
if any of the following symptoms are
observed at grade 2 or higher
 Malaise
 Myalgia
 Headache
 Dizziness/vertigo
An assessment of ‘signs of relapse
present’ should be made for this
category if there is an increase in the
CTCAE grade from baseline for any of
the following
 Malaise
 Myalgia
 Headache
 Dizziness/vertigo
3. Elevated
inflammation
markers
An assessment of ‘signs of relapse
present’ should be made for this category
if the following is observed
 CRP ≥1.0 mg/dL an  d ESR ≥30 mm/h
An assessment of ‘signs of relapse
present’ should be made for this
category if the following is observed
 CRP ≥1.0 mg/dL an  d ESR ≥30 mm/h
4. Vascular
signs and
symptoms
An assessment of ‘signs of relapse
present’ should be made for this category
if any of the following are observed;
 Renovascular hypertension
 Normal blood pressure
<120/80 mm Hg: has risen to
140/90 mm Hg or higher
 An assessment of ‘signs of relapse
present’ should be made for this
category if any of the following are
observed;
 If severe aortic valve incompetence
accompanied by symptoms of
cardiac failure occurs, it should be
deemed that relapse of TA  K has
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 Normal blood pressure
≥120/80 mm Hg: diastolic blood
pressure has risen by ≥20 mm Hg
 New vascular bruits (carotid artery,
subclavian artery, renal artery)
 New loss of pulse (carotid artery,
subclavian artery, brachial artery,
radial artery, femoral artery, popliteal
artery, posterior tibial artery, dorsalis
pedis artery)
 New difference in blood pressure
between left and right: new difference
in systolic blood pressure between left
and right ≥10 mm Hg
 Tenderness or spontaneous pain in
carotid artery: symptoms of CTCAE
grade 2 or higher
 Spontaneous pain in chest region or
back region: symptoms of CTCAE
grade 2 or higher
 Onset of aortic valve incompetence
(moderate or severe)
occurred, even if none of the criteria
for categories 1-3 or 5 are met
 Renovascular hypertension
 <120/80 mm Hg at baseline:
has risen to ≥140/90 mm Hg
 ≥120/80 mm Hg at baseline:
diastolic blood pressure has
risen by ≥20 mm Hg
 New vascular bruits (carotid artery,
subclavian artery, renal artery)
 New loss of pulse (carotid artery,
subclavian artery, brachial artery,
radial artery, femoral artery, popliteal
artery, posterior tibial artery, dorsalis
pedis artery)
 New difference in blood pressure
between left and right: new
difference in systolic blood pressure
between left and right of ≥10 mm Hg
 Tenderness or spontaneous pain in
carotid artery: increase in CTCAE
grade since baseline
 Spontaneous pain in chest region or
back region: increase in CTCAE
grade since baseline
 Aortic valve incompetence
(worsening from ‘no symptoms’ or
‘mild’ to at least ‘moderate’ or
worsening from ‘moderate’ to
‘severe’)
5. Ischaemic
symptoms
An assessment of ‘signs of relapse
present’ should be made for this category
if any of the following symptoms are
observed at grade 2 or higher
 Abdominal pain
 Seizure
 Syncope
 Intermittent claudication
 Ischaemic cardiac pain
An assessment of ‘signs of relapse
present’ should be made for this
category if there is an increase in the
CTCAE grade from baseline for any of
the following events. If symptoms of
grade 2 or higher (grade 3 or higher for
myocardial infarction) occur, it should
be deemed that TAK has occurred, even
if none of the criteria for categories 1-4
are met
 Abdominal pain
 Stroke
 Seizure
 Syncope
 Intermittent claudication
 Ischaemic cardiac pain
 Myocardial infarction
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Definitions of another relapse of TAK
 
Definition
Relapse of TAK by
having non-specific
symptoms
Participants meet 2 or more categories in the following 5 categories without
meeting 4) or 5) will be considered as relapse per non-specific symptoms:
1) Objective systemic symptoms; 2) Subjective systemic symptoms; 3)
Elevated inflammation markers; 4) Vascular signs and symptoms; 5) Ischemic
symptoms.
Relapse of TAK
according to Kerr’s
definition
Participants meet 2 or more categories in the following 4 categories will be
considered as relapse per Kerr’s definition: 1) Objective systemic symptoms or
subjective systemic symptoms, 2) Elevated inflammation markers, 3) Vascular
signs and symptoms or ischemic symptoms, 4) Imaging evaluation*.
 
*Imaging evaluation: whether typical imaging features is present (eg, long
segments of critical stenoses [>70%])
Relapse of TAK based
on clinical symptoms
only
Participants meet at least 1 category in the following 4 clinical categories are
considered as relapse per clinical symptom only definition: 1) Objective
systemic symptoms; 2) Subjective systemic symptoms; 3) Vascular signs and
symptoms; 4) Ischemic symptoms.
Definitions of remission of TAK
Category 
When the following 5 categories are assessed ‘absence of any of the
signs and symptoms’ as judged by the investigator, participants will
be judged as remission.
1. Systemic symptoms  
(objective assessment) 
An assessment of ‘absence of signs’ should be made for this category
if any of the following are not observed
 Fever: body temperature ≥38.0°C
 Weight loss: weight loss >2 kg in 4 weeks
 Arthritis: joint symptoms in ≥2 joints (arthralgia, swelling, and
tenderness in joints)
2. Systemic symptoms  
(subjective assessment) 
An assessment of ‘absence of signs’ should be made for this category
if any of the following symptoms are not observed at grade 2 or
higher
 Malaise
 Myalgia
 Headache
 Dizziness/vertigo
3. Elevated inflammation
markers*
An assessment of ‘absence of signs’ should be made for this category
if the following is not observed
 CRP ≥1.0 mg/dL and ESR ≥30 mm/h
4. Vascular signs and
symptoms
An assessment of ‘absence of signs’ should be made for this category
if any of the following are not observed
 Tenderness or spontaneous pain in carotid artery: symptoms of
CTCAE grade 2 or higher
 Spontaneous pain in chest region or back region: symptoms of
CTCAE grade 2 or higher
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5. Ischaemic symptoms 
An assessment of ‘absence of signs’ should be made for this category
if any of the following symptoms are not observed at grade 2 or higher
 Abdominal pain
 Seizure
 Syncope
 Intermittent claudication
 Ischaemic cardiac pain
*“3. Elevated inflammation markers” is not included in Assessment of “Remission of clinical symptoms”.
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10.4. 
Appendix 4: Relapse Judgement Flow
When participants meet the criteria of the TAK relapse described in Section 10.3 after
administration of study intervention during the study, the investigators will follow the processes
below to judge the relapse of TAK. The processes are shown in Figure 2.
Figure 2: 
Flow Chart For Relapse Judgement Process
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The flows of relapse judgement without adjudication and with adjudication are described below:
Relapse judgement process without adjudication
The schematic flow of relapse judgement process without adjudication is shown in Figure 3.
For the first relapse visit, the investigator or designee will record possible other causes on the
Source Document. For the Relapse Confirmation Visit, the investigator or designee will record the
reason for eliminating other causes in the eDC.
Inflammation marker results (ie, CRP) provided by central lab is encouraged to be used to judge
relapse of TAK in this process.
Figure 3: 
The flow of relapse judgement without adjudication
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Relapse judgement process with adjudication
The schematic flow of relapse judgement process with adjudication is shown in Figure 4.
For the first relapse visit, the investigator or designee will record the possible other causes, and the
Relapse Confirmation Visit date on the Source Document, and will submit these information to
the sponsor  within 3 working days. The sponsor’s medical monitor will verify it and may request
additional information as necessary until the Relapse Confirmation Visit. If the Relapse
Confirmation Visit is scheduled within 5 working days of the first relapse visit, the investigator or
designee should contact sponsor. For the Relapse Confirmation Visit, the investigator or designee
will record the reason for eliminating other causes in the eDC.
Inflammation marker results (ie, CRP) provided by central lab is encouraged to be used to judge
relapse of TAK in this process.
Figure 4: 
The flow of relapse judgement with adjudication
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10.5. 
Appendix 5: Definition of Inadequate Response or Intolerance to Biologics
The criteria for inadequate response or intolerance to biologics (TCZ or anti-TNF therapies
[infliximab, adalimumab, certolizumab pegol, etanercept, etc]) are described in items 1 and 2,
below. Participants who meet 1 of the 2 items are considered to be bio-failure.
1. Inadequate response to current or prior therapy with TCZ or anti-TNF therapy
Eligible participants must satisfy criteria a, b, c.
a. Have received at least 4 weeks treatment of:
1) Tocilizumab (at SC dose of 162 mg/week)
or
2) Anti-TNF therapy (infliximab, adalimumab, certolizumab pegol, golimumab, etc)
AND
b. Was not able to taper oral GC dose to 7.5 mg/day (prednisolone or equivalent) or less due
to disease activity of TAK based on clinical judgment of a treating physician.
The disease activity of TAK must have persisted ≥2 weeks after receiving one of the
biologic treatments.
AND
c. Have documentation available to the investigator that meets the following 2 requirements:
1) Provide the dates and doses of the failed TCZ or anti-TNF therapy.
2) Documents that the participant had inadequate response to TCZ or anti-TNF therapy.
Examples of acceptable documents include: medical records, letter provided by a
referring physician, or other “reason for referral” documents (eg, insurance authorization
form).
2. Current or prior intolerance to therapy with TCZ or anti-TNF therapy
Eligible participants must satisfy criteria a and b.
a. Have had an adverse reaction that meets 1 of the following 3 criteria: 1) significant
acute 
infusion/administration 
reaction; 
2) significant 
delayed
infusion/administration reaction (eg, delayed hypersensitivity or serum sickness-like
reaction); or 3) significant injection-site reaction. Definitions of these 3 criteria are
provided below.
Adverse reactions also must have followed 1 dose of TCZ, or anti-TNF therapy and,
in the treating physician’s opinion, precluded continued use of the therapy.
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1) A significant acute infusion/administration reaction is defined as an adverse reaction
that was:
 
Manifested through 1 of the following symptoms.
a. Fever greater than 100 F (37.8 C)
b. Chills or rigors
c. Itching
d. Rash
e. Flushing
f. Urticaria or angioedema
g. Breathing difficulties (dyspnea, chest paint or tightness, shortness of breath,
wheezing, stridor)
h. Clinical hypotension (pallor, diaphoresis, faintness, syncope), blood pressure
less than 90 mm Hg systolic and 60 mm Hg diastolic, or a systemic or
orthostatic drop in systolic blood pressure of greater than 20 mm Hg
and
 
Occurred within 24 hours after infusion/administration of tocilizumab or anti-
TNF therapy.
and
 
Was considered related to the infusion/administration of TCZ or anti-TNF
therapy.
2) A significant delayed infusion/administration reaction is defined as an adverse
reaction that:
 
Was manifested through 1 or more of the following symptoms:
a. Myalgias
b. Arthralgias
c. Fever greater than 100 F (37.8 C)
d. Malaise
e. Rash
and
 
Occurred >24 hours and <15 days after infusion/administration of TCZ or anti-
TNF therapy.
and
 
Was considered related to the infusion/administration of TCZ or anti-TNF
therapy.
3) A significant injection-site reaction is defined as an adverse reaction that:
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 
Was manifested through 1 or more of the following symptoms:
a. Significant bruising
b. Erythema
c. Hemorrhage
d. Irritation
e. Pain
f. Pruritus
g. “Injection-site reaction”
and
 
Occurred within 24 hours of infusion/administration of TCZ or anti-TNF therapy.
and
 
Was considered related to the injection.
b. Have documentation available to the investigator that meets the following 2
requirements:
1) Provides the date of discontinuation of TCZ or anti-TNF therapy.
2) Documents that the participant had intolerance to TCZ or anti-TNF therapy.
Examples of acceptable documents include: medical records, letter provided by a
referring physician, or other “reason for referral” documents (eg, insurance authorization
form).
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If dipstick result is abnormal, microscopy will be used to measure sediment.
In the microscopic examination, observations other than the presence of WBC, RBC,
and casts may also be reported by the laboratory.
Dipstick and sediment analysis of the urine samples will be performed in parallel at
screening, ie, in the same sample at the same time. Specific gravity, pH, glucose,
protein (eg, myoglobin), blood, ketones, bilirubin, and urobilinogen will be
determined using a dipstick. Red blood cells, WBC, epithelial cells, crystals, casts,
and bacteria will be measured using flow cytometry or microscopy. If there is
discordance between the dipstick results and the flow cytometric results, the
sediment will be examined microscopically. Crystals, casts, and bacteria will only be
reported if they are present.
Genetic test  
 
HLA-B52 at screening only
 
IL-12B at screening only
Other
Screening Tests
 
Urine pregnancy testing for women of childbearing potential only
 
Serum pregnancy test (at the discretion of the investigator)
 
Viral serology (HIV antibody, HBsAg, anti-HBs, anti-HBc total, and HCV
antibody) at screening only
 
Coagulation (prothrombin time [PT], activated partial thromboplastin time
[aPTT], and international normalized ratio) at screening only
 
IGRA (performed locally)
 
CRP and ESR
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10.8. 
Appendix 8: Regulatory, Ethical, and Study Oversight Considerations
10.8.1. 
Regulatory and Ethical Considerations
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the
protocol, current International Council for Harmonisation of Technical Requirements for
Pharmaceuticals for Human Use (ICH) guidelines on good clinical practice (GCP) and applicable
regulatory and country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing,
conducting, recording, and reporting studies that involve the participation of human participants.
Compliance with this standard provides public assurance that the rights, safety, and well-being of
study participants are protected, consistent with the principles that originated in the Declaration of
Helsinki and that the study data are credible.
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 participants, 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) involve only logistic or administrative aspects of the study, the IEC/IRB (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
listed in the Protocol Supplementary Information page(s), which will be provided as a separate
document. Except in emergency situations, this contact should be made before implementing any
departure from the protocol. In all cases, contact with the sponsor must be made as soon as possible
to discuss the situation and agree on an appropriate course of action. The data recorded in the eCRF
and source documents will reflect any departure from the protocol and the source documents will
describe this departure and the circumstances requiring it.
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.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study intervention
to the study site:
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 
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, participant 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
participant:
 
Completed investigator financial disclosure forms from all subinvestigators
 
Documentation of subinvestigator qualifications (eg, curriculum vitae)
 
Name and address of any local laboratory conducting tests for the study and a dated copy of
current laboratory normal ranges for these tests, if applicable
 
Local laboratory documentation demonstrating competence and test reliability
(eg, accreditation/license), if applicable
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB
with current and complete copies of the following documents (as required by local regulations):
 
Final protocol and, if applicable, amendments
 
Sponsor-approved ICF (and any other written materials to be provided to the participants)
 
IB (or equivalent information) and amendments/addenda
 
Sponsor-approved participant recruiting materials
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 
Information on compensation for study-related injuries or payment to participants 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 participants
 
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
participants, data or study conduct, unless required locally), the ICF, applicable recruiting materials,
and participant 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 participants, data, or study conduct)
 
Revision(s) to ICF and any other written materials to be provided to participants
 
If applicable, new or revised participant recruiting materials approved by the sponsor
 
Revisions to compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 
New edition(s) of the IB and amendments/addenda
 
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at
least annually)
 
Reports of AEs that are serious, unlisted/unexpected, and associated with the study
intervention
 
New information that may adversely affect the safety of the participants or the conduct of the
study
 
Deviations from or changes to the protocol to eliminate immediate hazards to the participants
 
