Clinical trial NCT03517722
Conditions: Lupus Erythematosus, Systemic
Sponsor: Janssen Research & Development, LLC
Start date: 2018-04-16; Completion date: 2020-11-05
Enrollment: 516 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy of ustekinumab in participants with active systemic lupus erythematosus (SLE) who have not adequately responded to one or more standard of care treatments.

Detailed description:
This study evaluates the efficacy, safety, and tolerability of ustekinumab in participants with active SLE according to Systemic Lupus International Collaborating Clinics (SLICC) criteria Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score greater than (\>=) 6, despite receiving one or more standard-of-care treatments (example, immunomodulators, antimalarial drugs, and/or glucocorticoids). The total duration of the study is up to 182 weeks, consisting of 3 study periods: a screening period (approximately 6 weeks), a double blind period (52 weeks), and an extension period (124 weeks). Other study evaluations will include pharmacokinetics, immunogenicity, biomarkers and pharmacogenomic evaluations. The safety of the participants enrolled in the study will be monitored on an ongoing basis throughout the study.

Arms: arm 1: Participants will receive ustekinumab approximately 6 milligram per kilogram (mg/kg) intravenously (IV) based on body weight-range at Week 0 followed by 90 mg ustekinumab subcutaneously (SC) at Week 8 and every 8 weeks (q8w) thereafter through Week 48 during double-blind period. Eligible participants who will enter the extension period will continue to receive 90 mg ustekinumab SC q8w through Week 160. arm 2: Participants will receive matching placebo to ustekinumab IV at Week 0, followed by matching placebo to ustekinumab SC at Week 8 and q8w thereafter through Week 48 during double-blind period. Eligible participants who will enter the extension period will cross-over to receive 90 mg ustekinumab SC q8w through Week 160.
Interventions: intervention 1: Placebo intervention 2: Ustekinumab (approximately 6 mg/kg) intervention 3: Ustekinumab 90 mg
Intervention descriptions: intervention 1: Participants will receive placebo matching to ustekinumab IV or SC. intervention 2: Participants will receive ustekinumab approximately 6 mg/kg via IV route based on body weight-range. intervention 3: Participants will receive 90 mg ustekinumab via SC route.

Protocol documents:
Prot_000.pdf: 
1
Status: Approved, Date: 23 January 2019
Janssen Research & Development *
Clinical Protocol
A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Study of 
Ustekinumab in Subjects with Active Systemic Lupus Erythematosus
Protocol CNTO1275SLE3001 Amendment 2; Phase 3
AMENDMENT 2
STELARA® (ustekinumab)
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen 
Biologics, BV; Janssen-Cilag International NV; Janssen Pharmaceutica NV; Janssen, Inc; Janssen 
Sciences Ireland UC; or Janssen Research & Development, LLC. The term “sponsor” is used throughout 
the protocol to represent these various legal entities; the sponsor is identified on the Contact Information 
page that accompanies the protocol.
US sites of this study will be conducted under US Food & Drug Administration IND regulations 
(21 CFR Part 312).
EudraCT NUMBER:  2017-001489-53
Status:
Approved
Date:
23 January 2019
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-ERI-138327930, 3.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed 
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential.
NCT03517722


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 7
SYNOPSIS.................................................................................................................................................. 22
TIME AND EVENTS SCHEDULE:  SCREENING PERIOD AND 52-WEEK DOUBLE-BLIND 
PERIOD ............................................................................................................................................. 29
TIME AND EVENTS SCHEDULE:  EXTENSION PERIOD ....................................................................... 34
ABBREVIATIONS ...................................................................................................................................... 37
DEFINITIONS OF TERMS.......................................................................................................................... 39
1.
INTRODUCTION................................................................................................................................ 40
1.1.
Background .................................................................................................................................... 41
1.2.
Overall Rationale for the Study...................................................................................................... 41
1.2.1.
Scientific Rationale for Use of Anti-IL-12/23p40 Therapy in Systemic Lupus 
Erythematosus............................................................................................................................ 41
1.2.2.
Results of CNTO1275SLE2001 Phase 2 Study ......................................................................... 42
1.2.3.
Justification for Dosing Regimen................................................................................................ 45
1.2.4.
Benefit/Risk Assessment............................................................................................................ 46
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 47
2.1.
Objectives ...................................................................................................................................... 47
2.1.1.
Primary Objective ....................................................................................................................... 47
2.1.2.
Secondary Objectives................................................................................................................. 47
2.1.3.
Additional Objectives .................................................................................................................. 48
2.2.
Endpoints ....................................................................................................................................... 48
2.2.1.
Primary Endpoint ........................................................................................................................ 48
2.2.2.
Secondary Endpoints.................................................................................................................. 48
2.2.3.
Additional Endpoints................................................................................................................... 49
2.3.
Hypothesis ..................................................................................................................................... 51
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 51
3.1.
Overview of Study Design.............................................................................................................. 51
3.2.
Study Design Rationale.................................................................................................................. 56
3.2.1.
Study Population......................................................................................................................... 56
3.2.2.
Blinding, Control, Study Phase/Periods, Treatment Groups ...................................................... 57
3.2.3.
Biomarker Collection................................................................................................................... 57
3.2.4.
Glucocorticoid Tapering.............................................................................................................. 57
3.2.5.
Patient-Reported Outcomes ....................................................................................................... 58
4.
SUBJECT POPULATION.................................................................................................................. 58
4.1.
Main Study ..................................................................................................................................... 58
4.1.1.
Inclusion Criteria......................................................................................................................... 58
4.1.2.
Exclusion Criteria........................................................................................................................ 64
4.2.
Prohibitions and Restrictions ......................................................................................................... 69
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 70
5.1.
Treatment Allocation ...................................................................................................................... 70
5.2.
Blinding .......................................................................................................................................... 71


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6.
DOSAGE AND ADMINISTRATION .................................................................................................. 71
7.
TREATMENT COMPLIANCE............................................................................................................ 72
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 72
8.1.
Prestudy and Concomitant Medications Through Week 52........................................................... 74
8.1.1.
Antimalarial Medications............................................................................................................. 76
8.1.2.
Glucocorticoid Therapy............................................................................................................... 76
8.1.3.
Nonsteroidal Anti-inflammatory Drugs........................................................................................ 78
8.1.4.
Anti-hypertensive Medications.................................................................................................... 79
8.1.5.
Non-biologic Immunomodulators................................................................................................ 79
8.1.6.
Topical Medications.................................................................................................................... 79
8.1.7.
Prohibited Therapies................................................................................................................... 79
8.2.
Concomitant Medications Use and Rescue Therapy During the Extension Period ...................... 81
9.
STUDY EVALUATIONS .................................................................................................................... 82
9.1.
Study Procedures........................................................................................................................... 82
9.1.1.
Overview..................................................................................................................................... 82
9.1.2.
Screening Phase ........................................................................................................................ 83
9.1.3.
Double-blind Treatment Phase................................................................................................... 85
9.1.4.
Extension Period......................................................................................................................... 86
9.1.5.
End of Study/Early Withdrawal ................................................................................................... 87
9.1.6.
Posttreatment Phase (Follow-Up) .............................................................................................. 87
9.2.
Efficacy Evaluations....................................................................................................................... 87
9.2.1.
SLE Disease Activity Index 2000................................................................................................ 88
9.2.2.
British Isles Lupus Assessment Group....................................................................................... 88
9.2.3.
Physician’s Global Assessment of Disease Activity................................................................... 89
9.2.4.
Modified SELENA Flare Index (mSFI)........................................................................................ 89
9.2.5.
Joint Count Assessments ........................................................................................................... 89
9.2.6.
Cutaneous Lupus Erythematosus Disease Area and Severity Index......................................... 90
9.2.7.
Patient Assessment of Pain Intensity ......................................................................................... 90
9.2.8.
Lupus Quality of Life Measure.................................................................................................... 90
9.2.9.
FACIT-Fatigue ............................................................................................................................ 90
9.2.10.
Short-form Health Survey-36 Standard (4-Week Recall) v2 ...................................................... 91
9.2.11.
EuroQol EQ-5D-5L Descriptive System ..................................................................................... 91
9.2.12.
Work Productivity and Activity Impairment Scale – Lupus ......................................................... 92
9.2.13.
Lupus Foundation of America Rapid Evaluation of Activity in Lupus (LFA-REAL) .................... 92
9.2.14.
SLICC/ACR Damage Index ........................................................................................................ 92
9.3.
Efficacy Endpoint Definitions ......................................................................................................... 93
9.3.1.
SRI Composite Response .......................................................................................................... 93
9.3.2.
Lupus Low Disease Activity State .............................................................................................. 93
9.3.3.
Definitions of Remission in Systemic Lupus Erythematosus...................................................... 93
9.3.4.
SLE Flare.................................................................................................................................... 94
9.3.5.
Reduction of Glucocorticoid Dose .............................................................................................. 95
9.3.6.
Major Clinical Response............................................................................................................. 95
9.3.7.
Medical Resource Utilization ...................................................................................................... 95
9.4.
Pharmacokinetics and Immunogenicity ......................................................................................... 95
9.4.1.
Evaluations ................................................................................................................................. 95
9.4.2.
Procedures and Analyses........................................................................................................... 96
9.5.
Biomarkers ..................................................................................................................................... 96
9.5.1.
Serum Analyses.......................................................................................................................... 96
9.5.2.
Whole Blood Gene Expression................................................................................................... 96
9.5.3.
Peripheral Blood Mononuclear Cells (Cellular Analysis)............................................................ 96
9.6.
Pharmacogenomic (DNA) Evaluations .......................................................................................... 97
9.7.
Safety Evaluations ......................................................................................................................... 97
9.7.1.
Adverse Events........................................................................................................................... 97
9.7.2.
Clinical Laboratory Tests ............................................................................................................ 98
9.7.3.
Electrocardiogram..................................................................................................................... 100


STELARA® (ustekinumab)
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9.7.4.
Vital Signs................................................................................................................................. 100
9.7.5.
Physical Examination................................................................................................................ 101
9.7.6.
Pregnancy................................................................................................................................. 101
9.8.
Cutaneous Disease Photography Substudy ................................................................................ 101
9.9.
Sample Collection and Handling.................................................................................................. 102
10.
SUBJECT COMPLETION / DISCONTINUATION OF STUDY AGENT / WITHDRAWAL 
FROM THE STUDY ......................................................................................................................... 102
10.1.
Study Completion......................................................................................................................... 102
10.2.
Discontinuation of Study Agent/Withdrawal from the Study ........................................................ 102
10.2.1.
Discontinuation of Study Agent ................................................................................................ 102
10.2.2.
Withdrawal From the Study ...................................................................................................... 103
10.3.
Withdrawal from the Use of Research Samples .......................................................................... 104
11.
STATISTICAL METHODS............................................................................................................... 104
11.1.
Subject Information ...................................................................................................................... 105
11.1.1.
Demographics and Baseline Characteristics............................................................................ 105
11.1.2.
Disposition Information ............................................................................................................. 105
11.1.3.
Treatment Compliance ............................................................................................................. 105
11.1.4.
Extent of Exposure ................................................................................................................... 105
11.1.5.
Protocol Deviations................................................................................................................... 106
11.1.6.
Prior and Concomitant Medications.......................................................................................... 106
11.2.
Sample Size Determination ......................................................................................................... 106
11.3.
Analysis Sets................................................................................................................................ 107
11.4.
Efficacy Analyses ......................................................................................................................... 108
11.4.1.
Primary Endpoint Analysis........................................................................................................ 108
11.4.2.
Major Secondary Analyses....................................................................................................... 109
11.4.3.
Other Planned Efficacy Analyses ............................................................................................. 109
11.4.4.
Handling Missing Data.............................................................................................................. 109
11.4.5.
Treatment Failure Criteria......................................................................................................... 110
11.5.
Pharmacokinetic Analyses........................................................................................................... 110
11.6.
Immunogenicity Analyses ............................................................................................................ 111
11.7.
Pharmacodynamic and Biomarker Analyses ............................................................................... 111
11.8.
Pharmacokinetic and Pharmacodynamic Analyses..................................................................... 112
11.8.1.
Pharmacokinetic/Pharmacodynamic Evaluations .................................................................... 112
11.9.
Safety Analyses ........................................................................................................................... 112
11.9.1.
Adverse Events......................................................................................................................... 112
11.9.2.
Clinical Laboratory Tests .......................................................................................................... 112
11.10.
Interim Analysis............................................................................................................................ 113
11.11.
Data Monitoring Committee ......................................................................................................... 113
12.
ADVERSE EVENT REPORTING .................................................................................................... 113
12.1.
Definitions .................................................................................................................................... 114
12.1.1.
Adverse Event Definitions and Classifications ......................................................................... 114
12.1.2.
Attribution Definitions................................................................................................................ 115
12.1.3.
Severity Criteria ........................................................................................................................ 116
12.2.
Special Reporting Situations........................................................................................................ 116
12.3.
Procedures................................................................................................................................... 116
12.3.1.
All Adverse Events.................................................................................................................... 116
12.3.2.
Serious Adverse Events ........................................................................................................... 118
12.3.3.
Pregnancy................................................................................................................................. 119
12.3.4.
Events of Special Interest......................................................................................................... 119
12.4.
Contacting Sponsor Regarding Safety......................................................................................... 119
13.
PRODUCT QUALITY COMPLAINT HANDLING............................................................................ 119
13.1.
Procedures................................................................................................................................... 120
13.2.
Contacting Sponsor Regarding Product Quality .......................................................................... 120