Report of deaths of participants 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
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For all protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, 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, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about
the study completion (if applicable, the notification will be submitted through the head of
investigational institution).
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
10.8.2. 
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial
information in accordance with local regulations to allow the sponsor to submit complete and
accurate financial certification or disclosure statements to the appropriate regulatory authorities.
Investigators are responsible for providing information on financial interests during the course of
the study and for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) for details on financial disclosure.
10.8.3. 
Informed Consent Process and Assent Form
Each participant (or a legally acceptable representative) must give written consent according to
local requirements after the nature of the study has been fully explained. The ICF(s) must be signed
before performance of any study-related activity. The ICF(s) that is used must be approved by both
the sponsor and by the reviewing IEC/IRB and be in a language that the participant 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 participants (or their legally acceptable representatives) the aims,
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort
participation in the study may entail. Participants will be informed that their participation is
voluntary and that they may withdraw consent to participate at any time. They will be informed
that choosing not to participate will not affect the care the participant will receive for the treatment
of his or her disease. Participants 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 participant 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 participant, to the extent permitted
by the applicable law(s) or regulations. By signing the ICF the participant or legally acceptable
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representative is authorizing such access, which includes permission to obtain information about
his or her survival status. It also denotes that the participant agrees to allow his or her study
physician to recontact the participant for the purpose of obtaining consent for additional safety
evaluations and subsequent disease-related treatments, if needed. The physician may also recontact
the participant for the purpose of obtaining consent to collect information about his or her survival
status.
The participant or legally acceptable representative 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 either the participant's or his or her legally
acceptable representative's personally dated signature. After having obtained the consent, a copy
of the ICF must be given to the participant.
Participants who are rescreened are required to sign a new ICF.
Participants 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 participant
or his or her legally acceptable representative 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 participant.
Where local regulations require, a separate ICF may be used for the required DNA component of
the study.
If the participant or legally acceptable representative is unable to read or write, an impartial witness
should be present for the entire informed consent process (which includes reading and explaining
all written information) and should personally date and sign the ICF after the oral consent of the
participant or legally acceptable representative is obtained.
Children (minors) or participants who are unable to comprehend the information provided can be
enrolled only after obtaining consent of a legally acceptable representative. Assent must be
obtained from children (minors) capable of understanding the nature of the study, typically
participants 7 years of age and older, depending on the institutional policies. Assent must be
obtained from participants who are able to write. A separate assent form in the language the
participant can understand must be developed for adolescents. After having obtained the assent, a
copy of the assent form must be given to the participant, and to the participant's parent(s) or if
applicable legally acceptable representative.
10.8.4. 
Data Protection
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be
limited to those data that are necessary to fulfill the objectives of the study.
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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 participants confidential.
The informed consent obtained from the participant (or his or her legally acceptable representative)
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 participant has the right to request through the investigator access to his or her personal data
and the right to request rectification of any data that are not correct or complete. Reasonable steps
will be taken to respond to such a request, taking into consideration the nature of the request, the
conditions of the study, and the applicable laws and regulations.
Exploratory biomarker, PK, and immunogenicity research is not conducted under standards
appropriate for the return of data to participants. 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 participants 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.
10.8.5. 
Long-term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local regulations)
for additional research. Samples will only be used to understand ustekinumab, to understand TAK,
to understand differential intervention responders, and to develop tests/assays related to
ustekinumab and TAK. The research may begin at any time during the study or the post-study
storage period.
10.8.6. 
Committees Structure
Data Monitoring Committee
A Data Monitoring Committee (DMC) will be established to monitor data on an ongoing basis to
review interim data to ensure the continuing safety of the participants enrolled in this study and to
meet efficacy objectives. The committee will meet periodically to review safety data and provide
recommendation to the sponsor on continuing the trial. The IDMC responsibilities, authorities, and
procedures will be documented in the IDMC charter.
One efficacy interim analysis is planned after 15 events have been occurred. The O’Brien-Fleming
alpha spending function as implemented by the Lan-DeMets method will be used to determine the
statistical boundary for early success (2-sided p-value ≤0.0012 for the efficacy interim analysis
when exactly 15 of 35 events were observed). Specific details will be provided in the IDMC
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Charter and IDMC SAP. This committee will consist of at least one medical expert in the relevant
therapeutic area and at least one statistician; committee membership responsibilities, authorities,
and procedures will be documented in its charter. The committee will meet periodically to review
interim data. After the review, the DMC will make recommendations regarding the continuation
of the study.
10.8.7. 
Publication Policy/Dissemination of Clinical Study Data
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 and 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 data from all study sites that participated in the study as per protocol. 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 for the study. Results of any 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 participant identifiers will not be used in publication of results. Any work created in
connection with performance of the study and contained in the data that can benefit from copyright
protection (except any publication by the investigator as provided for below) shall be the property
of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal
Editors (ICMJE) 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
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not mandate modifications to scientific content and does not have the right to suppress information.
For multicenter study designs and sub-study 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 18 months after the study end date 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 ICMJE Recommendations
for the conduct, reporting, editing, and publication of scholarly work in medical journals, which
state that the named authors must have made a significant contribution to the conception or design
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the
work or revised it critically for important intellectual content and given final approval of the
version to be published; and agreed to be accountable for all aspects of the work in ensuring that
questions related to the accuracy or integrity of any part of the work are appropriately investigated
and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required
by law. The disclosure of the final study results will be performed after the end of study in order
to ensure the statistical analyses are relevant.
10.8.8. 
Data Quality Assurance
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified
investigators and appropriate study sites, review of protocol procedures with the investigator and
study site personnel before the study, periodic monitoring visits by the sponsor, and direct
transmission of clinical laboratory data from a central laboratory into the sponsor's data base.
Written instructions will be provided for collection, handling, storage, and shipment of samples.
Guidelines for eCRF completion will be provided and reviewed with study site personnel before
the start of the study.
The sponsor will review eCRF 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.
10.8.9. 
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each participant in electronic
format. All data relating to the study must be recorded in eCRF. All eCRF entries, corrections, and
alterations must be made by the investigator or authorized study site personnel. The investigator
must verify that all data entries in the eCRF are accurate and correct.
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The study data will be transcribed by study site personnel from the source documents onto an
electronic eCRF, if applicable. Study-specific data will be transmitted in a secure manner to the
sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any
such worksheets will become part of the participant's source documents. Data must be entered into
eCRF in English. The eCRF must be completed as soon as possible after a participant visit and the
forms should be available for review at the next scheduled monitoring visit.
All participative measurements (eg, pain scale information or other questionnaires) will be
completed by the same individual who made the initial baseline determinations whenever possible.
If necessary, queries will be generated in the eDC tool. If corrections to an eCRF are needed after
the initial entry into the eCRF, this can be done in either of the following ways:
 Investigator and 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).
 Sponsor or sponsor delegate can generate a query for resolution by the investigator and study
site personnel.
10.8.10. 
Source Documents
At a minimum, source documents consistent in the type and level of detail with that commonly
recorded at the study site as a basis for standard medical care must be available for the following:
participant identification, eligibility, and study identification; study discussion and date of signed
informed consent; dates of visits; results of safety and efficacy parameters as required by the
protocol; record of all AEs and follow-up of AEs; concomitant medication; intervention
receipt/dispensing/return records; study intervention administration information; and date of study
completion and reason for early discontinuation of study intervention or withdrawal from the study,
if applicable.
The author of an entry in the source documents should be identifiable. Given that PROs are reports
of a patient's health condition that come directly from the patient, without interpretation by a
clinician or anyone else, the responses to PRO measures entered by trial participants into source
records cannot be overridden by site staff or investigators.
Specific details required as source data for the study and source data collection methods will be
reviewed with the investigator before the study and will be described in the monitoring guidelines
(or other equivalent document).
The following data will be recorded directly into the eCRF and will be considered source data:
 Race
 Blood pressure and pulse/heart rate
 Height and weight
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 Investigator-completed scales and assessments
 PROs
The minimum source documentation requirements for Section 5.1, Inclusion Criteria and
Section 5.2, 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 participant interview or other protocol required assessment (eg, physical examination,
laboratory assessment) and documented in the source documents.
An eSource system may be utilized, which contains data traditionally maintained in a hospital or
clinic record to document medical care (eg, electronic source documents) as well as the clinical
study-specific data fields as determined by the protocol. This data is electronically extracted for
use by the sponsor. If eSource is utilized, references made to the eCRF in the protocol include the
eSource system but information collected through eSource may not be limited to that found in the
eCRF.
10.8.11. 
Monitoring
The sponsor will use a combination of monitoring techniques central, remote, or on-site monitoring
to monitor this study.
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will
record dates of the visits in a study site visit log that will be kept at the study site. The first
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits,
the monitor will compare the data entered into the eCRF with the source documents
(eg, hospital/clinic/physician’s office medical records). At these visits, the monitor will compare
data entered into the eCRF with the source documents (eg, hospital/clinic/physician’s office
medical records); 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 eCRF 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 documents (medical records) must be allowed for the purpose of verifying
that the recorded data are consistent with the original source data. Findings from this review 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 documents 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.
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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.
10.8.12. 
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. Participant 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.
10.8.13. 
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF
and all source documents that support the data collected from each participant, 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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10.8.14. 
Study and Site Start and Closure
First Act of Recruitment
The first site open is considered the first act of recruitment and it becomes the study start date.
Study/Site Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been collected
and a study site closure visit has been performed.
The investigator may initiate study site closure at any time, provided there is reasonable cause and
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not
limited to:
 Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or
local health authorities, the sponsor's procedures, or GCP guidelines
 Inadequate recruitment of participants by the investigator
 Discontinuation of further study intervention development
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10.9. 
Appendix 9: Adverse Events, Serious Adverse Events, Product Quality
Complaints, and Other Safety Reporting: Definitions and Procedures for
Recording, Evaluating, Follow-up, and Reporting
10.9.1. 
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a
pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have
a causal relationship with the intervention. An AE can therefore be any unfavorable and unintended
sign (including an abnormal finding), symptom, or disease temporally associated with the use of a
medicinal (investigational or non-investigational) product, whether or not related to that medicinal
(investigational or non-investigational) product (Definition per ICH).
This includes any occurrence that is new in onset or aggravated in severity or frequency from the
baseline condition or abnormal results of diagnostic procedures, including laboratory test
abnormalities.
Note: The sponsor collects AEs starting with the signing of the ICF (refer to All Adverse Events
under Section 8.3.1, Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information, for time of last AE recording).
Serious Adverse Event
A SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for Human
Use is any untoward medical occurrence that at any dose:
 
Results in death
 
Is life-threatening
(The participant 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 participant 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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If a serious and unexpected AE occurs for which there is evidence suggesting a causal relationship
between the study intervention and the event (eg, death from anaphylaxis), the event must be
reported as a serious and unexpected suspected adverse reaction even if it is a component of the
study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable product
reference safety information. For ustekinumab, the expectedness of an AE will be determined by
whether or not it is listed in the IB.
10.9.2. 
Attribution Definitions
Assessment of Causality
The causal relationship to study intervention is determined by the investigator. The following
selection should be used to assess all AEs.
Related
There is a reasonable causal relationship between study intervention administration and the AE.
Not Related
There is not a reasonable causal relationship between study intervention administration and the
AE.
The term "reasonable causal relationship" means there is evidence to support a causal relationship.
10.9.3. 
Severity Criteria
An assessment of severity grade will be made using the following general categorical descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort, and not
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation.
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly
experienced by the participant (eg, laboratory abnormalities).
10.9.4. 
Special Reporting Situations
Safety events of interest on a sponsor study intervention in an interventional study that may require
expedited reporting or safety evaluation include, but are not limited to:
 
Overdose of a sponsor study intervention
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 
Suspected abuse/misuse of a sponsor study intervention
 
Accidental or occupational exposure to a sponsor study intervention
 
Any failure of expected pharmacologic action (ie, lack of effect if used according to the local
label) of a sponsor study intervention (to be reported as a PQC for marketed products)
 
Unexpected therapeutic or clinical benefit from use of a sponsor study intervention
 
Medication error, intercepted medication error, or potential medication error involving a
Johnson & Johnson medicinal product (with or without participant exposure to the Johnson &
Johnson medicinal product, eg, product name confusion, product label confusion, intercepted
prescribing or dispensing errors)
 
Exposure to a sponsor study intervention from breastfeeding
Special reporting situations should be recorded in the eCRF. Any special reporting situation that
meets the criteria of an SAE should be recorded on the SAE page of the eCRF.
10.9.5. 
Procedures
All Adverse Events
All AEs, regardless of seriousness, severity, or presumed relationship to study intervention, must
be recorded using medical terminology in the source document and the eCRF. 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 eCRF their opinion concerning the relationship of the
AE to study therapy. All measures required for AE management must be recorded in the source
document and reported according to sponsor instructions.
For all studies with an outpatient phase, including open-label studies, the participant 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 participant 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 personnel only)
 
Site number
 
Participant number
 
Any other information that is required to do an emergency breaking of the blind
Serious Adverse Events
All SAEs that have not resolved by the end of the study or that have not resolved upon the
participant's discontinuation from the study, must be followed until any of the following occurs:
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 
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 intervention or to factors unrelated
to study conduct
 
It becomes unlikely that any additional information can be obtained (participant or health care
practitioner refusal to provide additional information, lost to follow-up after demonstration of
due diligence with follow-up efforts)
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during
participation in the study must be reported as an SAE, except hospitalizations for the following:
 
Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as pending
placement in long-term care facility)
 
Surgery or procedure planned before entry into the study (must be documented in the eCRF).
Note: Hospitalizations that were planned before the signing of the ICF, and where the
underlying condition for which the hospitalization was planned has not worsened, will not be
considered SAEs. Any AE that results in a prolongation of the originally planned
hospitalization is to be reported as a new SAE.
For convenience the investigator may choose to hospitalize the participant for the duration of the
intervention period. The cause of death of a participant in a study within 16 weeks of the last dose
of study intervention, whether or not the event is expected or associated with the study intervention,
is considered an SAE.
Information regarding SAEs will be transmitted to the sponsor using an SAE reporting form, which
must be completed and signed by a physician from the study site and transmitted in a secure
manner to the sponsor within 24 hours. The initial and follow-up reports of an SAE should be
made by facsimile (fax). Telephone reporting should be the exception and the reporter should be
asked to complete the appropriate form(s) first.
10.9.6. 
Product Quality Complaint Handling
Definition
A 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, reliability, or
performance of a distributed product, including its labeling, drug delivery system, or package
integrity. A PQC may have an impact on the safety and efficacy of the product. In addition, it
includes any technical complaints, defined as any complaint that indicates a potential quality issue
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during manufacturing, packaging, release testing, stability monitoring, dose preparation, storage
or distribution of the product or the drug delivery system.
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.
A sample of the suspected product should be maintained under the correct storage conditions until
a shipment request is received from the sponsor.
10.9.7. 
Contacting Sponsor Regarding Safety, Including Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding safety issues, PQC, or questions regarding the study are listed in the ’Protocol
Supplementary Information page(s), which will be provided as a separate document.
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10.10. Appendix 10: Contraceptive and Barrier Guidance
Participants must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria.
Pregnancy information will be collected and reported as noted in Section 8.3.5, Pregnancy and
Section 10.9, Appendix 9: Adverse Events, Serious Adverse Events, Product Quality Complaints,
and Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up,
and Reporting.
Definitions
Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal unless
permanently sterile (see below).
Woman Not of Childbearing Potential
 
Premenarchal
A premenarchal state is one in which menarche has not yet occurred.
 
Postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical
cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the
postmenopausal range may be used to confirm a postmenopausal state in women not using
hormonal contraception or hormonal replacement therapy (HRT), however in the absence of
12 months 
of 
amenorrhea, 
a 
single 
FSH 
measurement 
is 
insufficient.
If there is a question about menopausal status in women on HRT, the woman will be required
to use one of the non-estrogen-containing hormonal highly effective contraceptive methods if
she wishes to continue HRT during the study.
 
Permanently sterile (for the purpose of this study)
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral
oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually
active becomes active), a woman must begin a highly effective method of contraception, as
described throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
Contraceptive (birth control) use by men or women should be consistent with local regulations
regarding the acceptable methods of contraception for those participating in clinical studies.
Typical use failure rates may differ from those when used consistently and correctly.
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Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
USER INDEPENDENT
Highly Effective Methods That Are User Independent Failure rate of <1% per year when used
consistently and correctly.
 Intrauterine device
 Intrauterine hormone-releasing system
 Bilateral tubal occlusion
 Azoospermic partner (vasectomized or due to medical cause)
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the
sole sexual partner of the woman of childbearing potential and the absence of sperm has been
confirmed. If not, additional highly effective method of contraception should be used.
Spermatogenesis cycle is approximately 74 days)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used
consistently and correctly.
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with
inhibition of ovulationb
 Oral
 Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from
heterosexual intercourse during the entire period of risk associated with the study intervention. The
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the
preferred and usual lifestyle of the participant.)
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY (not
considered to be highly effective - failure rate of 1% per year)
 Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary
mode of action.
 Male condom with or without spermicide
 Periodic abstinence (calendar, symptothermal, post-ovulation methods)
 Withdrawal (coitus-interruptus)
 Lactational amenorrhea method
a) Typical use failure rates may differ from those when used consistently and correctly.
b) Hormonal contraception may be susceptible to interaction with the study intervention, which may
reduce the efficacy of the contraceptive method. In addition, consider if the hormonal contraception
may interact with the study intervention.
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10.11. Appendix 11: Liver Safety: Suggested Actions and Follow-up
Assessments
A. STOPPING ALGORITHM
Study intervention will be discontinued for a participant if liver chemistry stopping criteria are met.
Phase 3-4 Liver Chemistry Stopping Criteria and Increased Monitoring Algorithm
Abbreviations: ALT=alanine transaminase; AST=aspartate transaminase; INR=international normalized ratio;
SAE=serious adverse event; ULN=upper limit of normal; Tbili=Total bilirubin.
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Phase 3-4 Liver Chemistry Increased Monitoring Algorithm with Continued Study
Intervention for Participants with ALT or AST ≥3xULN but <8xULN
Abbreviations: ALT=alanine transaminase; AST=aspartate transaminase; INR=international normalized ratio;
SAE=serious adverse event; ULN=upper limit of normal; Tbili=Total bilirubin.
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10.12. Appendix 12: Guidance on study conduct during COVID-19 pandemic
It is recognized that the COVID-19 pandemic may have an impact on the conduct of this clinical
study due to, for example, self-isolation/quarantine by participants and study-site personnel; travel
restrictions/limited access to public places, including hospitals; study site personnel being
reassigned to critical tasks. In alignment with recent health authority guidance, the sponsor is
providing options for study-related participant management in the event of disruption to the
conduct of the study. This guidance does not supersede any local or government guidelines or
requirements or the clinical judgement of the investigator to protect the health and well-being of
participants and site staff. If at any time a participant’s safety is considered to be at unacceptable
risk, study intervention will be discontinued, and study follow-up will be conducted. Scheduled
visits that cannot be conducted in person at the study site will be performed to the extent possible
remotely/virtually or delayed until such time that on-site visits can be resumed. At each contact,
participants will be interviewed to collect safety data. Key efficacy endpoint assessments should
be performed if required and as feasible. Participants will also be questioned regarding general
health status to fulfill any physical examination requirement. Every effort should be made to
adhere to protocol-specified assessments for participants on study intervention, including
follow-up. Modifications to protocol-required assessments may be permitted after consultation
between the participant, and investigator and with the agreement of the sponsor (see below).
The sponsor will continue to monitor the conduct and progress of the clinical study, and any
changes will be communicated to the sites and to the health authorities according to local guidance.
If a participant has tested positive for COVID-19, the investigator should contact the sponsor’s
medical officer or designee to discuss plans for study intervention and follow-up. Modifications
made to the study conduct as a result of the COVID-19 pandemic should be summarized in the
clinical study report.
ADDITIONAL ELEMENTS, WHERE APPLICABLE:
Certain protocol-mandated visits to the study site may not be possible during the COVID-19
outbreak. Therefore, temporary measures may be implemented if considered appropriate by the
sponsor and investigator to maintain continuity of patient care and study integrity. Certain
measures, such as those listed below, may be necessary and should be instituted in accordance
with applicable (including local) laws, regulations, guidelines, and procedures:
 
Remote (eg, by phone / telemedicine) or in person, off-site (eg, in-home) interactions between
site staff (or designees) and patients for study procedures eg, those related to safety
monitoring/efficacy evaluation/study intervention storage and administration (including
training where pertinent)
 
Procurement of study intervention by patients (or designee) or shipment of study intervention
from the study site directly to patients for at home administration
 
Laboratory assessments using a suitably accredited local laboratory; for selected measures (eg,
urine pregnancy), home testing may be employed
 
Other procedures may be conducted at an appropriate facility, missed assessments/visits will
be captured in the clinical trial management system for protocol deviations. Discontinuations
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of study interventions and withdrawal from the study should be documented with the prefix
“COVID-19-related” in the electronic case report form (eCRF).
 
Other relevant study data elements impacted by the pandemic should also be
documented/labeled as “COVID-19-related” in eCRFs and/or other study systems, as directed
by detailed sponsor guidance. These may include missed/delayed/modified study
visits/assessments/dosing and instances where temporary measures such as those above are
implemented.
NOTES on COVID-related exclusion:
1. If a participant is excluded due to recent COVID-19-related features, the reason for screen
failure should be documented in the case report form under the exclusion criterion of having
a condition for which participation would not be in the participant’s interest or could confound
study assessments.
2. The field of COVID-related testing (for presence of, and immunity to, the SARS-CoV-2 virus)
is rapidly evolving. Additional testing may be performed as part of screening and/or during
the study if deemed necessary by the investigator and in accordance with current
regulations/guidance from authorities/SOC. The sponsor will evaluate the totality of impact
of COVID-19 on collection of key study data and additional data analyses will be outlined in
study SAP(s).
Precaution: for those who may carry a higher risk for severe COVID-19 illness (eg, those aged
over 65 years), follow guidance from local health authorities when weighing the potential benefits
and risks of enrolling in the study and during participation in the study.
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10.14. Appendix 14: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located directly
before the Table of Contents (TOC).
Amendment 1 (7 April 2021)
Overall Rationale for the Amendment: To clarify the process related to relapse confirmation and put
minor modifications throughout the protocol.
Section Number 
and Name
Description of Change 
Brief Rationale
1.3. Schedule of 
Activities, Table 1 
e. Imaging assessment will be performed during 
screening period, every 24 weeks from Week 0 (eg, 
Week 24, 48, 72), and relapse visit Relapse 
Confirmation Visit using CTA or MRA, if CTA is
not feasible. When imaging assessment has been
performed within 12 weeks prior to scheduled
imaging assessment visit, imaging assessment may
not be performed, and the prior results will be used
for this scheduled assessment. Imaging assessment
for screening visit should be performed and the
prior imaging results for screening assessment will
not be allowed. Additional imaging assessment
may be performed if investigator deems a need for
further evaluation of participant’s disease activities.
At relapse visit Relapse Confirmation Visit,
imaging assessment will be performed within 4
weeks after the investigator confirms participants
meets the relapse criteria and it is recommended to
be performed prior to Week OL-0.
Text was added to clarify the
potential additional imaging
assessment.
1.3. Schedule of
Activities, Table 1
p. When participants meet the relapse criteria, the
cause of relapse will be evaluated at relapse visit
unless the investigator deems to require urgent GC
treatment. The relapse visit will be made at
participants’ next visit or unscheduled visit prior to
the next visit at investigator’s discretion.
o.   Relapse Confirmation Visit is the second
relapse assessment visit after participants meet the
relapse criteria once at scheduled visit or
unscheduled visit (This visit will be treated as “1st
relapse visit”). At Relapse Confirmation Visit,
TAK Disease Assessment S&S and CRP/ESR must
be performed and the other items are not needed to
perform if they already performed at “1st relapse
visit”. If participants are judged as relapse once, all
the assessments at Relapse Confirmation Visit
should be performed.
Updated to clarify “Relapse
Confirmation Visit” (Footnote p on
the initial protocol was updated as
Footnote o on the amendment 1
due to footnote order change).
1.3. Schedule of
Activities, Table 2
j. Relapse Confirmation Visit is the second relapse
assessment visit after participants meet the relapse
criteria for the first time at scheduled visit or
unscheduled visit (This visit will be treated as “1st
relapse visit”). At Relapse Confirmation Visit,
TAK Disease Assessment S&S and CRP/ESR must
Updated to clarify “Relapse
Confirmation Visit”.
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Section Number 
and Name
Description of Change 
Brief Rationale
be performed and the other items are not needed to
perform if they already performed at “1st relapse
visit”. If participants are judged as relapse once, all
the assessments at Relapse Confirmation Visit
should be performed.
 
5.1. Inclusion 
Criteria 9. 
Criterion modified per Amendment 1 
 
9.1   If receiving an oral anti-platelet therapy 
(including but not limited to aspirin,
clopidogrel, ticlopidine) or anti-coagulation
therapy (including but not limited to warfarin)
for treatment of TAK, the dose must have
been stable for at least 2 weeks prior to first
administration of the study intervention. In
terms of warfarin, the dose should be
controlled 1-5 mg/day to maintain PT-INR
target range between 2.0-3.0 (if participants
are over 70 years old, PT-INR target range
should be between 1.6-2.6).
Text was added to clarify the dose
of warfarin based on medical
practice in Japan.
6.8. Concomitant 
Therapy  
Anti-platelet or Anti- 
coagulation Therapy  
Participants are permitted to receive stable doses 
(>2 weeks prior to first study intervention  
administration) of anti-platelet therapy (including 
but not limited to aspirin, clopidogrel, ticlopidine)
or anti-coagulation therapy (including but not
limited to warfarin) according to the local practice
at the discretion of the investigator. In terms of
warfarin, the dose should be controlled 1-5mg/day
in order to maintain PT-INR target range between
2.0-3.0 (if participants are over 70 years old, PT-
INR target range should be between 1.6-2.6).
Text was added to clarify the dose
of warfarin based on medical
practice in Japan.
8.1.1. TAK Disease 
Signs and Symptoms 
In assessment of disease activities of TAK, cause 
of relapse will be confirmed by eliminating other 
causes such as infections, allergic disorders, and 
unexplained physical symptoms, unless the
investigator deems to require emergent GC
treatment. Even participants meet the definition of
relapse once, they will not receive a GC rescue
therapy and continue to receive protocol-defined
GC taper regimen unless except for the following
cases. In the following cases, participants will be
judged as relapse once.
• Emergent hospitalization caused by worsening
of TAK and GC treatment required
• Severe aortic valve incompetence accompanied
by symptoms of cardiac failure occurs under
‘vascular signs and symptoms’
• CTCAE grade 2 or higher (grade ≥3 for
myocardial infarction) occurs under ‘ischemic
symptoms’
• Both categories ‘vascular signs and symptoms’
and ‘ischemic symptoms’ meet the criteria
Except for above cases, the investigators will
Text was added to clarify the
conditions which participants are
judged as relapse once.
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Section Number 
and Name
Description of Change 
Brief Rationale
reconfirm whether the participants meets definition
of relapse including the same items of the first
assessment at least and the relapse was caused by
worsening of TAK to make a final judgement of
the relapse at Relapse Confirmation Visit next visit
or unscheduled visit prior to the next visit.
 
10.4. Appendix 4: 
Relapse Judgement 
Flow 
Relapse judgement process without adjudication 
 
The schematic flow of relapse judgement process 
without adjudication is shown in Figure 3.
 
For the first relapse visit, the investigator or
designee will record the evidence of worsening
TAK and possible other causes on the Source
Document in the electronic data capture (eDC). For
the second relapse visit Relapse Confirmation
Visit, the investigator or designee will record the
evidence of worsening TAK and reason for
eliminating other causes in the eDC.
Inflammation marker results (ie, CRP) provided by
central lab is encouraged to be used will be used to
judge relapse of TAK in this process.
“Relapse judgement process
without adjudication” was updated
for clarification.
10.4. Appendix 4: 
Relapse Judgement 
Flow  
Relapse judgement process with adjudication  
 
The schematic flow of relapse judgement process 
with adjudication is shown in Figure 4.
 
For the first relapse visit, the investigator or
designee will record the evidence of worsening
TAK, possible other causes, and the Relapse
Confirmation Visit date on the Source Document,
and will submit these information to the sponsor
next scheduled relapse visit in the eDC within 3
working days. The sponsor’s medical monitor will
verify it the evidence and may request additional
information as necessary until the Relapse
Confirmation Visit next scheduled visit. If the
Relapse Confirmation Visit second relapse visit is
scheduled within 5 working days of the first relapse
visit, the investigator or designee should contact
sponsor. For the second relapse visit Relapse
Confirmation Visit, the investigator or designee
will record the reason for evidence of worsening
TAK and eliminating other causes in the eDC.
 
Inflammation marker results (ie, CRP) provided by
central lab is encouraged to be used to judge
relapse of TAK in this process.
Inflammation marker results (ie, CRP) provided by
central lab will be used to judge relapse of TAK for
both visits (turnaround time for central lab result of
CRP is generally 1 business day), unless
participants require emergent GC rescue therapy. If
“Relapse judgement process with
adjudication” was updated for
clarification.
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Section Number 
and Name
Description of Change 
Brief Rationale
emergent GC rescue is needed, local CRP result
will be permitted to judge relapse of TAK for both
visits. The rationale for emergent therapy required
and the value of local CRP will be recorded in
eDC.
 
10.9. Appendix 9: 
Adverse Events, 
Serious Adverse 
Events, Product 
Quality Complaints, 
and Other Safety 
Reporting: 
Definitions and 
Procedures for 
Recording, 
Evaluating, Follow- 
up, and Reporting 
 
Disease progression should not be recorded as an 
AE or SAE term; instead, signs and symptoms of 
clinical sequelae resulting from disease 
progression/lack of efficacy will be reported if they
fulfill the SAE definition (refer to Adverse Event
Definitions and Classifications in Section 10.9,
Appendix 9: Adverse Events, Serious Adverse
Events, Product Quality Complaints, and Other
Safety Reporting: Definitions and Procedures for
Recording, Evaluating, Follow up, and Reporting).
Expected progression of disease should not be
considered an AE (or SAE). However, if
determined by the investigator to be more likely
related to the study intervention than the underlying
disease, the clinical signs or symptoms of
progression and the possibility that the study
intervention is enhancing disease progression,
should be reported per the usual reporting
requirements.
Text was deleted to collect safety
information adequately based on
the PMDA feedback.
 
Throughout the
protocol
Minor grammatical, formatting, and/or spelling
changes were made.
Minor errors were noted.
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11. 
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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
 
Date:
  
 
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
 
Date:
  
 
(Day Month Year)
 
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Janssen Pharmaceutical K.K.
Signature: 
electronic signature appended at the end of the protocol 
Date:
  
 
(Day Month Year)
 
Note: If the address or telephone number of the investigator changes during the course of the study, written
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD
NCT04882072


Signature
User 
Date 
Reason
15-Aug-2022
08:46:15
(GMT)
Document Approval
PPD
NCT04882072

SAP_001.pdf: 
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
1 
Status: Approved,  Date: 30 June 2023 
 
Janssen Pharmaceutical K.K.* 
 
Statistical Analysis Plan 
 
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group 
Study of Ustekinumab in Participants With Takayasu Arteritis 
 
Protocol CNTO1275TAT3001; Phase 3 
 
 CNTO1275  (Ustekinumab)  
 
* This study is being conducted by Janssen Pharmaceutical K.K. in Japan. The term “sponsor” is used 
throughout the protocol to represent Janssen Pharmaceutical K.K. in Japan. 
Status: 
Approved 
Date: 
30 June 2023 
Prepared by: 
Janssen Pharmaceutical K.K. 
Document No.: EDMS-RIM-478213 
 
Compliance:  The study described in this report was performed according to the principles of Good Clinical Practice (GCP).  
Confidentiality Statement 
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient 
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise. 
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CNTO1275  (Ustekinumab)  
 
 
 
Statistical Analysis Plan CNTO1275TAT3001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
2 
Status: Approved,  Date: 30 June 2023 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS .......................................................................................................................... 2 
VERSION HISTORY................................................................................................................................ 4 
1. 
INTRODUCTION ............................................................................................................................ 7 
1.1. 
Objectives and Endpoints ............................................................................................................ 7 
1.2. 
Study Design .............................................................................................................................. 9 
2. 
STATISTICAL HYPOTHESES...................................................................................................... 10 
3. 
SAMPLE SIZE DETERMINATION ................................................................................................ 11 
4. 
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS .................................................................. 11 
5. 
STATISTICAL ANALYSES .......................................................................................................... 12 
5.1. 
General Considerations............................................................................................................. 12 
5.1.1. 
Visit Windows ........................................................................................................................ 12 
5.1.2. 
Analysis Phase ...................................................................................................................... 12 
5.1.3. 
Baseline ................................................................................................................................ 13 
5.1.4. 
Reference Date ..................................................................................................................... 13 
5.1.5. 
Study Day .............................................................................................................................. 13 
5.2. 
Participant Dispositions ............................................................................................................. 13 
5.3. 
Primary Endpoint(s) Analysis .................................................................................................... 14 
5.3.1. 
Definition of Endpoint(s) ......................................................................................................... 14 
5.3.2. 
Primary Estimand .................................................................................................................. 15 
5.3.2.1. 
Main Estimator of Primary Estimand ................................................................................... 16 
5.3.3. 
Supplementary Estimand 1 .................................................................................................... 16 
5.3.3.1. 
Main Estimator of Supplementary Estimand 1 ..................................................................... 17 
5.3.4. 
Supplementary Estimand 2 .................................................................................................... 17 
5.3.4.1. 
Main Estimator of Supplementary Estimand 2 ..................................................................... 18 
5.3.5. 
Analysis Methods of Primary Estimand .................................................................................. 18 
5.3.6. 
Analysis Methods of Supplementary Estimand 1 .................................................................... 19 
5.3.7. 
Analysis Methods of Supplementary Estimand 2 .................................................................... 19 
5.3.8. 
Subgroup Analyses of Primary Efficacy Endpoint ................................................................... 20 
5.4. 
Secondary Endpoint(s) Analysis ................................................................................................ 20 
5.4.1. 
Key Confirmatory Secondary Endpoint(s) ............................................................................... 20 
5.4.1.1. 
Definition of Endpoint(s) ...................................................................................................... 20 
5.4.1.2. 
Estimand(s) ........................................................................................................................ 20 
5.4.1.3. 
Analysis Methods ................................................................................................................ 20 
5.4.2. 
Supportive Secondary Endpoint(s) ......................................................................................... 21 
5.4.2.1. 
Definition of Endpoints ........................................................................................................ 21 
5.4.2.2. 
Analysis Methods ................................................................................................................ 22 
5.5. 
Tertiary/Exploratory Endpoint(s) Analysis .................................................................................. 24 
5.5.1. 
Definition of Endpoints ........................................................................................................... 24 
5.5.2. 
Analysis Method .................................................................................................................... 25 
5.6. 
Other Safety Analyses............................................................................................................... 26 
5.6.1. 
Extent of Exposure ................................................................................................................ 26 
5.6.2. 
Adverse Events ..................................................................................................................... 27 
5.6.3. 
Additional Safety Assessments (if applicable)......................................................................... 28 
5.6.3.1. 
Clinical Laboratory Tests ..................................................................................................... 28 
5.6.3.2. 
Vital Signs .......................................................................................................................... 29 
5.6.3.3. 
Electrocardiogram ............................................................................................................... 29 
5.7. 
Other Analyses ......................................................................................................................... 30 
5.7.1. 
Pharmacokinetics .................................................................................................................. 30 
NCT04882072