STELARA® (ustekinumab)
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14.
STUDY AGENT INFORMATION..................................................................................................... 120
14.1.
Physical Description of Study Agent(s)........................................................................................ 120
14.1.1.
Intravenous Administration ....................................................................................................... 120
14.1.2.
Subcutaneous Administration................................................................................................... 121
14.2.
Packaging .................................................................................................................................... 121
14.3.
Labeling........................................................................................................................................ 121
14.4.
Preparation, Handling, and Storage............................................................................................. 121
14.5.
Drug Accountability ...................................................................................................................... 122
15.
STUDY-SPECIFIC MATERIALS..................................................................................................... 122
16.
ETHICAL ASPECTS ....................................................................................................................... 123
16.1.
Study-Specific Design Considerations......................................................................................... 123
16.2.
Regulatory Ethics Compliance..................................................................................................... 124
16.2.1.
Investigator Responsibilities ..................................................................................................... 124
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................. 124
16.2.3.
Informed Consent and Assent Form......................................................................................... 126
16.2.4.
Privacy of Personal Data .......................................................................................................... 127
16.2.5.
Long-term Retention of Samples for Additional Future Research............................................ 127
16.2.6.
Country Selection ..................................................................................................................... 128
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 128
17.1.
Protocol Amendments.................................................................................................................. 128
17.2.
Regulatory Documentation .......................................................................................................... 128
17.2.1.
Regulatory Approval/Notification .............................................................................................. 128
17.2.2.
Required Prestudy Documentation........................................................................................... 128
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 129
17.4.
Source Documentation................................................................................................................. 130
17.5.
Case Report Form Completion .................................................................................................... 130
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 131
17.7.
Record Retention ......................................................................................................................... 131
17.8.
Monitoring .................................................................................................................................... 132
17.9.
Study Completion/Termination..................................................................................................... 133
17.9.1.
Study Completion/End of Study................................................................................................ 133
17.9.2.
Study Termination..................................................................................................................... 133
17.10.
On-site Audits............................................................................................................................... 133
17.11.
Use of Information and Publication.............................................................................................. 133
REFERENCES.......................................................................................................................................... 136
ATTACHMENTS....................................................................................................................................... 139
INVESTIGATOR AGREEMENT ............................................................................................................... 147
LIST OF IN-TEXT TABLES AND FIGURES 
TABLES
Table 1:
TIME AND EVENTS SCHEDULE - Screening Period and 52-Week Double-blind 
Period........................................................................................................................................ 29
Table 2:
TIME AND EVENTS SCHEDULE – Extension Period (Week 56 Through Week 176)............ 34
Table 3:
Overall Summary of Adverse Events Through Week 24; Safety Analysis Set 
(Study CNTO1275SLE2001) .................................................................................................... 44
Table 4:
Permitted Concomitant Medications for SLE, the Minimum Stabilization Period before 
Randomization, and the Maximum Allowed Doses at Study Randomization........................... 74
Table 5:
Blinded Study Period - Protocol Requirements for Permitted Concomitant SLE 
Medications............................................................................................................................... 75
Table 6:
Extension Period- Protocol Requirements for Permitted Concomitant SLE Medications ........ 81


STELARA® (ustekinumab)
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Table 7:
Power to Detect a Significant Treatment Difference in the Proportion of Subjects with 
SRI-4 Response at Week 52 .................................................................................................. 107
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 55


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
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PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
11 December 2017
Amendment 1
15 February 2018
Amendment 2
23 Jan 2019
Amendments below are listed beginning with the most recent amendment.
Amendment 2 (23 Jan 2019)  
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The overall reason for the amendment is to add, based on input from the 
Japanese Pharmaceuticals and Medical Devices Agency (PMDA), a site visit at the beginning of the extension 
period in order to more closely monitor subjects crossing over from placebo to ustekinumab. Additional 
clarifications to the protocol have been implemented as well based on feedback from the United States Food and 
Drug Administration (FDA), key opinion leaders, and study investigators.
Applicable Section(s)
Description of Change(s)
Rationale: The extension period will now begin at Week 56 (instead of at Week 56 or Week 64) and the Week 64 
visit will become a mandatory site visit in order to more closely monitor subjects crossing over from placebo to 
ustekinumab.
Synopsis, Dosage and 
Administration;
6. Dosage and Administration; 
9.1.4. Extension Period; 
9.1.4.2. Dosing Regimen
(Deleted text is struck-through and new text is in bold and underlined):
During the extension period beginning at either Week 56 or Week 64.
Time and Events Schedule –
Screening Period and 52-Week 
Double-blind Period
Footnote c revised:
c.
Mandatory at-site visit for subjects who enter the study extension.
Subjects who will participate in the extension period do not need to return for 
the Week 64 visit.
Time and Events Schedule –
Extension Period
Week 56 and Week 64 visits have been separated into new columns in Table 2 
Time and Events Schedule and footnote b revised:
b. Mandatory at-site visit for subjects who enter the study extension. There 
will be a window to enter the extension at either Week 56 or Week 64. 
Subjects who enter the extension period should follow the Time and Events 
procedures outlined for “Week 56 or Week 64” in the table of Extension 
procedures (Table 2).
3.1 Overview of Study Design
Figure 1 revised to reflect change in visits.


STELARA® (ustekinumab)
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Applicable Section(s)
Description of Change(s)
Rationale: The Week 80 visit (Extension Period) has been changed from an at-home to an at-site visit for all 
subjects. This change was made to better assess efficacy and safety in subjects randomized to placebo 24 weeks 
following their crossover to ustekinumab in the extension period. This allows better comparability with subjects 
randomized to ustekinumab in the double-blind period. Reciprocally, the Week 88 visit was changed from an at-site 
to an at-home visit.
Time and Events Schedule –
Extension Period
Column heading under “Week” changed from 88 to 80.
Rationale: Text was corrected to remove mention of consent/assent requirement for whole blood gene expression 
analysis by RNA sequencing since RNA sequencing will not be performed.
Time and Events Schedule: 
Screening Period and 52-week 
double-blind period, footnotes 
e and f
whole blood gene expression analysis by RNA sequencing
Rationale: Detailed treatment failure criteria were added at the request of the FDA.
11.4.5. Treatment Failure 
Criteria
A new section detailing treatment failure criteria was added.