CNTO1275  (Ustekinumab)  
 
 
 
Statistical Analysis Plan CNTO1275TAT3001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
3 
Status: Approved,  Date: 30 June 2023 
5.7.2. 
Immunogenicity ..................................................................................................................... 32 
5.7.3. 
Pharmacodynamics ............................................................................................................... 33 
5.7.4. 
Pharmacokinetic/Pharmacodynamic Relationships ................................................................. 33 
5.7.5. 
Biomarkers ............................................................................................................................ 34 
5.7.6. 
Health Economics .................................................................................................................. 34 
5.7.7. 
Other Variables and/or Parameters ........................................................................................ 34 
5.7.7.1. 
Definition ............................................................................................................................ 34 
5.7.7.2. 
Analysis Method ................................................................................................................. 34 
5.7.8. 
Definition of Subgroups .......................................................................................................... 34 
5.8. 
Interim Analyses ....................................................................................................................... 35 
5.8.1. 
Data Monitoring Committee (DMC) or Other Review Board .................................................... 35 
6. 
SUPPORTING DOCUMENTATION .............................................................................................. 36 
6.1. 
Appendix 1 List of Abbreviations ............................................................................................... 36 
6.2. 
Appendix 2 Demographics and Baseline Characteristics ........................................................... 37 
6.3. 
Appendix 3 Protocol Deviations ................................................................................................. 38 
6.4. 
Appendix 4 Prior and Concomitant Medications ......................................................................... 39 
6.5. 
Appendix 5 Medical History ....................................................................................................... 40 
6.6. 
Appendix 6 Intervention Compliance ......................................................................................... 41 
6.7. 
Appendix 7 Adverse Events of Special Interest .......................................................................... 42 
6.8. 
Appendix 8 Major Protocol Deviation for Intercurrent Events...................................................... 43 
6.9. 
Appendix 9 Laboratory Toxicity Grading .................................................................................... 46 
7. 
REFERENCES ............................................................................................................................. 51 
 
 
 
 
NCT04882072


CNTO1275  (Ustekinumab)  
 
 
 
Statistical Analysis Plan CNTO1275TAT3001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
4 
Status: Approved,  Date: 30 June 2023 
VERSION HISTORY 
Table 1: 
SAP Version History Summary 
SAP Version 
Approval Date 
Change 
Rationale 
1 
26 July 2021 
Not Applicable 
Initial release 
2 
30 June 2023 
1. Section 5.3.5 and Section 5.8: 
remove alpha spending for 
interim analyses; Section 5.8: add 
a sentence “However, the study 
turned out to be early terminated 
by sponsor before occurrence of 
15 events, and the planned 
interim analyses will therefore not 
be performed. " 
2. Section 5.3.5 and 5.8: Change 
significance level of interim 
analysis to 0.0012, and final 
analysis to 0.0496 
3. Section 4: Split PK, PD 
analysis set to DB and OLE 
period 
4. Section 5.6.2: add “AEs during 
receiving study intervention 
ustekinumab through the Study 
will also be summarized” 
5. Section 5.6.2: add summary for 
AEs related to COVID-19 
6. Section 5.7.1: “In Escape arm 
OLE period and OLE period, 
serum ustekinumab 
concentrations will be 
summarized by DB period 
intervention arm (ustekinumab 
arm or placebo arm) in table.” 
were changed to “In Escape arm 
OLE period and OLE period, 
serum ustekinumab 
concentrations will be 
summarized by intervention arm 
(Ustekinumab -> Ustekinumab or 
Placebo -> Ustekinumab) in 
table.” 
7. Section 5.4.2.2: removed “and 
percent of change from baseline” 
from “The observed values, 
change from baseline and percent 
of change from baseline of 
inflammatory markers will be 
descriptively summarized by 
visit.” 
8. Section 5.6.2, add “AEs 
leading to death” and “SAEs by 
relationship to study intervention” 
9. Table 4, add FACIT, PtGA and 
SF-36 
10. Section 5.7.1: Participants 
who received IV intervention at 
Remove alpha spending for 
interim analyses and some other 
changes were made due to study 
early termination before time of 
interim analysis; Some of the 
analysis were updated after 
review of data presentation 
specification for alignment based 
on clinical team requests; Also 
due to protocol amendment 2 and 
early termination of the study, the 
SAP was updated accordingly to 
incorporate the changes and 
clarifications; Some other minor 
changes include type error and 
wordings correction. 
NCT04882072


CNTO1275  (Ustekinumab)  
 
 
 
Statistical Analysis Plan CNTO1275TAT3001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
5 
Status: Approved,  Date: 30 June 2023 
SAP Version 
Approval Date 
Change 
Rationale 
Week 0 and continuously 
received next IV intervention at 
Week OL-0 (which mean without 
SC intervention) will be 
summarized in a separate table 
which will include serum 
concentrations at Week 0, 2, 4, 8, 
Week OL-0 and OL-8. 
11. Section 4: change “IV 
intervention of ustekinumab at 
Week OL-0 or SC intervention of 
ustekinumab” to “dose” for 
“Pharmacokinetics Analysis Set 
in Escape arm OLE period” 
12. Add “Time to relapse by 4 
categories (Kerr’s definition)” in 
Section 5.4.2.1 
13. Appendix 9: Add more 
parameters for CTCAE table 
14. Add endpoint in Section 5.5: 
Proportion of participants who 
achieve 7.5mg/day or less during 
OLE period. 
15. Section 5.6.2: add AESI for 
summary and listing 
16. Section 5.4.2.2: add “Last 
observed GC dose before relapse 
will also be presented for 
participants who had relapse. The 
last observed GC dose (during 
DB) is the average GC dose in 
last 7 days before the date of 
relapse (first visit of relapse will 
be used for relapse need to be 
confirmed) for participants who 
had relapse, or average GC dose 
in last 7 days on or before end of 
DB period.” and removed “The 
prednisolone dose that is used at 
the date of relapse will be also 
presented.” 
17. Section 5.3.2, 5.3.3, 5.3.4, 
5.3.5,5.4.2.2, And change “95% 
CIs” to “95% Wald CIs”. 
18. Appendix 2, Table 4, “18-64 
years” was changed to “15-64 
years”, Section 1.2 and 5.7.8: 18 
was changed to 15 
19. Section 5.3.5, 5.4.2.2: 
removed “on or prior to the 
situation”  
20. Section 5.7.8 and Appendix 
6.2, add subgroup 5-7 and >=18 
for age groups 
NCT04882072


CNTO1275  (Ustekinumab)  
 
 
 
Statistical Analysis Plan CNTO1275TAT3001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
6 
Status: Approved,  Date: 30 June 2023 
SAP Version 
Approval Date 
Change 
Rationale 
21. Section 5.4.2.2 and 5.5.2: add 
spaghetti plot for GC dose 
overtime 
22. Section 5.1.1, add: For serum 
ustekinumab concentrations by 
timepoint summary, if PK 
assessment is missing at 
scheduled visit or timepoints, the 
visit of early termination and 
unscheduled visit will be mapped 
to the scheduled visit if it's within 
protocol specified visit window 
23. Section 5.3.5, 5.3.6, 5.3.7, 
5.4.2.2: Other (eg, withdrawal of 
consent to study participation, lost 
to follow-up) were changed to: 
other (ie, other participants not 
included in above situations) 
24. Section 5.6.2, add “Serious 
Infections” 
25. Section 5.1.2, change “16 
weeks after the follow-up starting 
date or early discontinuation, 
whichever comes first” to “Last 
date of study discontinuation or 
last participation date” 
26. Section 6.9, add “If a 
laboratory value falls within the 
grading as specified below but 
also within the local laboratory 
normal limits, the value is 
considered to be normal and will 
be reset to grade 0.” 
27. Section 6.2, add categorical 
variables for BMI, update 
category for RACE and Ethnicity 
28. Section 4: Removed 
“randomized” in definition for 
“FAS in OLE period”. 
Add “Safety Analysis Set” and 
“Full Analysis Set”. 
29. Section 5.7.2: the definition of 
“Subject ADA status” was minor 
changed 
30. Section 5.4.4.2, add: Note: for 
“death or treatment 
discontinuation”: use data on or 
prior to death or treatment 
discontinuation through end of 
DB period; for major protocol 
deviation and other situations: use 
data through end of DB period. 
31. Other minor changes 
 
NCT04882072


CNTO1275  (Ustekinumab)  
 
 
 
Statistical Analysis Plan CNTO1275TAT3001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
7 
Status: Approved,  Date: 30 June 2023 
1. 
INTRODUCTION 
This statistical analysis plan (SAP) for the CNTO1275TAT3001 phase 3 trial describes the 
statistical analyses and definitions to evaluate the efficacy and safety of ustekinumab in patients 
with Takayasu Arteritis (TAK). 
1.1. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 To evaluate the efficacy of ustekinumab compared to 
placebo, in combination with oral glucocorticoid 
(GC) taper regimen, in participants with relapsing 
TAK. 
 Time to relapse of TAK according to 
protocol-defined criteria through the end 
of DB period. 
Secondary 
 To evaluate the safety of ustekinumab in combination 
with oral GC taper regimen, in participants with 
relapsing TAK 
 Number/proportion of participants with 
TEAEs through the end of study 
 Number/proportion of participants with 
TEAEs by system organ class with a 
frequency threshold of 5% or more 
through the end of study 
 Number/proportion of participants with 
treatment-emergent SAEs through the 
end of study 
 To evaluate the efficacy of ustekinumab compared to 
placebo, in combination with oral GC taper regimen, 
in participants with relapsing TAK as measured by 
alternative definitions of relapse criteria, relapse rate, 
GC sparing effects, and disease activity 
 Time to relapse of TAK according to 
Kerr’s definition through the end of DB 
period 
 Time to relapse of TAK based on 
clinical symptoms only through the end 
of DB period 
 Time to relapse of TAK in each of the 5 
categories through the end of DB period 
 Relapse rate in each of the 5 categories 
through the end of DB period 
 Cumulative oral GC dose (prednisolone 
or equivalent) through the end of DB 
period  
 Change from baseline in oral GC dose 
(prednisolone or equivalent) through the 
end of DB period  
 Number/proportion of participants 
achieving GC dose of 5 mg/day or less 
through the end of DB period 
 Change from baseline in imaging 
evaluation through the end of DB period 
 Change from baseline in inflammatory 
markers (CRP, ESR) through the end of 
DB period 
NCT04882072


CNTO1275  (Ustekinumab)  
 
 
 
Statistical Analysis Plan CNTO1275TAT3001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
8 
Status: Approved,  Date: 30 June 2023 
Objectives 
Endpoints 
 To evaluate the PK and immunogenicity of 
ustekinumab in combination with oral GC taper 
regimen, in participants with relapsing TAK 
 Serum concentrations of ustekinumab in 
participants receiving ustekinumab 
through the end of study 
 Number/proportion of participants who 
are positive for anti-ustekinumab 
antibodies in participants receiving 
ustekinumab through the end of study 
Exploratory 
 To explore changes in the PRO instruments and the 
physician reported outcome 
 Changes from baseline on PROs through 
the end of study 
 SF-36 
 PtGA of disease activity on VAS 
 FACIT-Fatigue 
 Change from baseline on physician 
reported outcome: PhGA through the 
end of study 
 To explore the efficacy of ustekinumab in 
combination with oral GC taper regimen, in 
participants with relapsing TAK during OLE period 
 Number/proportion of participants who 
experience relapse of TAK according to 
protocol-defined criteria during OLE 
period 
 Number/proportion of participants who 
experience relapse of TAK according to 
Kerr’s definition during OLE period 
 Number/proportion of participants who 
experience relapse of TAK based on 
clinical symptoms only during OLE 
period 
 Number/proportion of participants who 
experience relapse of TAK in each of 
the 5 categories during OLE period 
 Cumulative oral GC dose (prednisolone 
or equivalent) during OLE period 
 Change from baseline in oral GC dose 
(prednisolone or equivalent) during OLE 
period  
 Number/proportion of participants 
achieving GC dose of 5 mg/day or less 
during OLE period 
 Change from baseline in imaging 
evaluation during OLE period 
 Change from baseline in inflammatory 
markers (CRP, ESR) during OLE period  
NCT04882072


CNTO1275  (Ustekinumab)  
 
 
 
Statistical Analysis Plan CNTO1275TAT3001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
9 
Status: Approved,  Date: 30 June 2023 
1.2. 
Study Design 
This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter, interventional study 
in participants ≥15 years and ≤75 years of age with TAK to evaluate the efficacy, safety, 
pharmacokinetic (PK), and immunogenicity of intravenous (IV) and subcutaneous (SC) 
ustekinumab. 
The total duration of the study will be approximately 2 years, consisting of (1) a ≤6-week screening 
period in which a participant’s eligibility will be reviewed prior to administration of the first dose 
of study intervention; (2) a double-blind (DB) period: up to participant’s relapse of TAK or end of 
the DB period (a total of 35 relapse events occur), whichever is earlier; (3) an open-label extension 
(OLE) period: 52 weeks or 32 weeks from the first SC administration after the end of DB period, 
whichever is later; and (4) a safety follow-up period: 16 weeks. 
Participants must have experienced TAK relapse within 12 weeks prior to administration of study 
intervention and the relapse must have occurred at oral GC dose of at least 7.5 mg/day 
(prednisolone or equivalent). The relapse must have been adequately treated with ≥15 mg/day of 
prednisone or equivalent and participants must subsequently have achieved remission at least 1 
week prior to the first administration of the study intervention. 
Approximately 50 participants will be randomized at Week 0 in a blind fashion to 1:1 ratio 
stratified by oral GC dose at Week 0 (<0.5 mg/kg/day, ≥0.5 mg/kg/day of prednisolone or 
equivalent) and status of previous biologic medication (bio-nonfailure or bio-failure) to receive 
either ustekinumab or matching placebo with the following treatment regimens during the DB 
period until participants develop relapse or a total of 35 relapse events have occurred. 
Ustekinumab group: The participants will receive body weight-range based IV administration of 
ustekinumab (~6 mg/kg) at Week 0 followed by ustekinumab 90 mg SC administered 8 weeks 
after the initial IV dose and then every 8 weeks (q8w) thereafter. 
Placebo group: The participants will receive IV administration of placebo at Week 0 followed by 
placebo SC administered 8 weeks after the initial IV dose and then q8w thereafter. 
During the DB period, participants will receive IV administration of study intervention followed 
by SC administration of study intervention, with starting the protocol defined oral GC taper 
regimen from Week 2 visit (baseline oral GC dose will be stable until Week 2). Participants who 
develop relapse will receive rescue medication of oral GC that is at least double the oral GC dose 
at the relapse. These participants will be assessed whether they achieve remission at the next 
scheduled administration visit from the relapse (Week OL-0) to enter Escape arm regardless of 
remission status, and then receive IV administration of ustekinumab at Week OL-0 followed by 
ustekinumab 90 mg SC administered 8 weeks after the IV dose at Week OL-0, then q8w thereafter. 
Escape arm is identical to OLE period except participants in Escape arm will receive IV 
ustekinumab at Week OL-0 instead of SC ustekinumab. Participants in Escape arm may receive 
continuous administrations of IV ustekinumab with 8-week interval once in the study if they 
relapse prior to Week 8. 
NCT04882072


CNTO1275  (Ustekinumab)  
 
 
 
Statistical Analysis Plan CNTO1275TAT3001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
10 
Status: Approved,  Date: 30 June 2023 
When a total of 35 relapse events occur, the DB period will end and rest of the participants in the 
DB period will enter OLE period except for participants who reach oral GC dose of 5 mg/day 
(prednisolone or equivalent) or less in the placebo group to avoid unnecessary administration of 
ustekinumab for those who are considered to be placebo responders. These participants will 
continue or switch (if participants receive placebo in DB period) to receive SC ustekinumab 
administered q8w with maintaining the originally dosing schedule. For these participants, the first 
dosing visit from the end of DB period will be regarded as Week OL-0. In transition period from 
the end of DB period to completion of the database lock (DBL), participants who reach oral GC 
dose of 5 mg/day (prednisolone or equivalent) or less at the end of DB period will continue to 
receive study intervention assigned in DB period until completion of the DBL for DB period in 
order to maintain the blind. The data occurred in the transition period will be handled as that of 
OLE period. Participants assigned to the placebo group who reach oral GC dose of 5 mg/day 
(prednisolone or equivalent) or less at the end of DB period will terminate the study intervention 
administration and conduct early-termination (early-term) visit after completion of the DBL for 
DB period. 
Figure 1: 
Schematic Overview of the Study 
 
Abbreviations: DB=double-blind; DBL=database lock; Early-Term=early-termination; GC=glucocorticoids; 
IC=informed consent; IV=intravenous; OLE=open-label extension; UST=ustekinumab; PBO=placebo; 
SC=subcutaneous; Scr=screening; UST=ustekinumab; q8w=every 8 weeks. 
* When a total of 35 relapse events occur, participants who reach oral GC dose of 5 mg/day (prednisolone or 
equivalent) or less at the end of the DB period in the placebo group will terminate the study intervention 
administration and conduct early-term visit. 
2. 
STATISTICAL HYPOTHESES 
The hypothesis is that ustekinumab will prolong time to relapse while attempting corticosteroids 
tapering as compared with placebo in participants with TAK. 
NCT04882072


CNTO1275  (Ustekinumab)  
 
 
 
Statistical Analysis Plan CNTO1275TAT3001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
11 
Status: Approved,  Date: 30 June 2023 
3. 
SAMPLE SIZE DETERMINATION 
Thirty-five events of relapse will have a power of 80% to detect a hazard ratio of 0.371 at a 2-
sided alpha level of 0.05 (fixed design with no interim analysis is assumed) assuming a relapse-
free rate of 55% in ustekinumab group and 20% in placebo group at Week 24. The assumptions of 
relapse-free rate at Week 24 are based on the results of clinical trial of TCZ showing trend of its 
steroid sparing effects in moderate to severe TAK participants. Total sample size is approximately 
50 (25/treatment group) participants with which 35 events will occur 105 weeks after the first 
participant was enrolled. Regarding study duration, enrollment speed is assumed uniform every 6 
months for 2 years; 5 participants for the first 6 months, 12 participants for the next 6 months, 18 
participants for the next 6 months, and 15 participants for the last 6 months. Relapse free rate will 
carefully be monitored by using blind data during DB period and the actual number of participants 
enrolled in this study will be flexibly determined through the trial. 
4. 
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS 
Analysis Sets 
Description 
Randomized 
The randomized analysis set includes all participants 
who were randomized in the study. 
Full Analysis Set (FAS) 
The full analysis set (FAS) includes all randomized 
participants (or directly enrolled into OLE period 
without randomization) who received at least 1 dose of 
study intervention. 
FAS in DB period 
FAS includes all randomized participants who received 
at least 1 dose of study intervention through DB period. 
FAS in OLE period 
FAS includes all participants who received at least 1 
dose of study intervention through OLE period. 
Safety Analysis Set 
The safety analysis set includes all participants who 
received at least 1 dose of study intervention. 
Safety Analysis Set in DB period 
The safety analysis set includes all participants who 
received at least 1 dose of study intervention through 
DB period. 
Safety Analysis Set in OLE period 
The safety analysis set includes all participants who 
received at least 1 dose of study intervention through 
OLE period. 
Pharmacokinetics Analysis Set 
The PK analysis set is defined as participants who 
received at least 1 complete dose of ustekinumab and 
have at least 1 valid postdose PK data 
Pharmacokinetics Analysis Set in DB period 
The PK analysis set in DB period is defined as 
participants who received at least 1 complete dose of 
ustekinumab and have at least 1 valid postdose PK data 
through DB period 
Pharmacokinetics Analysis Set in Escape arm OLE 
period 
Pharmacokinetics Analysis Set in Escape arm OLE 
period is defined as participants who experienced 
relapse in DB period and received at least 1 complete 
dose of ustekinumab and have at least 1 valid postdose 
PK data from Week OL-0 to end of OLE-period. 
Pharmacokinetics Analysis Set in OLE period 
Pharmacokinetics Analysis Set in OLE period is 
defined as participants who didn’t experience relapse in 
DB period and received at least 1 complete SC 
intervention of ustekinumab at Week OL-0 and have at 
least 1 valid postdose PK data from Week OL-0 to end 
of OLE period. 
NCT04882072


CNTO1275  (Ustekinumab)  
 
 
 
Statistical Analysis Plan CNTO1275TAT3001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
12 
Status: Approved,  Date: 30 June 2023 
Analysis Sets 
Description 
Immunogenicity Analysis Set 
The immunogenicity analysis set is defined as all 
participants who received at least 1 dose of 
ustekinumab and have at least 1 postdose valid 
immunogenicity data. 
Pharmacokinetics/Pharmacodynamics (PD) Analysis 
set in DB period 
PK/PD Analysis set is defined as all participants 
(including participants who received placebo 
intervention) who have at least 1 paired PK and PD data 
collected at same time point needed for each PK/PD 
analysis. If participants who receive placebo 
intervention and have no concentration data during DB 
period, serum ustekinumab concentrations will be 
imputed as zero and should be included into PK/PD 
analyses for DB period as well. 
Pharmacokinetics/Pharmacodynamics Analysis set in 
OLE period 
PK/PD Analysis set is defined as all participants who 
have at least 1 paired PK and PD data collected at same 
time point needed for each PK/PD analysis.in OLE 
period. 
5. 
STATISTICAL ANALYSES 
5.1. 
General Considerations 
5.1.1. 
Visit Windows 
Unless otherwise specified, nominal visits will be used for all by visit analyses. The study visits 
scheduled after randomization should occur at the times delineated in the Time and Events 
Schedule of the protocol. 
For serum ustekinumab concentrations by timepoint summary, if PK assessment is missing at 
scheduled visit or timepoints, the visit of early termination and unscheduled visit will be mapped 
to the scheduled visit if it's within protocol specified visit window. 
5.1.2. 
Analysis Phase 
Analysis phase 
Start date 
End date 
Screening 
The date of signing the 
informed consent 
1 day before the first study 
intervention 
Double-blind 
period 
(DB 
period) 
Date 
of 
the 
first 
study 
intervention 
Date of 35th relapse event 
occurred  
If participants discontinued 
study intervention, date of 
treatment discontinuation will 
be used for the end date. 
If participants had relapse and 
moved to escape arm, then 1 
day before date of the first 
study 
intervention 
after 
NCT04882072


CNTO1275  (Ustekinumab)  
 
 
 
Statistical Analysis Plan CNTO1275TAT3001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
13 
Status: Approved,  Date: 30 June 2023 
Analysis phase 
Start date 
End date 
having relapse and moving to 
escape arm will be used. 
Open-label extension period 
(OLE period) 
Date 
of 
the 
first 
study 
intervention 
after 
having 
relapse and moving to escape 
arm or 1 day after the end of 
DB period 
Date of last observed visit or 
early treatment 
discontinuation, whichever 
comes first 
Follow-up* 
The end of DB period or OLE 
period, whichever comes later 
+ 1 day 
Date of study discontinuation 
or last participation date 
*Note:  For summaries and analysis by study period, follow-up period may be analyzed together 
with DB period (ie, for participants early discontinue study intervention administrations before the 
end of DB period) or OLE period, rather than analyzing separately. 
If the participants received Placebo treatment and achieved GC dose <= 5 mg/day at the end of 
DB period and discontinued treatment after DB period, the data from date of 1 day after DB period 
to treatment discontinuation date will be summarized separately for safety, and will not be 
summarized for efficacy, demographics and concomitant medication and only presented in the 
listing. 
5.1.3. 
Baseline 
The baseline measurement is defined as the closest measurement taken prior to or at the date of 
the first study intervention.  
For patients who did not receive the first study intervention, use the reference date below to obtain 
baseline measurements. 
5.1.4. 
Reference Date 
The reference date is used to calculate relative day variables. It is defined as the date of the initial 
study intervention. If the administration date is missing or the administration is not done, then the 
randomization date should be used. 
5.1.5. 
Study Day 
Study day is defined as the number of days from the study reference date to the event/visit date. 
Note that the reference date is referred to as Day 1 and the previous day is Day -1. 
5.2. 
Participant Dispositions 
Participant dispositions will be summarized by analysis phase (DB period and OLE period). 
NCT04882072


CNTO1275  (Ustekinumab)  
 
 
 
Statistical Analysis Plan CNTO1275TAT3001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
14 
Status: Approved,  Date: 30 June 2023 
The number of participants in the following disposition categories will be summarized by 
intervention group and overall: 
 
Participants who completed the study 
 
Participants who terminated study prematurely at DB period 
 
Participants who terminated study prematurely at OLE period 
 
Reasons for termination of study at DB period 
 
Reasons for termination of study at OLE period 
 
Participants completed study intervention at DB period 
 
Participants who discontinued study intervention at DB period 
 
Reasons for discontinuation of study intervention at DB period 
 
Participants completed study intervention at OLE period 
 
Participants who discontinued study intervention at OLE period 
 
Reasons for discontinuation of study intervention at OLE period 
Listings of participants will be provided for the following categories: 
 
Participants who discontinued study intervention 
 
Participants who terminated study prematurely 
 
Participants who were randomized yet did not receive study intervention. 
5.3. 
Primary Endpoint(s) Analysis 
The primary efficacy endpoint is the time to relapse of TAK according to protocol-defined criteria 
through the end of DB period. 
5.3.1. 
Definition of Endpoint(s) 
Time to relapse of TAK is defined from randomization date to the date of 1st visit of relapse through 
the end of DB period according to protocol-defined criteria (Protocol Section 8.1.1). Relapse of 
TAK is defined by 5 categories:  
 
Systemic symptoms (objective assessment). 
 
Systemic symptoms (subjective assessment). 
 
Elevated inflammation markers (CRP, ESR). 
 
Vascular signs and symptoms. 
 
Ischemic symptoms. 
When 2 or more categories meets the criteria, participants will be judged as relapse. Even if signs 
of relapse are not present in 2 of 5 categories, participants will be judged as relapse if emergent 
hospitalization caused by worsening of TAK and GC treatment required or if severe aortic valve 
incompetence accompanied by symptoms of cardiac failure occurs under ‘vascular signs and 
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symptoms’ or if CTCAE grade 2 or higher (grade ≥3 for myocardial infarction) occurs under 
‘ischemic symptoms’. 
To evaluate if the symptoms caused by TAK, 2 consecutive evaluations are needed for the relapse 
judgement. If the relapse is confirmed in both 1st and 2nd visit, 1st visit date will be used for the 
date of relapse in the analysis. If the following emergent cases are caused by worsening of TAK, 
the participants will be judged as relapse at 1st visit only, and the 1st visit date will be used for the 
analysis. 
 
Emergent hospitalization caused by worsening of TAK and GC treatment required 
 
Severe aortic valve incompetence accompanied by symptoms of cardiac failure occurs under 
‘vascular signs and symptoms’ 
 
CTCAE grade 2 or higher (grade ≥3 for myocardial infarction) occurs under ‘ischemic 
symptoms’ 
 
Both categories ‘vascular signs and symptoms’ and ‘ischemic symptoms’ meet the criteria 
5.3.2. 
Primary Estimand 
Primary Trial Objective: To evaluate the efficacy of ustekinumab compared to placebo, in 
combination with oral GC taper regimen, in participants with relapsing TAK. 
Estimand Scientific Question of Interest: What’s the effect on time to relapse of assigning 
participants with TAK to ustekinumab vs placebo, in combination with protocol allowed oral GC 
taper regimen? 
Primary Estimand, based on the primary objective and scientific question of interest above, is 
defined by the following 5 components: 
 
Population: Participants with TAK who have not adequately responded to conventional 
therapy 
 
Endpoint: Time from randomization to relapse through DB period 
 
Treatment: ustekinumab versus placebo, in combination with protocol allowed oral GC taper 
regimen  
 
Intercurrent Events (ICE) and their corresponding strategies: 
Intercurrent Events 
Name of Strategy for Addressing Intercurrent Events 
and Its Description 
Death or treatment discontinuation at 
DB period  
While on treatment strategy: use time to relapse on or 
before this ICE. 
Major protocol deviation (eg, protocol 
prohibited concomitant medication and 
therapy) 
Treatment Policy strategy: use time to relapse through 
DB period, regardless of major protocol deviations 
 
 
Population level summary: Hazard ratio for time to relapse 
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Status: Approved,  Date: 30 June 2023 
5.3.2.1. 
Main Estimator of Primary Estimand 
 
Data included:  
 
Without ICE: Time from randomization to relapse through DB period. If no relapse events 
up to clinical cutoff, censored at last disease assessment through DB period. 
 
With ICE: If the ICE is death or treatment discontinuation at DB period, censored at last 
disease assessment on or prior to the ICE. For major protocol deviation, time from 
randomization to relapse during study intervention through DB period is used for analysis. 
If no relapse events up to clinical cutoff, censored at last disease assessment through DB 
period 
 
Missing data or data not included: Not applicable. 
 
Assumptions:  
 
Noninformative censoring assumed for all types of censoring 
 
Distinct baseline hazard for each stratum, proportional hazard ratio across strata 
 
Main estimator: A stratified Cox proportional hazard model with study intervention as 
explanatory variable, and with oral GC dose at Week 0 and the status of previous biologic 
medication as stratification factors. Hazard ratio and its 95% Wald confidence intervals (CIs) 
will be estimated. 
5.3.3. 
Supplementary Estimand 1 
The supplementary estimand 1 is defined to apply “while on treatment strategy” to major protocol 
deviation (Protocol prohibited concomitant medication and therapy) of the intercurrent event. 
Other components are the same as primary estimand. 
 
Population: Same attributes as primary estimand. 
 
Endpoint: Same attributes as primary estimand  
 
Treatment: Same attributes as primary estimand  
 
Intercurrent Events (ICE) and their corresponding strategies: 
Intercurrent Events 
Name of Strategy for Addressing Intercurrent Events 
and Its Description 
Death or treatment discontinuation at 
DB period  
Same strategy as primary estimand 
Major protocol deviation (Protocol 
prohibited concomitant medication and 
therapy) 
While on treatment strategy: use time to relapse 
through DB period, and on or before this ICE 
 
 
Population level summary: Same attributes as primary estimand  
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Status: Approved,  Date: 30 June 2023 
5.3.3.1. 
Main Estimator of Supplementary Estimand 1 
 
Data included:  
 
Without ICE: Time from randomization to relapse through DB period. If no relapse events 
up to clinical cutoff, censored at last disease assessment through DB period 
 
With ICE: Censored at last disease assessment on or prior to the ICE if no relapse events 
prior to the ICE. Time from randomization to relapse if relapse occurred prior to the ICE.  
 
Missing data or data not included: Not applicable. 
 
Assumptions:  
 
Noninformative censoring assumed for all types of censoring 
 
Distinct baseline hazard for each stratum, proportional hazard ratio across strata 
 
Main estimator: A stratified Cox proportional hazard model with study intervention as 
explanatory variable, and with oral GC dose at Week 0 and the status of previous biologic 
medication as stratification factors. Hazard ratio and its 95% Wald CIs will be estimated. 
5.3.4. 
Supplementary Estimand 2 
The supplementary estimand 2 is defined to apply “composite strategy” to death, treatment 
discontinuation (due to AE of disease worsening, disease relapse, initiated prohibited medication 
and lack of efficacy) and major protocol deviation (Protocol prohibited concomitant medication 
and therapy) of the intercurrent event. Other components are the same as primary estimand. 
 
Population: Same attributes as primary estimand. 
 
Endpoint: Same attributes as primary estimand  
 
Treatment: Same attributes as primary estimand  
 
Intercurrent Events (ICE) and their corresponding strategies: 
Intercurrent Events 
Name of Strategy for Addressing Intercurrent Events 
and Its Description 
Death or treatment discontinuation at 
DB period (AE of disease worsening, 
disease relapse, initiated prohibited 
medication and lack of efficacy)  
Composite strategy: A participant with this intercurrent 
event is considered to have a relapse at the time of this 
event. 
Treatment discontinuation at DB period 
due to other reasons  
While on treatment strategy: use time to relapse on or 
before this ICE. 
Major protocol deviation (Protocol 
prohibited concomitant medication and 
therapy) 
Composite strategy: A participant with this intercurrent 
event is considered to have a relapse at the time of this 
event. 
 
 
Population level summary: Same attributes as primary estimand  
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Status: Approved,  Date: 30 June 2023 
5.3.4.1. 
Main Estimator of Supplementary Estimand 2 
 
Data included:  
 
Without ICE: Time from randomization to relapse through DB period. If no relaplse 
events up to clinical cutoff, censored at last disease assessment through DB period 
 
With ICE: ICEs with death, treatment discontinuation (due to AE of disease worsening, 
disease relapse, initiated prohibited medication and lack of efficacy) or major protocol 
deviation of prohibited concomitant medication are considered as relapse event and time 
from randomization to ICE through DB period will be used. For treatment discontinuation 
due to other reason, use data through last disease assessment prior to the ICE.  
 