STELARA® (ustekinumab)
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Applicable Section(s)
Description of Change(s)
Rationale:  Endpoints have been modified, added, or removed based on input from key opinion leaders to enhance 
the value of the data obtained. In addition, the endpoints for certain PROs (for which validated definitions for 
clinically meaningful improvement do not exist) were revised to clarify that change from baseline, not clinically 
meaningful improvement from baseline, is being assessed. These endpoints were grouped into a separate bullet.
2.2.3 Additional Endpoints
Measures of Improvement in Global Disease Activity

The proportions of subjects with SRI-4, SRI-5, SRI-6, SRI-7, and SRI-8 
composite responses, sustained composite response over time

The proportion of subjects with an SRI-4 composite response at ≥50% 
of the study visits from baseline to Week 52

The proportion of subjects with at least a 4-point improvement 
compared with baseline in S2K RI-50 over time
Mucocutaneous Disease

The proportion of subjects who achieve a 20% or 50% reduction from 
baseline in CLASI activity score over time in those with a baseline 
CLASI activity score of at least 8
Assessment of Organ Domain Activity and Damage

The proportion of subjects with BILAG worsening, no BILAG worsening 
compared with baseline over time 

Time to first CLASI damage score worsening (defined as CLASI damage 
score >0) in those subjects with CLASI damage score = 0 at baseline

Proportion of subjects who remain free of CLASI damage progression 
(defined as CLASI damage score = 0) over time

Proportion of subjects with CLASI damage accrual (defined as change from 
baseline in CLASI damage score >0) over time
Disease-specific Clinical Biomarkers

The proportions of subjects with normalization, improvement of anti-dsDNA 
and other autoantibodies, C3, C4 levels over time in subjects with abnormal 
levels of that serologic marker at baseline*
Patient-reported Outcomes/ Health Economics and Outcomes Research

The proportion of subjects with clinically meaningful improvement in 
patient-reported outcomes (PROs) over time:  pain visual analogue scale 
(VAS),* Functional Assessment of Chronic Illness Therapy - Fatigue 
(FACIT-Fatigue), 36-Item Short Form Health Survey (SF-36v2; physical 
component score [PCS], mental component score [MCS], both PCS and 
MCS, individual domains), EuroQol 5-dimensional, 5-level questionnaire 
(EQ-5D-5L) index score and VAS score,* Lupus Quality of Life 
(LupusQoL) domain scores,* Work Productivity and Activity Impairment 
Questionnaire–Lupus (WPAI-Lupus) total and domain scores, LFA-REAL 
PRO* 

Change from baseline in PROs over time: EuroQol 5-dimensional, 5-level 
questionnaire (EQ-5D-5L) index score and VAS score,* Work Productivity 
and Activity Impairment Questionnaire–Lupus (WPAI-Lupus) total and 
domain scores, LFA-REAL PRO*


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
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Approved, Date: 23 January 2019
Applicable Section(s)
Description of Change(s)
Rationale:  It was clarified that the results of certain exploratory assessments will be summarized in a separate 
report
Synopsis, Efficacy 
Evaluations; 2.2.3 Additional 
Endpoints
Certain efficacy evaluations and exploratory endpoints were asterisked and the 
following note added to the section:
* Results of these exploratory assessments will be summarized in a separate 
report.
Rationale: Inclusion/Exclusion Criteria and Prohibitions and Restrictions were clarified/added in order to enhance 
subject safety and/or the quality of the trial.
4.1.1 Inclusion Criteria, #6
6.1
Had a documented medical history (ie, met at least 1 of the bulleted 
criteria below) that subject met the SLICC classification criteria for SLE41
(meeting at least 4 SLICC criteria in total including at least 1 immunologic 
criteria; Attachment 1) at least 3 months prior to first dose of study agent:

Met a total of at least 4 SLICC criteria, including at least 1 immunologic
and at least 1 clinical (Attachment 1). 

Had a diagnosis of lupus nephritis, confirmed by renal biopsy, and at 
least 1 of the following autoantibodies: ANA or anti-dsDNA.
4.1.2 Exclusion Criteria, #1
Criterion modified per Amendment 2:
1.1
Has any unstable or progressive manifestation of SLE (lupus cerebritis, optic 
neuritis, transverse myelitis, psychosis, uncontrolled seizures, systemic 
vasculitis, end-stage renal disease, severe or rapidly progressive Class III or 
IV glomerulonephritis, isolated Class V lupus nephritis [ie, without 
coexistent Class I, II, III, or IV nephritis], Class VI lupus nephritis, 
pulmonary hemorrhage, myocarditis) that is likely to warrant escalation in 
therapy beyond permitted background medications. Subjects requiring 
renal hemodialysis or peritoneal dialysis are also excluded.
Exclusion Criteria, #45
45. Has undergone a splenectomy.
4.2 Prohibitions and 
Restrictions, #3
Agree to avoid excess exposure to natural or artificial (tanning beds, 
phototherapy, etc) sunlight. In addition, it is advised that subjects maintain 
their typical use of sun protective measures (such as a hat, sunglasses, protective 
clothing, sunscreen)., limit prolonged exposure to natural sunlight, and avoid 
artificial sunlight (tanning beds or phototherapy) from baseline. The time period 
for this requirement is from the start of screening until the last dose of study 
agent has been received.


STELARA® (ustekinumab)
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Applicable Section(s)
Description of Change(s)
Rationale: Text describing prestudy and concomitant medication requirements has been clarified to enhance 
subject safety and/or the quality of the trial.
4.1.2 Exclusion Criteria
Exclusion Criteria, #8
Criterion modified per Amendment 2:
8.1 Exclusions for treatment with B-cell targeted therapies (eg, belimumab, 
rituximab, epratuzumab)* are as follows:
a. Treatment with a single B-cell targeted therapy within 3 months prior to 
first dose of study agent.
b. Treatment with >1 previous B-cell targeted therapy within 6 months prior 
to first dose of study agent.
c. Treatment with B-cell depleting therapy (eg, rituximab, epratuzumab) 
within 12 months prior to first dose of study agent or have evidence of 
continued B-cell depletion following such therapy. 
*If a subject has received one or more B-cell targeted therapies, the length of 
time required before administering the first dose of study agent should be 
whichever is the longest applicable washout period.
Exclusion Criteria, #12
Criterion modified per Amendment 2:
12.1 Has received topical cream/ointment preparations of cyclosporine A (except 
for ophthalmic use), high-potency topical glucocorticoids (World Health 
Organization [WHO] encoding dictionary), or other topical 
immunomodulatory agents (such as tacrolimus, pimecrolimus) within 4 
weeks prior to the first administration of study agent.
8.1 Prestudy and Concomitant 
Medications Through 
Week 52, Table 4
Revised column header to be consistent with other references to concomitant 
medication use (Deleted text is struck-through and new text is in bold and 
underlined):
Stabilization Period Before Randomization Prior to First Administration of 
Study Agent
8.1.2 Glucocorticoid Therapy, 
Epidural, Intravenous, 
Intramuscular, Intra-articular, 
Intrabursal injection, and 
Intralesional Glucocorticoids
If clinically necessary, a total of 1 or 2 IA injections may be permitted for SLE up 
to the Week 12 dosing and should be recorded as a medical procedure; 
however, joints treated with IA injections should will be considered imputed as
“active” in all subsequent assessments. After Week 12, IA glucocorticoid use 
may also cause subjects to be considered treatment failures.
8.1.3. Nonsteroidal Anti-
inflammatory Drugs
Subjects are permitted to receive the usual marketed doses approved in the 
country in which the study is being conducted. NSAIDs, including aspirin or 
selective cyclooxygenase-2 (COX-2) inhibitors, and other analgesics (including 
topical or injectable NSAIDs, analgesics or other pain-relieving agents such as 
capsaicin) that are used on an “as needed” basis should not be used within 48 
hours before a study visit.


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Applicable Section(s)
Description of Change(s)
8.1.6 Topical Medications
Regular use of topical medications is permitted. However, topical compounds 
cannot include a prohibited medication. For example, topical ointments or creams 
of cyclosporine A, tacrolimus, or pimecrolimus, dapsone, thalidomide, etc, are 
prohibited through Week 52; however, ophthalmic use of cyclosporine A is 
permitted. “As needed” use of topical NSAIDs, analgesics, or other pain-
relieving agents such as capsaicin cannot be used for is permitted, but not within
48 hours prior to study visit. “As needed” use of topical low (Class VI, VII) to 
moderate (Class IV, Class V) potency glucocorticoids (according to the World 
Health Organization (WHO) classification of topical glucocorticoids) are 
permitted but should not be used for is permitted, but not within 48 hours prior 
to a study visit. High potency topical glucocorticoids are not allowed through 
Week 52 for all subjects with cutaneous involvement.
Rationale: “Active” joints and joint assessments were further defined for greater clarity.
9.2.5 Joint Count Assessments
Assessment of active joints (defined as joints demonstrating pain and signs of 
inflammation), tender joints, and swollen joints will be performed at visits 
indicated in Table 1 and Table 2. To be considered an active joint, an affected 
joint must be painful as reported by the subject and must demonstrate 
tenderness and at least one additional sign of inflammation (eg, observed 
swelling such as edema or effusion) on physical examination as determined 
by the joint assessor. Each of 64 joints will be evaluated for tenderness and 62 
joints for swelling (hips are excluded for swelling). 
The joint assessment should be performed by an adequately trained joint assessor. 
The joint assessor should preferably be a rheumatologist, but if a 
rheumatologist is not available, it should be a health care provider with at 
least 1 year of experience in performing joint assessments. A health care 
provider with less than 1 year of experience may serve as a joint assessor 
based upon the approval of the sponsor. It is strongly recommended that the 
same joint assessor perform these assessments at every visit. It is recommended 
that the designated assessor identify an appropriate back-up joint assessor in case 
the designated joint assessor is unavailable.
Rationale:  Revisions were made to clarify the qualifications required for ClinRO assessors.
Time and Events Schedule –
Screening Period and 52-Week 
Double-blind Period, 
Footnote q.
q.           Whenever possible, patient-reported outcome assessments should be 
conducted before any tests, procedures, or other consultations for that 
visit to prevent influencing subjects’ perceptions. It is recommended that 
PROs be performed in the following sequence: Patient Assessment of 
Pain Intensity (VAS), FACIT-Fatigue, SF-36, EQ-5D-5L, LupusQoL, 
WPAI-Lupus, and LFA-REAL PRO. It is recommended that ClinRO 
procedures be performed in the following sequence: BILAG, 
SLEDAI-2K, mSFI, PGA, joint count assessment, CLASI, LFA-REAL 
ClinRO, and SLICC/ACR Damage Index. ClinRO assessments should 
be performed by an adequately trained assessor (see Section 9.2 for 
details).