Missing data or data not included: Not applicable. 
 
Assumptions:  
 
Noninformative censoring assumed for all types of censoring 
 
Distinct baseline hazard for each stratum, proportional hazard ratio across strata 
 
Main estimator: A stratified Cox proportional hazard model with study intervention as 
explanatory variable, and with oral GC dose at Week 0 and the status of previous biologic 
medication as stratification factors. Hazard ratio and its 95% Wald CIs will be estimated. 
5.3.5. 
Analysis Methods of Primary Estimand 
For the primary endpoint of time to relapse, primary analysis will consist of test using a Cox 
proportional hazard regression model for comparison between 2 treatment groups based on FAS 
in DB period. Oral GC dose at Week 0 and the status of previous biologic medication will be 
considered as stratification factors. Oral GC dose at Week 0 will be derived as following formula: 
Oral GC dose at Week 0 = Sum of oral GC dose from Day -6 to randomization date (mg) / [Number 
of days treated with GC dose from Day -6 to Randomization date × Weight at Week 0 (kg)]. If 
weight at Week 0 is missing, weight at screening period will be used. 
The hazard ratio and its 2-sided 95% Wald CIs will be also estimated. Efron’s method will be used 
to handle ties.  
The Kaplan-Meier method will be used to estimate the distribution of time to relapse for each 
treatment. The median relapse event with 95% CI will be provided. In addition, the number and 
percentage of participants who had relapse event or were censored will be presented. 
The definition of censoring is described as below: 
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Status: Approved,  Date: 30 June 2023 
Situation 
Date of Relapse or Censoring 
Outcome 
Relapse  
Date of 1st visit judged as 
relapse through end of DB 
period 
Relapse event 
Death or treatment discontinuation 
Date of last disease assessment 
on or prior to death or treatment 
discontinuation through end of 
DB period 
Censored 
Major protocol deviation (Protocol 
prohibited concomitant medication and 
therapy) 
Date of last disease assessment 
through end of DB period  
Censored 
Other (ie, other participants not included 
in above situations) 
Date of last disease assessment  
through end of DB period 
Censored 
5.3.6. 
Analysis Methods of Supplementary Estimand 1 
Similar analysis will be performed as primary estimand. Censoring definition will be changed from 
analysis method of primary estimand as below: 
Situation 
Date of Relapse or Censoring Outcome 
Relapse 
Same as analysis method of primary estimand 
Death or treatment discontinuation 
Same as analysis method of primary estimand 
Major protocol deviation 
(Protocol 
prohibited 
concomitant 
medication and therapy) 
Date 
of 
last 
disease 
assessment on or prior to 
major 
protocol 
deviation 
through end of DB period 
Censored 
Other (ie, other participants not 
included in above situations) 
Same as analysis method of primary estimand 
If the participant has concomitant medication related major protocol deviation, the censoring date 
will be the last disease assessment date on or prior to the major protocol deviation. The details of 
major protocol deviation described in Appendix 8. 
5.3.7. 
Analysis Methods of Supplementary Estimand 2 
Similar analysis will be performed as primary estimand. Censoring definition will be changed from 
analysis method of primary estimand as below: 
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Status: Approved,  Date: 30 June 2023 
Situation 
Date of Relapse or Censoring Outcome 
Relapse 
Same as analysis method of primary estimand 
Treatment discontinuation due to 
other reasons (ie, other than AE of 
disease worsening, disease relapse, 
initiated prohibited medication or 
lack of efficacy) 
Same as analysis method of primary estimand 
Death or treatment discontinuation 
due to AE of disease worsening, 
disease relapse, initiated prohibited 
medication and lack of efficacy 
Date of ICE 
Relapse event 
Major protocol deviation 
(Protocol 
prohibited 
concomitant 
medication and therapy) 
Date of ICE 
Relapse event 
Other (ie, other participants not 
included in above situations) 
Same as analysis method of primary estimand 
5.3.8. 
Subgroup Analyses of Primary Efficacy Endpoint 
All baseline characteristics described in Section 5.7.8 will be used for subgroup analysis. Hazard 
ratio and its 95% CIs will be presented. The subgroup analysis will be applied only for the primary 
estimand. 
5.4. 
Secondary Endpoint(s) Analysis 
No key confirmatory secondary endpoints are defined in this study. 
5.4.1. 
Key Confirmatory Secondary Endpoint(s) 
Not applicable. 
5.4.1.1. 
Definition of Endpoint(s) 
Not applicable. 
5.4.1.2. 
Estimand(s) 
Not applicable. 
5.4.1.3. 
Analysis Methods 
Not applicable. 
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5.4.2. 
Supportive Secondary Endpoint(s) 
The supportive secondary endpoints are as following: 
 
Time to relapse of TAK according to Kerr’s definition through the end of DB period 
 
Time to relapse of TAK based on clinical symptoms only through the end of DB period 
 
Time to relapse of TAK in each of the 5 categories through the end of DB period 
 
Relapse rate in each of the 5 categories through the end of DB period 
 
Cumulative oral GC dose (prednisolone or equivalent) through the end of DB period  
 
Change from baseline in oral GC dose (prednisolone or equivalent) through the end of DB 
period  
 
Number/proportion of participants achieving GC dose of 5 mg/day or less through the end of 
DB period 
 
Change from baseline in imaging evaluation through the end of DB period 
 
Change from baseline in inflammatory markers (CRP, ESR) through the end of DB period 
5.4.2.1. 
Definition of Endpoints 
Time to relapse by 5 categories (Protocol-defined criteria) 
As described in Section 5.3.1, protocol-defined criteria consist of 5 categories: 1) Systemic 
symptoms (objective assessment), 2) Systemic symptoms (subjective assessment), 3) Elevated 
inflammation markers, 4) Vascular signs and symptoms and 5) Ischemic symptoms. Time to 
relapse will be calculate by each category independently. According to protocol, confirmation visit 
is not needed for each category, so 1st visit that the criterion met will be used as relapse date. If the 
participant met at least one criterion described above and it met due to disease worsening, it is 
considered as relapse event and time from randomization to the date of meeting the criterion will 
be used in the analysis. 
Time to relapse (Kerr’s definition) 
Time to relapse is defined from the date of randomization to the judged date of relapse through the 
end of DB period based on Kerr’s definition as following.  
Participants meet 2 or more categories in the following 4 categories will be considered as relapse 
per Kerr’s definition: 1) Objective systemic symptoms or subjective systemic symptoms, 2) 
Elevated inflammation markers, 3) Vascular signs and symptoms or ischemic symptoms, 4) 
Imaging evaluation.  
Time to relapse by 4 categories (Kerr’s definition) 
As described above, Kerr’s definition consists of 4 categories. Time to relapse will be calculate 
independently. According to protocol, confirmation visit is not needed for each category, so 1st 
visit that the criterion met will be used as relapse date. Only if the participant meets the criteria 
and its symptoms comes from worsening of TAK, it is considered to be an event. 
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Status: Approved,  Date: 30 June 2023 
Time to relapse (clinical symptoms) 
Time to relapse is defined from the date of randomization to the judged date of relapse through 
end of DB period based on clinical symptoms as following. 
Participants meet at least 1 category in the following 4 clinical categories are considered as relapse 
per clinical symptom only definition: 1) Objective systemic symptoms; 2) Subjective systemic 
symptoms; 3) Vascular signs and symptoms; 4) Ischemic symptoms. 
Oral GC dose 
Oral GC dose (prednisolone or equivalent) used from randomization date to last observed date 
prior to the date of relapse will be included in the analysis if the participant has relapse. If the 
participant has no relapse, oral GC dose used from randomization to last observed date through 
the end of DB period will be included in the analysis. 
Inflammatory markers 
CRP and ESR will be analyzed as inflammatory markers. Data from central lab will be used for 
CRP, and local lab data will be used for ESR. For CRP, if central lab data is missing, local lab data 
will be used for analysis at the same visit. 
5.4.2.2. 
Analysis Methods 
Unless otherwise specified, the analysis population will be the FAS in DB period defined in 
Section 4. 
Time to relapse 
Time-to-relapse using other definitions such as Kerr’s definition, based on clinical symptoms only 
and each of 5 categories will be estimated by Kaplan-Meier method. The hazard ratio and its 2-
sided 95% Wald CIs will be estimated using Cox proportional hazard regression model. Oral GC 
dose at Week 0 and the status of previous biologic medication will be considered as stratification 
factors. Efron’s method will be used to handle ties. Proportion of number of relapsed participants 
through treatment period will be also summarized by each definition of relapse.  
The definition of censoring is described as below: 
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Status: Approved,  Date: 30 June 2023 
Situation 
Date of Relapse or Censoring 
Outcome 
Relapse  
Date of 1st visit judged as 
relapse through end of DB 
period 
Relapse event 
Death or treatment discontinuation 
Date of last disease assessment 
on or prior to death or treatment 
discontinuation through end of 
DB period 
Censored 
Major protocol deviation (Protocol 
prohibited concomitant medication and 
therapy) 
Date of last disease assessment 
through end of DB period  
Censored 
Other (ie, other participants not included 
in above situations) 
Date of last disease assessment 
through end of DB period 
Censored 
Note: for “death or treatment discontinuation”: use data on or prior to death or treatment 
discontinuation through end of DB period; for major protocol deviation and other situations: use 
data through end of DB period. 
Time to relapse by categories 
Forest plot including number of participants who have relapse, median time, hazard ratio and its 
95% CI will be displayed. Censoring rule will be used as described above.  
Oral GC dose 
Prednisolone dose or equivalent will be descriptively summarized including cumulative dose and 
change from baseline. Change from baseline is defined as the change between the GC dose at 
randomization and the last observed GC dose. Last observed GC dose before relapse will also be 
presented for participants who had relapse. The last observed GC dose (during DB) is the average 
GC dose in last 7 days before the date of relapse (first visit of relapse will be used for relapse need 
to be confirmed) for participants who had relapse, or average GC dose in last 7 days on or before 
end of DB period. Number and proportion of participants who achieved GC dose of 5mg/day or 
less through the end of DB period will be also summarized. If actual GC dose average in last 7 
days through the end of DB period (for participants with relapse during DB, data before the date 
of relapse will be used) is 5mg/day or less, the participants are considered to achieve GC dose of 
5mg/day or less. A spaghetti plot of oral GC dose (mg/day) overtime through DB period will be 
provided for individual participants. GC dose after study treatment discontinuation of DB will not 
be included in summary of analysis. 
Inflammatory markers 
The observed values, change from baseline of inflammatory markers will be descriptively 
summarized by visit. These values will be also graphically displayed by line plot. 
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5.5. 
Tertiary/Exploratory Endpoint(s) Analysis 
Exploratory endpoints are as follows: 
 
Proportion of participants who experienced relapse using each definition such as protocol-
defined criteria, Kerr’s definition, based on clinical symptoms only and each of five categories 
during OLE period. 
 
Changes from baseline on PROs through the end of study (SF-36, PtGA of disease activity on 
VAS, FACIT-Fatigue) through the end of study. 
 
Change from baseline PhGA through the end of study. 
 
Cumulative oral GC dose during OLE period. 
 
Change from baseline in oral GC dose during OLE period. 
 
Proportion of participants achieving oral GC dose of 5 mg/day or less during OLE period. 
 
Proportion of participants who achieve 7.5mg/day or less during OLE period. 
 
Change from baseline in imaging evaluation during OLE period. 
 
Change from baseline in inflammatory markers (CRP, ESR) during OLE period. 
5.5.1. 
Definition of Endpoints 
36-item Short Form 
The SF-36 consists of 8 subscales: limitations in physical functioning due to health problems, 
limitations in usual role activities due to physical health problems, bodily pain, general mental 
health (psychological distress and well-being), limitations in usual role activities due to personal 
or emotional problems, limitations in social functioning due to physical or mental health problems, 
vitality (energy and fatigue), and general health perception. These subscales 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). 
8 subscales and 2 summary score will be calculated by using web scoring system that is provided 
by Qualitest Inc. 
Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-Fatigue): 
The Functional Assessment of Chronic Illness Therapy – Fatigue Scale (FACIT-Fatigue) version 
4.0 is a 13-item questionnaire formatted for self-administration that assesses patient-reported 
fatigue and its impact upon daily activities and function over the past seven days. Subjects will be 
asked to answer each question using a 5-point Likert-type scale (0 = Not at all; 1 = A little bit; 2 = 
Somewhat; 3 = Quite a bit; and 4 = Very Much). The interpretation of FACIT-Fatigue scores is 
such that a higher score indicates less fatigue, with a range of possible scores of 0-52, with 0 being 
the worst possible score and 52 the best. 
FACIT-Fatigue scale is scored so that a high score is good. To achieve this, the score for 
negatively-phrased questions will be reversed (4 – item response), then sum the item response. If 
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Status: Approved,  Date: 30 June 2023 
there are >= 7 missing items in the FACIT-Fatigue, the score will be set as missing. Otherwise, 
the total score will be prorated: 
FACIT-Fatigue scale score = (Summation of the individual item scores × 13) / Number of items 
answered. 
Patient Global Activity-Visual Analog Scale (PtGA-VAS): 
Patient Global Activity is partially validated tool to measure the global evaluation by the 
participant of the patient's overall disease activity at the time of assessment using a 10 cm VAS. 
Physician Global Activity-Visual Analog Scale (PhGA-VAS): 
Physician Global Activity is partially validated tool to measure the global evaluation by the 
physician of the participant's overall disease activity at the time of assessment using a 10 cm VAS. 
5.5.2. 
Analysis Method 
For exploratory endpoints, the continuous variables will be summarized by intervention group and 
week using descriptive statistics, which will include the number of participants (N), mean, standard 
deviation (SD), median, minimum, and maximum. The categorical variables will be summarized 
by intervention group and week using frequencies and percentages. Unless otherwise specified, 
analysis of exploratory endpoints for OLE period will be based on FAS in OLE period. 
For participants with relapse in OLE period, percentage of participants who experience relapse 
will be summarized by study intervention. Also, events rate in hundred patient-year will be also 
summarized and calculated as (the number of relapse × 365.25/ Sum of total duration of disease 
assessment in OLE period in days) * 100.  
For continuous variables of patient reported outcomes (PROs) in DB period, descriptive analysis 
followed by mixed model repeated measures (MMRM) will be used with change from baseline as 
dependent variable, baseline score as covariate, and intervention group, GC dose at baseline, 
previous biologic medication, week, and interaction between treatment and week as fixed effects. 
An unstructured covariance structure will be used to model the within-patient error. In case of 
convergence problems, the autoregressive matrix structure and compound symmetry structure will 
be used till convergence is achieved. Parameters will be estimated using residual (restricted) 
maximum likelihood, the Kenward-Roger method will be used for calculating the denominator 
degrees of freedom. Based on the MMRM model described above, treatment effects at each visit 
in DB period will be estimated based on the differences of least-square (LS) means with 95% CIs. 
For continuous variables of PROs in OLE period, only descriptive summary will be performed by 
intervention group and visit, intervention comparison will not be performed.  
GC dose during OLE period (on or before treatment discontinuation) will be descriptively 
summarized as following: 
 
Cumulative oral GC dose 
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 
GC dose and change from baseline in GC dose by 4 weeks. Baseline is defined as 7 days 
average from Day -6 to OLE Week 0. GC dose by 4 weeks summary will used the average in 
4 weeks. 
 