STELARA® (ustekinumab)
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Approved, Date: 23 January 2019
Applicable Section(s)
Description of Change(s)
Time and Events Schedule –
Extension Period, Footnote i.
i.
Whenever possible, patient-reported outcome assessments should be 
conducted before any tests, procedures, or other consultations for that 
visit to prevent influencing subjects’ perceptions. It is recommended that 
PROs be performed in the following sequence: FACIT-Fatigue, SF-36, 
and WPAI-Lupus. It is recommended that ClinRO procedures be 
performed in the following sequence: BILAG, SLEDAI-2K, PGA, joint 
count assessment, CLASI, and SLICC/ACR Damage Index. ClinRO 
assessments should be performed by an adequately trained assessor 
(see Section 9.2 for details).
9.1.1 Study Overview
It is recommended that PROs be performed in the following sequence: Patient 
Assessment of Pain Intensity (VAS), FACIT-Fatigue, SF-36, EQ-5D-5L, 
LupusQoL, WPAI-Lupus, and LFA-REAL PRO. It is recommended that ClinRO 
procedures be performed in the following sequence: BILAG, SLEDAI-2K, mSFI, 
PGA, joint count assessment, CLASI, LFA-REAL ClinRO, and SLICC/ACR 
Damage Index. ClinRO assessments should be performed by an adequately 
trained assessor (see Section 9.2 for details). 
9.2 Efficacy Evaluations
All efficacy evaluations should be performed consistently by the same study 
Investigator or subinvestigator at every visit to achieve comparable measures 
over time. It is recommended that the designated assessor identify an 
appropriate backup in case the designated assessor is unavailable.
ClinROs, including joint assessments, should be performed by an adequately 
trained assessor, preferably a rheumatologist. If a rheumatologist is not 
available, the assessor should be a health care provider with at least 1 year of 
experience in scoring these instruments. A health care provider with less than 
1 year of experience may serve as a ClinRO assessor only with the approval 
of the sponsor. It is recommended that the designated assessor identify an 
appropriate backup.
Rationale: Text listing the serum chemistry panel to be collected has been revised to clarify that an aldolase reflex
test should also be allowed at screening.
9.7.2. Clinical Laboratory 
Tests, Serum Chemistry Panel
-Aldolase (if creatine kinase is elevated at screening then perform aldolase test at 
screening, Week 0, and follow-up as needed)
Rationale:  Revisions were made to screening period wording to ensure consistency of concept in the protocol.
4. Subject Population 
Screening for eligible subjects must be performed no more than 6 weeks prior to 
the randomization visit (Week 0).within 6 weeks before the first administration 
of the study agent.
Rationale:  Revisions were made to retesting/rescreening wording to clarify that 1) retesting for ANA, anti-dsDNA, 
anti-Smith is also permitted; 2) that local laboratories are not permitted to substitute for central lab testing; and 3) 
that rescreening should be discussed with the sponsor.
4.1.1 Inclusion Criteria, #19; 
9.1.2.1. Retesting/Rescreening
A one-time repeat of screening laboratory tests (eg, hemoglobin, lymphocytes, 
neutrophils, platelets, serum creatinine, AST, and ALT, ANA, anti-dsDNA, 
anti-Smith) is allowed during the 6-week screening period and the Investigator 
may consider the subject eligible if the previously exclusionary laboratory test 
result is within an acceptable range per eligibility criteria on repeat testing at the 
central laboratory. …


STELARA® (ustekinumab)
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Approved, Date: 23 January 2019
Applicable Section(s)
Description of Change(s)
A request to use a local laboratory test to replace the central laboratory test should 
be discussed with the medical monitor prior to retesting. …
If the investigator wishes to rescreen a subject who has failed screening, the 
investigator should discuss it with the study sponsor and/or their designee. 
Only 1 rescreening is allowed per subject. If a subject is a screen failure, the 
subject may be rescreened 1 additional time after a period of at least 30 days. 
Subjects who are rescreened will be assigned a new subject number, undergo the 
informed consent process again, and start a new screening phase.
Rationale: Text was added to clarify which COAs are collected using paper and which using electronic devices.
15. Study-Specific Materials.

Certain Clinical Outcome Assessments (COAs; includes both PROs and 
ClinROs) will be collected using an electronic device while others will be 
collected on paper worksheets. Therefore, the following materials will be 
provided:

COA questionnaires and completion instructions. The following 
ClinROs and PROs will be collected on the paper worksheets 
provided:
o
ClinROs:

SLEDAI-2K RI-50

BILAG

mSFI

CLASI

LFA REAL – ClinRO portion

SLICC/ACR Damage Index
o
PROs:

LFA REAL – PRO portion. Collection only in US for 
native English speakers.

Electronic COA device and user manual. The following ClinROs and 
PROs will be collected using an electronic device:
o
ClinROs:

PGA VAS

Joint count assessment (used to obtain number of active 
joints for entry into SLEDAI-2K-RI50)
o
PROs:

Patient Assessment of Pain Intensity VAS

FACIT-Fatigue 

SF-36 v2

EQ-5D-5L Descriptive System

LupusQoL 

WPAI-Lupus


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
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Approved, Date: 23 January 2019
Applicable Section(s)
Description of Change(s)
17.4 Source Documentation
Subject- and Investigator-completed scales and assessments designated by the 
sponsor may by be recorded on paper or directly into an electronic device and will 
be considered source data.  
Rationale: “Gold” has been removed from the name of the QuantiFERON®-TB test so that the name applies to both 
the “Gold” and “Gold Plus” tests, and the Attachment describing the QuantiFERON®-TB test has been deleted to 
keep test references consistent with product name changes.
Throughout the protocol
QuantiFERON®-TB Gold test
Attachment 2: 
QuantiFERON®-TB Gold 
Testing
Entire Attachment deleted and succeeding Attachments renumbered.
Rationale: Text was added to ensure that sites can comply with local standards of practice regarding TB screening.
Time and Events Schedule –
Screening Period and 52-Week 
Double-blind Period, 
Footnote l.
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 (performed locally, consistent with local regulations), and 
QuantiFERON®-TB test should be performed. A TST is additionally required if 
the QuantiFERON®-TB test is not registered/approved locally or the TST is 
mandated by local health authorities. Additional safety procedures may be 
performed if clinically indicated or mandated by local standards of practice.
Rationale:  Text was revised to clarify training on self-administration of study drug and subject’s inability to
self-administer study drug at home.
Table 2 Time & 
Events Schedule: 
Extension 
Period, 
footnote e; 
e. Following training on study agent administration, study agent may be administered by the 
subject (or trained designee) at home via SC injection every 8 weeks. Subjects will be 
required to document administered doses in their subject diaries. Subjects who are 
unwilling or unable to self-administer study agent at home (eg, because they are following 
standard practice in their country or because recommended storage conditions are not 
feasible) are permitted to receive SC injections by a trained designee at the study site or at 
home.
6 Dosage and 
Administration; 
During the double-blind study period, subjects will be administered study agent at the study 
site. Subjects (or their designee) should be trained to administer study agent during the 
Week 56 and the Week 64 visit of the extension period. Additional training sessions are 
permitted per Investigator discretion. During the extension period beginning at either
Week 56 or Week 64 and continuing to Week 160 (and after appropriate and documented 
training), subjects will be encouraged to administer self-administer study agent at home; study 
agent will be provided to subjects for at-home administration. Subjects who are unwilling or
unable to self-administer study agent at home (eg, because they are following standard 
practice in their country or because recommended storage conditions are not feasible) are 
permitted to receive SC injections at the study site or at home by a trained designee. See 
Section 14 for further instructions on the IV and SC administration of the study agent. 
Additional details may be provided in a pharmacy manual/study site investigational product (IP) 
and procedures manual that is provided separately (Section 15). 