Last observed GC dose that is presented as the average in the last 7 days in OLE period 
 
The number and proportion of participants who achieve 5mg/day or less during at least 7 days, 
and the duration that these participants achieve 5mg/day or less 
 
The number and proportion of participants who achieve 5mg/day or less at least 7days and 
continue until the end of OLE period, and the duration that these participants achieve 5mg/day 
or less 
 
The number and proportion of participants who achieve 7.5mg/day or less during at least 7 
days, and the duration that these participants achieve 7.5mg/day or less 
 
The number and proportion of participants who achieve 7.5mg/day or less at least 7days and 
continue until the end of OLE period, and the duration that these participants achieve 
7.5mg/day or less 
 
A spaghetti plot of oral GC dose (mg/day) overtime during OLE period (including GC dose 
after treatment discontinuation) will be provided for individual participants. 
5.6. 
Other Safety Analyses 
All safety analyses will be based on the safety analysis set in DB/OLE period based on actual 
intervention received, unless otherwise specified. 
For all continuous safety variables, descriptive statistics by intervention group will include the N, 
mean, standard deviation, median, minimum, and maximum. Categorical variables will be 
summarized by intervention group using frequency counts and percentages. 
5.6.1. 
Extent of Exposure 
Extent of exposure will be summarized by analysis phase (DB period and OLE period) and type 
of administration (IV and SC). 
The number and percentage of participants who receive each study intervention within each 
analysis phase will be summarized.  
Descriptive statistics for duration of study intervention (N, mean, SD, median, and range 
(minimum, maximum)) will be summarized by study intervention.  
Study intervention duration is defined as (date of last dose of study intervention – date of first dose 
of study intervention) +1. 
Number of administrations and Cumulative dose will be also summarized by study intervention. 
Study intervention compliance will be summarized descriptively. See Appendix 6 for further 
details. 
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5.6.2. 
Adverse Events 
Adverse events will be summarized by analysis phase (DB period and OLE period). AEs during 
receiving study intervention ustekinumab through the Study will also be summarized. 
The verbatim terms used in the CRF by investigators to identify adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). Any AE occurring at or after the 
initial administration of study intervention through the day of last dose is considered to be 
treatment emergent. If the event occurs on the day of the initial administration of study intervention, 
and either event time or time of administration are missing, then the event will be assumed to be 
treatment emergent. If the event date is recorded as partial or completely missing, then the event 
will be considered to be treatment emergent unless it is known to be prior to the first administration 
of study intervention based on partial onset date or resolution date. All reported treatment-
emergent adverse events will be included in the analysis.  For each adverse event, the number and 
percentage of participants who experience at least 1 occurrence of the given event will be 
summarized by intervention group. 
Summary tables will be provided for treatment-emergent adverse events: 
 
AEs 
 
AEs per hundred patient-years of follow-up that will be calculated as (the number of adverse 
events ×365.25/ Sum of total duration of follow-up in days) * 100 
 
Serious AEs (SAEs) 
 
AEs leading to death 
 
AEs leading to discontinuation of study intervention 
 
AE with a frequency threshold of 5% or more 
 
AEs by severity (mild, moderate, severe) 
 
AEs by relationship to study intervention 
 
SAEs by relationship to study intervention 
 
Infections 
 
Serious Infections 
 
Infusion reactions 
 
Injection-site reactions 
 
Hypersensitivity Reactions (either Infusion reactions or Injection-site reactions) 
 
AEs related to COVID-19 
 
Other AESI 
In addition to the summary tables, listings will be provided for participants who: 
 
AEs 
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 
SAEs 
 
AEs leading to discontinuation of study intervention 
 
Death 
 
Infections 
 
Serious Infections 
 
Infusion reactions 
 
Injection-site reactions 
 
Hypersensitivity Reactions 
 
Other AESIs 
5.6.3. 
Additional Safety Assessments (if applicable) 
5.6.3.1. 
Clinical Laboratory Tests 
Clinical Laboratory Tests will be summarized by analysis phase (DB period and OLE period). 
Clinical laboratory tests will be displayed for the participants included in the safety analysis set. 
Descriptive statistics and graphical displays will be presented for selected chemistry and 
hematology laboratory tests at scheduled time points. 
Change from baseline over time will be summarized for chemistry and hematology tests and 
displayed by intervention group. A box plot of change from baseline to over time will be provided 
for the following laboratory tests: 
 
Hematology: Hemoglobin, Hematocrit, Red blood cell (RBC) count, White blood cell (WBC), 
Platelet count, Lymphocytes, Monocytes, Neutrophils, Bands, Eosinophils, Basophils 
 
Chemistry: Albumin, Alkaline phosphatase, Alanine aminotransferase (ALT/SGPT), 
Aspartate aminotransferase (AST/SGOT), Total carbon dioxide (CO2), Total bilirubin, BUN, 
Calcium, Chloride, Creatinine, Glucose, Potassium, Total protein, Sodium, CK 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE; 
version 5.0) will be used in the summary of laboratory data (Grade 0-4).  The proportion of subjects 
with postbaseline values by maximum toxicity grade for clinical laboratory tests will be 
summarized by intervention group. Shift summaries from baseline laboratory value to the worst 
on-treatment grade in chemistry and hematology tests with NCI toxicity grades will be presented. 
Subjects with toxicity grades ≥ 2 will be listed. 
In addition, the incidence of markedly abnormal laboratory values will be presented by 
intervention group.  Additionally, the markedly abnormal laboratory values will be listed.  
Markedly abnormal criteria are defined as Table 2: 
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Table 2: 
Markedly abnormal laboratory criteria 
Item 
Criterion of markedly abnormal criteria 
Hematology & Differential panel 
 
Hemoglobin 
≤10݃/݀ܮ 
WBC 
Out of normal range 
Neutrophils 
Out of normal range 
Lymphocytes 
Out of normal range 
Chemistry panel 
 
ALT 
≥3 × ܷܮܰ 
AST 
≥3 × ܷܮܰ 
LDH 
≥3 × ܷܮܰ 
Creatinine 
≥1.5 × ܷܮܰ 
Glucose 
≥300݉݃/݀ܮ 
 
All laboratory values will be listed. 
5.6.3.2. 
Vital Signs 
Vital signs will be summarized by analysis phase (DB period and OLE period). Continuous vital 
sign parameters including temperature, respiratory rate, weight, pulse and blood pressure (systolic 
and diastolic, right and left hands separately) will be summarized at each assessment time point. 
Change from baseline will be summarized at each assessment timepoint. Descriptive statistics 
(mean, standard deviation, median, minimum and maximum) will be presented. 
Incidence of clinically important vital signs during intervention, as defined in Table 3, will be 
summarized for participants who had a baseline assessment and at least 1 postbaseline assessment 
for that vital sign. A listing of participants with treatment-emergent [clinically important/markedly 
abnormal] vital signs will be presented, along with a listing of all vital sign measurements. 
Table 3: 
Clinically Important Vital Signs 
Vital Sign 
Criteria 
Pulse 
>120 bpm and with >15 bpm increase from baseline 
 
<50 bpm and with >15 bpm decrease from baseline 
Systolic blood pressure 
>180 mm Hg and with >20 mm Hg increase from baseline 
 
<90 mm Hg and with >20 mm Hg decrease from baseline 
Diastolic blood pressure 
>105 mm Hg and with >15 mm Hg increase from baseline 
 
<50 mm Hg and with >15 mm Hg decrease from baseline 
Temperature 
>38oC  
Respiratory rate 
>24 breaths per minute 
Weight 
>10% kg increase from baseline 
 
>10% kg decrease from baseline 
5.6.3.3. 
Electrocardiogram 
ECG will be summarized by analysis phase (DB period and OLE period). 
The interpretation of the ECGs as determined by a qualified physician (investigator or qualified 
designee) will be displayed by the number and percentage of participants meeting the normality 
criteria. The interpretation will be summarized over time by intervention group. 
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A listing of clinically relevant ECG abnormalities will also be provided. 
5.7. 
Other Analyses 
5.7.1. 
Pharmacokinetics 
Blood samples will be collected for serum ustekinumab concentrations at the specified visits as 
indicated in the Schedule of Activities in protocol. PK analyses will be performed on the PK 
analysis set (see Section 4). 
Serum ustekinumab concentrations summary and analysis will be based on the observed data; 
therefore, no imputation of missing data will be performed. All participants and samples excluded 
from the analysis will be clearly documented (eg, unknown or unreliable drug intake information). 
All PK data including actual sampling time will be listed. All serum ustekinumab concentrations 
below the lower limit of quantification (LLOQ) or missing data will be labeled as such in the 
concentration data listing or statistical analysis system dataset. 
Descriptive statistics (N, mean, SD, median, range, CV (%) and IQ range) will be used to 
summarize serum ustekinumab concentrations at each sampling time point.  
For descriptive statistics of serum concentration of ustekinumab, the following data handling rules 
will be applied; 
 
Participants will be excluded from the PK analysis if their data do not allow for accurate 
assessment of the PK. In particular, all serum concentration summaries will exclude, from the 
time of occurrence, data collected for participants who 1) discontinue ustekinumab, 2) skip an 
infusion or injection, 3) receive an incomplete infusion or injection, 4) receive an incorrect 
infusion or injection, 5) receive an additional infusion or injection, and/or 6) receive 
commercial ustekinumab. Exclusion data from PK analysis due to such inadequate 
administration will be specified by PK analyst. In addition, PK samples taken outside the 
scheduled visit window (Week 2 and Week 4 visits:  ±4 days; Week 8 and thereafter:  ±7 
days) will be excluded from the summaries. 
 
Serum ustekinumab concentrations below the LLOQ will be imputed as zero in the summary 
statistics. 
 
When more than half (>50%) of the serum concentrations of ustekinumab are BQL at each 
scheduled time point, mean, median, minimum and 25% quartile will be shown as ‘BQL’, and 
SD, %CV and 75% quartile will be shown as ‘NC’ (not calculated). Maximum observed value 
will be presented as maximum. 
 
When all serum concentration data are BQL at each scheduled time point, mean and median 
will be reported as ‘BQL’; SD and %CV are reported as ‘NC’ (not calculated); IQ range, 
maximum and minimum will be reported as ‘BQL’. 
 
When the number of serum concentrations data of ustekinumab at each scheduled time point 
is less than or equal to 2, N, mean and median will be calculated, and SD, %CV, 25% quartile 
and 75% quartile will be shown as ‘NC’. Minimum and maximum will be shown as ‘NC’ 
(quantifiable data=1) or will be reported as observed including BQL (quantifiable data =2). 
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 
At the time point where no observation is obtained, ‘NA (not applicable)’ is reported. 
 
Data of samples with no information about the sampling date and time and/or the drug 
administration (time and dosage) will be excluded from descriptive statistics. 
 
Sampling time at Week 0 predose will be substituted with “0” in the figure. If, as the result of 
calculations (eg, descriptive statistics), a concentration value is less than the LLOQ (eg, 
0.16880 μg/mL), the value should be reported as calculated. 
Definition of analysis period 
 
DB period: Serum ustekinumab concentration is defined as the data derived from participants 
who were randomized ustekinumab arm and the duration is from Week 0 to end of DB period 
(see the definition in Section 5.1.2). 
 
Escape arm OLE period: Serum ustekinumab concentration is defined as the data derived from 
participants who experienced relapse in DB period and received IV intervention at Week OL-
0 and the duration is from Week OL-0 to end of OLE-period (see the definition in Section 
5.1.2). 
 
OLE period: Serum ustekinumab concentration is defined as the data derived from participants 
who didn’t experience relapse in DB period and received SC intervention at Week OL-0 and 
the duration is from Week OL-0 to end of OLE period.  
Serum ustekinumab concentrations will be summarized in tabular or graphical formats with 
nominal sampling timepoint. 
Table 
In DB period, serum ustekinumab concentrations from all patients received the active treatmnet 
will be summarized in table. In Escape arm OLE period and OLE period, serum ustekinumab 
concentrations will be summarized by intervention arm (Ustekinumab -> Ustekinumab  or Placebo 
-> Ustekinumab) in table. In addition, to assess the impact of weight-based dosing, serum 
ustekinumab concentrations up to Week 8 in DB period and up to Week OL-8 in Escape arm OLE 
period will be summarized in a separate table by weight-range based dose category. Participants 
who received IV intervention at Week 0 and continuously received next IV intervention at Week 
OL-0 (which mean without SC intervention) will be summarized in a separate table which will 
include serum concentrations at Week 0, 2, 4, Week OL-0 and OL-8. 
Figure 
Serum ustekinumab concentration data may be displayed graphically in separate graph.  
 
Median (IQR) of serum ustekinumab concentration time profiles through DB period (in linear 
and semilog scales) will be presented in figure. 
 
Median (IQR) of serum ustekinumab concentration time profiles through Escape arm OLE 
period or OLE period (in linear and semilog scales) will be presented in figure by DB period 
intervention arm. 
Serum ustekinumab concentration data may also be displayed graphically, such as median (IQR) 
of serum ustekinumab concentrations over time by the following subgroups: 
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 
Antibodies to ustekinumab status by subject who have at least one positive ADA sample or 
no positive ADA sample through DB period or end of OLE period 
Listing 
The elapsed time[day] from last dosing to next PK sampling point will be described in listing. 
Other 
If sufficient data are available, then population PK analysis using serum concentration-time data 
of ustekinumab will be performed using nonlinear mixed-effects modeling. Details will be given 
in a population PK analysis plan and the results of the analysis will be presented in a separate 
report. 
5.7.2. 
Immunogenicity 
Blood samples will be collected for the detection of antibodies to ustekinumab at the specified 
visits as indicated in the Schedule of Activities in protocol. Immunogenicity analyses will be 
performed on the Immunogenicity analysis set (see Section 4). 
“Sample ADA status” and sample titer as well as the cumulative “subject ADA status” and peak 
titer through the visit will be coded and provided by the bioanalytical group.  
“Subject ADA status” is defined as below.  
 
Participants with treatment-emergent ADA positive to ustekinumab include: 
 
Participants with treatment-induced antibodies to ustekinumab  
 
Participants with treatment-boosted antibodies to ustekinumab 
 
Participants with treatment-induced antibodies to ustekinumab have a negative sample prior 
to administration and at least one positive sample after administration. 
 
Participants with treatment-boosted antibodies to ustekinumab have a positive sample prior to 
administration and at least one positive sample after administration with increase in titer over 
baseline. 
The analysis will be based on the observed data; therefore, no imputation of missing data will be 
performed. 
Incidence of antibody (evaluable, baseline ADA positive, treatment-emergent ADA positive, 
treatment-emergent ADA negative) status, neutralizing antibodies (NAb) and the maximum titers 
of anti-ustekinumab antibodies from Week 0 to OLE period will be summarized by intervention 
groups. The summary of participants with baseline positive samples is taken from the sample status 
at baseline. Sample ADA status at baseline is not considered for “subject ADA status”. A ‘Total’ 
column that combines all intervention groups will be also presented.  
The summary of following endpoints (time to relapse of TAK, relapse status, achieving GC dose 
criteria status, and injection site reactions status) will be presented by intervention group by 
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treatment-emergent ADA status. For 1 and 2, only DB period data will be assessed. For 3 and 4, 
both DB and OLE period data will be assessed:  
1. Time to relapse of TAK according to protocol-defined criteria through the end of DB period 
2. Relapse status through the end of DB period 
3. Achieving GC dose criteria (5 mg/day or less or not) 
4. Injection-Site Reactions status through DB period/OLE period  
5.7.3. 
Pharmacodynamics 
See Section 5.7.5. 
5.7.4. 
Pharmacokinetic/Pharmacodynamic Relationships 
Pharmacokinetic/Pharmacodynamic analyses will be based on the PK/PD analysis set (see Section 
4). In DB period, the serum ustekinumab concentration data derived from participants who 
received placebo treatment will be complemented as zero. Exploratory PK-PD analyses, including 
graphical exploration of PK-PD data, may be performed.  
Following PD indicator will be used: time to relapse, the proportions of relapse, the proportions of 
participants achieving GC dose of 5 mg/day or less and CRP/ESR. 
Serum ustekinumab concentrations at DB or OLE relapse timing is defined as serum ustekinumab 
concentration at 1st relapse visit. If PK sample is not collected at 1st relapse visit, serum 
ustekinumab concentration at relapse confirmation visit will be used. For participants who didn’t 
experience relapse, serum ustekinumab at end of DB will be treated as those at DB relapse timing. 
Serum ustekinumab at end of OLE will be treated as those at OLE relapse timing. 
The definition of end of DB period and end of OLE period is shown in Section 5.1.2. 
Time to relapse at DB period versus serum ustekinumab concentrations at DB relapse timing are 
plotted using the data from individual subjects for both ustekinumab arm and placebo arm (vertical 
axis: time to relapse DB period, horizontal axis: serum ustekinumab concentration). 
Relationship between the proportions of relapse at end of DB period and end of OLE period and 
serum ustekinumab concentrations will be tabulated. In case DB period, the following category 
(ustekinumab arm: <=median or >median) will be used. In case OLE period, the following 
category (<=median or >median) will be used. DB period and OLE period will be summarized in 
separate table. 
Relationship between the proportions of participants achieving GC dose of 5 mg/day or less 
through DB period and serum ustekinumab concentrations in ustekinumab arm at end of DB period 
will be summarized by ustekinumab concentration category (<=median or >median). 
CRP/ESR value at DB relapse visit or at OLE relapse visit versus serum ustekinumab 
concentrations at DB or OLE relapse timing will be plotted using the data from individual 
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participants (vertical axis: the change from baseline in CRP/ESR, horizontal axis: serum 
ustekinumab concentration) by intervention arm (DB relapse visit: ustekinumab arm/placebo arm, 
OLE relapse visit: ustekinumab arm/placebo->ustekinumab arm) and relapse status. For 
participants who didn’t experience relapse, CRP/ESR values at end of DB period or at end of OLE 
period (date of last observed visit or early discontinuation whichever comes first) will be used. 
If deemed feasible and necessary, exposure-response modeling analyses may be performed. The 
analysis methods may be summarized in a separate analysis plan. Results of such analyses may be 
presented in a separate technical report. 
5.7.5. 
Biomarkers 
Biomarker results will be summarized in a separate technical report. Changes in biomarkers over 
time may be summarized by intervention group. Planned biomarker analyses may be deferred if 
emerging study data show no likelihood of providing useful scientific information or insufficient 
number of samples are available for analyses. Any biomarker samples received by the contract 
vendor or sponsor after the cutoff date will not be analyzed and therefore, excluded from the 
biomarker analysis. 
5.7.6. 
Health Economics 
Not applicable. 
5.7.7. 
Other Variables and/or Parameters 
Not applicable. 
5.7.7.1. 
Definition 
Not applicable. 
5.7.7.2. 
Analysis Method 
Not applicable. 
5.7.8. 
Definition of Subgroups 
Subgroup 
Definition 
Age Group 
 15-64 
 >= 65 
 