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
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Approved, Date: 23 January 2019
Applicable Section(s)
Description of Change(s)
7. Treatment 
Compliance
During the extension period, if a study visit occurs on the same day that a subject is due to 
receive his or her next dose, ustekinumab may be administered at the study site. Subjects who 
are unwilling or unable to self-administer ustekinumab (eg, because they are following 
standard practice in their country or because recommended storage conditions are not 
feasible) may return to the study side for additional visits to have study agent administered. 
Additional visits to the study site should be documented. Subjects will be required to document 
in their diaries study agent administered at home (see Section 6).
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment 1 (15 February 2018)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.  
The overall reason for the amendment: Based on feedback from the United States Food and Drug Administration 
(FDA), the randomization algorithm using dynamic allocation has been be changed to permuted block 
randomization, and region was dropped as a stratification factor. Instead, region will be adjusted for in the statistical 
models for the primary and major secondary endpoints. Additional clarifications to the protocol have been
implemented as well based on feedback from the Japanese Pharmaceuticals and Medical Devices Agency (PMDA),
and investigators in Japan and China.
Applicable 
Section(s)
Description of Change(s)
Rationale:  The randomization algorithm using dynamic allocation has been changed to permuted block 
randomization in accord with FDA feedback. Because of this change, region was deleted as a stratification factor.
Synopsis 
Overview of 
Study Design; 
3.1 Overview of 
Study Design; 
3.2.2 Blinding, 
Control, etc; 5.1 
Treatment 
Allocation 
Treatment Allocation was modified as follows (Deleted text is struck-through and new text is in 
bold and underlined):
Permuted block central randomization will be implemented in this study using an 
interactive web response system (IWRS). Subjects will be randomly assigned to 1 of 2 
treatment groups based on a computer-generated randomization schedule prepared 
before the study under the supervision of the sponsor; however, the sponsor will not be 
privy to the actual randomization schedule. Dynamic central randomization will be 
implemented in conducting this study. Subjects will be assigned to 1 of 2 agent groups based on 
an algorithm implemented in the interactive web response system (IWRS) before the study. 
Dynamic central randomization minimizes the imbalance in the distribution of the number of 
subjects across treatment groups within the levels of each individual stratification factor:
Subjects will be stratified by race, region,baseline lupus nephritis, and baseline SLE 
medications and SLEDAI-2K score (a combined factor).
****************************************************************************
Based on the computer-generated randomization schedulealgorithm, the IWRS will assign a 
unique treatment code, which will dictate the treatment assignment and matching study agent 
kit for each subject. A detailed description of the dynamicpermuted block allocation procedure 
and algorithm will be included in the SAP. 


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
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Approved, Date: 23 January 2019
Applicable 
Section(s)
Description of Change(s)
Rationale:  Region has been removed as a stratification factor and so was added as an analysis adjustment.
Synopsis Primary 
Efficacy 
Analysis; 11.4 
Efficacy 
Analyses; 11.4.1 
Primary 
Endpoint 
Analysis;
(Deleted text is struck-through and new text is in bold and underlined)
Logistic regression, adjusting for baseline stratifications factors, region, and baseline SLEDAI-
2K, will be used to analyze the primary endpoint.
Rationale:  Region has been removed as a stratification factor and so was added as an analysis adjustment.
5.1 Treatment 
allocation
(Deleted text is struck-through and new text is in bold and underlined)
Subjects will be stratified by race, region, baseline lupus nephritis, and baseline SLE 
medications and SLEDAI-2K score (a combined factor).  
Permuted block randomization with the following stratification factors will be used:
•
race (white, black, all other categories combined)
•
presence of lupus nephritis at baseline (Y/N)
•
composite of baseline SLE medications and SLEDAI score (high medications and 
SLEDAI ≥10, high medications and SLEDAI <10, medium medications and SLEDAI 
≥10, medium medications and SLEDAI <10)

Subjects will be defined as receiving high medications if they are receiving any 
of the following: ≥15 mg/wk MTX, or ≥1.5 mg/kg/day AZA/6-MP, or ≥1.5 g/day 
MMF/1.125 g/day MPA, and/or ≥15 mg/day prednisolone or equivalent. 

Subjects receiving baseline medication(s) for SLE that do not meet the criteria 
above for the category of “high” medications would be included in the 
“medium” medication category.   
Rationale: In describing the futility analysis, “may” be performed was changed to “will” be performed to clarify 
that the futility analysis would definitely be performed. In addition, wording describing the timing of the analysis 
was revised at the request of the FDA. 
Synopsis 
Overview of 
Study Design; 
3.1 Overview of 
Study Design; 
11.10 Interim 
Analysis; 11.11 
Data Monitoring 
Committee  
(Deleted text is struck-through and new text is in bold and underlined)
A futility analysis maywill be carried out after approximately 50% of the subjects complete 
Week 24 24 weeks after approximately 50% of the planned subjects have been 
randomized.
Rationale: Endpoints/analyses for glucocorticoid dose reduction were revised to clarify the population being 
analyzed.
Synopsis 
Endpoints; 2.2.2 
Secondary 
Endpoints; 2.2.3 
Additional 
Endpoints; 
(Deleted text is struck-through and new text is in bold and underlined)
6. The proportion of subjects receiving glucocorticoids at baseline with SRI-4 composite 
response at Week 52 in the subpopulation who achieved reduction in glucocorticoid dose by 
Week 40, and sustained that reduction through Week 52, and achieve an SRI-4 composite 
response at Week 52   