 15-17 
 >= 18 
Glucocorticoid at baseline  
 <0.5 mg/kg/day 
 >=0.5 mg/kg/day 
Status of previous biologic 
medication 
 Bio-nonfailure 
 Biofailure 
Weight 
 <50 kg 
 >=50kg 
Disease duration 
 <5 years 
 >=5years 
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5.8. 
Interim Analyses 
One efficacy interim analysis is planned to confirm early success after 15 events have been 
occurred. The O’Brien-Fleming alpha spending function as implemented by the Lan-DeMets 
method will be used to determine the statistical boundary for early success (2-sided p-value 
≤0.0012 for the efficacy interim analysis when exactly 15 of 35 events were observed). Specific 
details will be provided in the IDMC Charter and IDMC SAP. 
However, the study turned out to be early terminated by sponsor before occurrence of 15 events, 
and the planned interim analyses will therefore not be performed.   
5.8.1. 
Data Monitoring Committee (DMC) or Other Review Board 
An IDMC will be established to monitor data on an ongoing basis to ensure the continuous safety 
and well-being of the participants enrolled in this study. The committee will meet periodically to 
review safety data and provide recommendation to the sponsor on continuing the trial. The IDMC 
responsibilities, authorities, and procedures will be documented in the IDMC charter. 
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6. 
SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1 List of Abbreviations 
 
ADA 
anti-drug antibody 
AE 
adverse event 
ALT/SGPT 
alanine aminotransferase 
AST/SGOT 
aspartate aminotransferase 
ATC 
anatomic and therapeutic class 
BMI 
body mass index 
CI 
confidence interval 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DB 
Double-blind 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
ESR 
erythrocyte sedimentation rate 
FACIT 
The Functional Assessment of Chronic Illness Therapy 
F (%) 
absolute SC bioavailability 
FAS 
full analysis set 
GC 
glucocorticoid 
ICE 
Intercurrent events 
IQ 
interquartile 
LLOQ 
lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
NAb 
neutralizing antibodies 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PtGA 
Patient’s global assessment 
SAEs 
serious adverse events 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SF-36 
Short form-36 
TAK 
Takayasu arteritis 
TEAEs 
treatment-emergent adverse events 
VAS 
visual analog scale 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 
 
 
 
 
 
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6.2. 
Appendix 2 Demographics and Baseline Characteristics 
The number of participants in each analysis set will be summarized by intervention group, and 
overall.  
Table 4 presents a list of the demographic variables that will be summarized by intervention group 
and overall for the randomized analysis set. 
Table 4: 
Demographic Variables 
Continuous Variables: 
Summary Type 
Age (years) 
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum], and IQ range). 
Weight (kg) 
Height (cm) 
Body Mass Index (BMI) (kg/m2) 
Disease duration (years) 
Glucocorticoid at baseline (mg/kg/day) 
Categorical Variables 
 
Age (15-64 years, and =>65 years; 15-17 years, and >=18 years) 
Frequency distribution with the 
number and percentage of 
participants in each category. 
Weight (<50kg, >=50kg) 
Sex (male, female, unknown, undifferentiated) 
Racea (Asian (Japanese), Other) 
Ethnicity (Hispanic or Latino, not Hispanic or Latino) 
 
BMI (Underweight <18.5, Normal 18.5-<25, Overweight 25-<30, Obese >=30) 
Glucocorticoid at baseline (<0.5 mg/kg/day, =>0.5 mg/kg/day)b 
Status of previous biologic medication (Bio-nonfailure, Biofailure) 
Treatment (Tocilizumab, TNF, other)c 
Disease duration (< 5 year, >= 5 year) 
aIf multiple race categories are indicated, the Race is recorded as 'Multiple' 
bGC dose will be calculated as following formula: 
Oral GC dose at Baseline = Sum of oral GC dose from Day -6 to randomization date (mg) / [Number of days treated 
with GC dose from Day -6 to Randomization date × Weight at Week 0 (kg)] 
*Weight at screening may be used in case Weight at Week 0 were not collected. 
cIf the previous medication status is biofailure 
 
 
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6.3. 
Appendix 3 Protocol Deviations 
A listing of participants with major protocol deviations including participant ID, type of deviation, 
and reasons for deviation will be provided. Major and minor COVID-19 related protocol deviation 
will also be listed. 
 
 
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6.4. 
Appendix 4 Prior and Concomitant Medications 
Prior and Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). Prior medications are defined as any therapy used before the day of first 
dose (partial or complete) of study intervention. Concomitant medications are defined as any 
therapy used on or after the same day as the first dose of study intervention, including those that 
started before and continue on after the first dose of study intervention. 
Summaries of concomitant medications will be presented by anatomic and therapeutic class (ATC) 
term and intervention group. The proportion of participants who receive each concomitant 
medication will be summarized as well as the proportion of participants who receive at least 1 
concomitant medication. The concomitant medication that is used through DB period and through 
the study will be summarized.  
Prior medications will be summarized by intervention group and ATC term. 
 
 
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6.5. 
Appendix 5 Medical History 
Medical history will be collected at screening. A summary table and a subject listing will be 
provided for general medical history and COVID-19 medical history for the randomized analysis 
set. 
 
 
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6.6. 
Appendix 6 Intervention Compliance 
Intervention compliance will be summarized by analysis phase (DB period and OLE period) and 
type of administration (IV and SC). 
Compliance will be summarized descriptively by study intervention. Compliance to randomized 
intervention versus actual intervention will be presented in a summary table. 
Compliance will be calculated as follows: 
100 x (actual amount of study intervention)/ protocol defined amount of study intervention 
 
 
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6.7. 
Appendix 7 Adverse Events of Special Interest 
Opportunistic infection, active tuberculosis and malignancy are defined as special interest AE. 
AEs are determined by clinical review and detailed definitions are described in Data Presentation 
Specifications. 
 
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6.8. 
Appendix 8 Major Protocol Deviation for Intercurrent Events 
Sequence 
 number  
Description  
 
[Copy or select the description from 
the Protocol and/or decide with Study 
Team on additional Protocol Deviations 
to be identified] 
Protocol Deviation Description 
(DVTERM) as entered in Study 
Specific Issue System 
 
This is suggestive wording to ensure 
review of PDs is consistent. 
PD Criterion  
 
(100 character limit required) 
Protocol 
Deviation 
Coded Term 
(DVDECOD) 
 
* Check/Listing 
* Medical Listing 
** Source 
documents  
(if applicable) 
Remarks 
(optional) 
CONCOMITANT MEDICATION (Study Specific Issue System Category  Received a disallowed concomitant treatment) 
62 
Taken a prohibited medication and 
regimen after study drug 
administration 
Anti-IL-6 (eg, actemra), anti-TNF therapy (eg, 
remicade, humira) 
Received protocol prohibited 
medication (Anti-IL-6, anti-TNF 
therapy) <specify medication > 
Received protocol proh bited 
medication 
Received a 
disallowed 
concomitant 
treatment 
 
Source documents 
 
Medical Listing 
 
63 
Taken a prohibited medication and 
regimen after study drug 
administration 
Anti-IL-23, anti- IL-12/23 p40, anti-IL-17 
therapy 
Received protocol prohibited 
medication (Anti-IL-23, anti- IL-
12/23 p40, anti-IL-17 therapy) 
<specify medication> 
Received protocol proh bited 
medication 
Received a 
disallowed 
concomitant 
treatment 
 
Source documents 
 
Medical Listing 
 
64 
Taken a prohibited medication and 
regimen after study drug 
administration 
JAK inhibitors (eg, tofacitinib, upadacitinib) 
Received protocol prohibited 
medication (JAK inhibitors) 
<specify medication> 
Received protocol proh bited 
medication 
Received a 
disallowed 
concomitant 
treatment 
 
Source documents 
 
Medical Listing 
 
65 
Taken a prohibited medication and 
regimen after study drug 
administration 
Cell-depleting therapies (eg, abatacept, 
rituximab, alemtuzumab) 
Received protocol prohibited 
medication (Cell-depleting therapies) 
<specify medication> 
Received protocol proh bited 
medication 
Received a 
disallowed 
concomitant 
treatment 
 
Source documents 
 
Medical Listing 
 
66 
Taken a prohibited medication and 
regimen after study drug 
administration 
Cytotoxic acylating agents (eg, chlorambucil, 
cyclophosphamide) 
Received protocol prohibited 
medication (Cytotoxic acylating 
agents) <specify medication> 
Received protocol proh bited 
medication 
Received a 
disallowed 
concomitant 
treatment 
 
Source documents 
 
Medical Listing 
 
67 
Taken a prohibited medication and 
regimen after study drug 
administration 
Immunomodulator (eg, MTX, AZA, MMF, 
TAC, cyclosporine) 
Received protocol prohibited 
medication (Immunomodulator) 
<specify medication> 
Received protocol proh bited 
medication 
Received a 
disallowed 
concomitant 
treatment 
 
Source documents 
 
Medical Listing 
 
68 
Taken a prohibited medication and 
regimen after study drug 
administration 
Intra-muscular, intra-articular, intra-bursal, 
epidural, intra-lesional or IV GC 
Received protocol prohibited 
medication (Intra-muscular, intra-
articular, intra-bursal, epidural, intra-
lesional or IV GC) <specify 
medication and route> 
Received protocol proh bited 
medication 
Received a 
disallowed 
concomitant 
treatment 
 
Source documents 
 
Medical Listing 
 
NCT04882072


CNTO1275  (Ustekinumab)  
 
 
 
Statistical Analysis Plan CNTO1275TAT3001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
44 
Status: Approved,  Date: 30 June 2023 
Sequence 
 number  
Description  
 
[Copy or select the description from 
the Protocol and/or decide with Study 
Team on additional Protocol Deviations 
to be identified] 
Protocol Deviation Description 
(DVTERM) as entered in Study 
Specific Issue System 
 
This is suggestive wording to ensure 
review of PDs is consistent. 
PD Criterion  
 
(100 character limit required) 
Protocol 
Deviation 
Coded Term 
(DVDECOD) 
 
* Check/Listing 
* Medical Listing 
** Source 
documents  
(if applicable) 
Remarks 
(optional) 
CONCOMITANT MEDICATION (Study Specific Issue System Category  Received a disallowed concomitant treatment) 
69 
Taken a prohibited medication and 
regimen after study drug 
administration 
Other investigational agents 
Received protocol prohibited 
medication (Other investigational 
agents) <specify medication> 
Received protocol proh bited 
medication 
Received a 
disallowed 
concomitant 
treatment 
 
Source documents 
 
 
70 
Violation of Glucocorticoid tapering 
rules 
Week 0 through Week 2: No adjustments in 
glucocorticoid dose are permitted. 
Received a disallowed 
glucocorticoid therapy at Week 0 
through Week 2. 
Received a disallowed 
glucocorticoid therapy 
Received a 
disallowed 
concomitant 
treatment 
Source documents 
 
Check/Listings 
 
Medical Listings 
If the subject 
misses a 
dose or 
overdose for 
more than 2 
days at the 
actual daily 
dose per a 
week in 
tapering 
schedule, it 
will be 
handled as 
Major PD. 
71 
Violation of Glucocorticoid tapering 
rules 
Week 2 through participant’s relapse or end of 
DB period 
GC tapering will start from Week 2 based on 
defined GC taper schedule (See Table 5).  
If current daily prednisolone or equivalent 
dose is ≥30 mg/day, GC dose will be tapered 
by 5 mg/week.  
If current prednisolone or equivalent dose is 
<30 mg/day and ≥20 mg/day, GC dose will be 
tapered by 2.5 mg/week.  
If current prednisolone or equivalent dose is 
<20 mg/day and ≥5 mg/day, GC dose will be 
tapered by 10%/week according to the below 
formula. 
Dose* of Week N=Dose of Week “N-1” ×0 9 
*Should be rounded decimals to the nearest 
whole number. 
 
Once the daily prednisolone dose (or 
equivalent) reaches 5 mg/day, while GC taper 
by 1 mg/4-8 weeks is encouraged to achieve 
GC-free remission, GC taper regimen is 
Received a disallowed 
glucocorticoid therapy at Week 2 
through participant’s relapse or 
end of DB period. 
Received a disallowed 
glucocorticoid therapy 
Received a 
disallowed 
concomitant 
treatment 
Source documents 
 
Medical Listings 
If the subject 
misses a 
dose or 
overdose for 
more than 2 
days at the 
actual daily 
dose per a 
week in 
tapering 
schedule, it 
will be 
handled as 
Major PD. 
NCT04882072


CNTO1275  (Ustekinumab)  
 
 
 
Statistical Analysis Plan CNTO1275TAT3001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
45 
Status: Approved,  Date: 30 June 2023 
Sequence 
 number  
Description  
 
[Copy or select the description from 
the Protocol and/or decide with Study 
Team on additional Protocol Deviations 
to be identified] 
Protocol Deviation Description 
(DVTERM) as entered in Study 
Specific Issue System 
 
This is suggestive wording to ensure 
review of PDs is consistent. 
PD Criterion  
 
(100 character limit required) 
Protocol 
Deviation 
Coded Term 
(DVDECOD) 
 
* Check/Listing 
* Medical Listing 
** Source 
documents  
(if applicable) 
Remarks 
(optional) 
CONCOMITANT MEDICATION (Study Specific Issue System Category  Received a disallowed concomitant treatment) 
ultimately at discretion of investigator at 5 mg 
or less based on disease activities of TAK in 
participants. 
 
72 
Anti-platelet or Anti-coagulation 
Therapy 
Participants are newly received anti-platelet 
therapy (including but not limited to aspirin, 
clopidogrel, ticlopidine) or anti-coagulation 
therapy (including but not limited to warfarin) 
during DB period. 
 
Newly received a disallowed anti-
platelet or anti-coagulation therapy 
during double blind period. 
Received a disallowed anti-
platelet or anti-coagulation 
therapy 
Received a 
disallowed 
concomitant 
treatment 
Source documents 
 
Medical Listings 
Regardless 
of whether or 
not it has 
been 
discussed 
with the 
sponsor 
medical 
monitor in 
advance, a 
new use is 
regarded as 
Major PD. 
73 
Anti-hypertensive Therapy 
Participants are newly received anti-
hypertensive treatment during DB period. 
Newly received a disallowed newly 
received anti-hypertensive 
treatment during double blind 
period. 
Received a disallowed anti-
hypertensive treatment 
Received a 
disallowed 
concomitant 
treatment 
Source documents 
 
Medical Listings 
Regardless 
of whether or 
not it has 
been 
discussed 
with the 
sponsor 
medical 
monitor in 
advance, a 
new use is 
regarded as 
Major PD. 
74 
Oral NSAIDs  
Participants are newly received oral NSAIDs 
treatment during DB period. 
Newly received a disallowed oral 
NSAIDs treatment during double 
blind period. 
Received a disallowed oral 
NSAIDs treatment 
Received a 
disallowed 
concomitant 
treatment 
Source documents 
 
Medical Listings 
Regardless 
of whether or 
not it has 
been 
discussed 
with the 
sponsor 
medical 
monitor in 
advance, a 
new use is 
regarded as 
Major PD. 
NCT04882072


CNTO1275  (Ustekinumab)  
 
 
 
Statistical Analysis Plan CNTO1275TAT3001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
46 
Status: Approved,  Date: 30 June 2023 
6.9. 
Appendix 9 Laboratory Toxicity Grading 
The grading scale use for lab assessments is based on ‘Common Terminology Criteria for Adverse 
Events (CTCAE) v5.0’. 
If a laboratory value falls within the grading as specified below but also within the local laboratory 
normal limits, the value is considered to be normal and will be reset to grade 0. 
Prebaseline measurements will use the same grading ranges as applied to baseline measurements. 
In case a test has two sets of ranges – one for baseline normal and one for baseline abnormal, the 
one for baseline normal will be applied for all measurements taken prebaseline and on baseline. 
 
NCT04882072


NCT04882072


NCT04882072


NCT04882072


NCT04882072


CNTO1275  (Ustekinumab) 
Statistical Analysis Plan CNTO1275TAT3001 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
51 
Status: Approved,  Date: 30 June 2023 
7.
REFERENCES
Not Applicable.
NCT04882072