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
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Approved, Date: 23 January 2019
Applicable 
Section(s)
Description of Change(s)
Rationale:  Certain exclusion criteria were added or revised to clarify meaning.
Section 4.1.2 
Exclusion 
Criteria:
(Deleted text is struck-through and new text is in bold and underlined)
Criterion 17
Expanded for greater clarity: 
Use of traditional/oriental medicines, herbs, acupuncture, or ointments are prohibited during the 
study. Use of complementary therapies, including traditional/Chinese medicines, herbs, 
ointments, or procedures (eg, acupuncture), that have the potential to activate (eg, echinacea) or 
inhibit (eg, Tripterygium wilfordii Hook F) the immune system is prohibited within 6 weeks of 
the first administration of study agent. In addition, use of complementary therapies, including
traditional/Chinese medicines, herbs, that have the potential to interact with antithrombotic 
agents (eg, St. John’s Wort) is prohibited within 6 weeks of the first administration of study 
agent in those taking antithrombotic agents. Any questions or concerns with the use of these 
therapies should be discussed with the study sponsor and/or medical monitor.
NOTE:  See also Exclusion 43 and Exclusion 44.
Added based on feedback from PMDA: 
Additional concomitant or previous medical therapies received:
Criterion 43
Use of IV gamma globulin, apheresis therapy (including but not limited to 
plasmapheresis, photopheresis, leukocytapheresis), or immunoadsorption is prohibited 
within 6 months prior to the first administration of study agent and within 4 months after 
receiving the last administration of study agent.
Criterion 44
Added based on feedback from experts in Asia:
Has ever received stem cell transplantation (including hematopoietic stem cell 
transplantation and mesenchymal stem cell transplantation).
Rationale:  Interleukin-2 was added as a prohibited therapy based on feedback from experts in Asia
4.1.2 Exclusion 
Criteria, 
Criterion 10; 
8.1.7 Prohibited 
Therapies
(New text is in bold and underlined)
Interleukin-2 inhibitors or exogenous IL-2 therapy
Rationale:  Language describing the use of complementary therapies was revised to clarify its meaning.
8.1.7 Prohibited 
Therapies
(Deleted text is struck-through and new text is in bold and underlined)
The use of complementary therapies that may trigger activation of lupus or mitigate the 
symptoms of SLE, including traditional Chinese medicine (eg, herbal/alternative preparations) 
is prohibited (see Section 4.1.2). (eg, herbs, ointments, traditional Chinese medicine, 
acupuncture) that have the potential to activate or inhibit the immune system is 
prohibited (see Section 4.1.2). In addition, use of complementary therapies that have the 
potential to interact with antithrombotic agents is prohibited in those taking 
antithrombotic agents.
The use of other complementary therapies is strongly discouraged; in individual cases, use 
may be permitted following discussion with the study sponsor and/or medical monitor.


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
19
Approved, Date: 23 January 2019
Applicable 
Section(s)
Description of Change(s)
Rationale:  Text was revised to ensure a consistent description of subject options if the subject cannot self-
administer study drug at home.
Table 2 Time & 
Events Schedule, 
footnote e; 6 
Dosage and 
Administration; 
7. Treatment 
Compliance; 
9.1.4.2 Dosing 
Regimen
(Deleted text is struck-through and new text is in bold and underlined)
Following training on study agent administration, study agent may be administered by the 
subject (or trained designee) at home via SC injection every 8 weeks. Subjects will be required 
to document the self-administered doses in their subject diaries. Subjects who are unable to self-
administer study agent at home are permitted to receive SC injections by a trained designee at 
the study site or at homeby trained personnel employed by a home healthcare agency.
Rationale:  Text was revised to ensure a consistent description of the CLASI activity score enrollment requirement.
Synopsis Subject 
Population; 3.2.1 
Study Population
(Deleted text is struck-through)
Additionally, subjects must have a CLASI activity score of at least 4 (excluding diffuse 
non-inflammatory alopecia)at screening and confirmed at Week 0 or at least 4 joints with pain 
and signs of inflammation (active joints) at screening, or at Week 0, or both.
Rationale:  Text was revised to clarify that biomarker collection may not occur at all sites.
3.2.3 Biomarker 
Collection
(New text is in bold and underlined)
Biomarker samples will be collected at selected sites to evaluate the mechanism of action of 
ustekinumab to help explain interindividual variability in clinical outcomes, or to help identify 
population subgroups that respond differently to ustekinumab.
Rationale:  Text was revised to clarify that subjects must be able to read and write and give informed consent/assent 
without assistance to be eligible for study participation.
16.2.3 Informed 
Consent and 
Assent Form
(Deleted text is struck-through and new text is in bold and underlined)
If the subject (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 subject (or legally acceptable representative) is obtained.
Children (minors) or subjects 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, depending on 
the institutional policies. Written assent should be obtained from subjects who are able to write.
A separate assent form written in language the subject can understand should be developed for 
subjects who are not considered to be adults legally (per local requirements). After having 
obtained the assent, a copy of the assent form must be given to the subject, and to the subject's 
parent or, if applicable, legally acceptable representative.
Subjects must be able to read and write and give informed consent/assent without 
assistance. A subject who is unable to read or write or to give informed consent/assent is 
not eligible to participate in the study.


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
20
Approved, Date: 23 January 2019
Applicable 
Section(s)
Description of Change(s)
Rationale: Editorial revisions were made to clarify the classification of endpoints and analyses.  “Exploratory” used 
as a description of endpoints/analyses was changed to “Additional” and text was modified to be consistent with this 
change.
Synopsis Other 
Efficacy 
Analyses, 
Pharmacodynami
c and Biomarker 
Analyses; 2.2.3 
Additional 
Endpoints; 9.3.7 
Medical 
Resource 
Utilization; 11.2 
Sample Size 
Determination; 
11.7 
Pharmacodynami
c and Biomarker 
Analyses; 16.2.4. 
Privacy of 
Personal Data; 
17.11. Use of 
Information and 
Publication
(Deleted text is struck-through)
Pharmacodynamic and Biomarker Analyses
Exploratory Biomarker analyses may be performed, including serum analysis for levels of 
interferon (IFN) as well as molecular pathway profiling for evidence of IL-12 and IL-23 
pathway modulation. The biomarkers analyzed may include inflammatory markers, RNA, auto-
antibodies, T, B, and NK cell immunophenotyping, and other categories of biomarkers 
potentially involved in the development and the progression of SLE. Biomarker results are 
considered exploratory and will be summarized in a separate technical report.
Genetic (DNA) analyses will be conducted only in subjects who sign the optional DNA consent 
form. These analyses are considered exploratory and will be summarized in a separate technical 
report.
Rationale: Revised description of biomarker endpoints to clarify that the analyses would be performed on subjects 
with abnormal levels of that serologic marker at baseline.
2.2.3 Additional 
Endpoints
(New text is in bold and underlined)
Disease-specific Clinical Biomarkers

The change from baseline in serological activity (eg, levels of anti-dsDNA, and other 
autoantibodies, C3 and C4 levels) over time in subjects with abnormal levels of that 
serologic marker at baseline

The proportions of subjects with normalization, improvement of anti-dsDNA 
autoantibodies, C3, C4 levels over time in subjects with abnormal levels of that 
serologic marker at baseline
Rationale:  Text was revised to include specific mention of SAEs involving medical device incidents. 
12.1.1 Adverse 
Event Definitions 
and 
Classifications, 
Serious Adverse 
Events
(New text is in bold and underlined)

Results in serious injury/death possibly caused by device malfunction

Results in medical or surgical intervention to prevent permanent impairment or 
damage caused by device malfunction.


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
21
Approved, Date: 23 January 2019
Applicable 
Section(s)
Description of Change(s)
Rationale:  Text concerning missing data was revised in response to the change in randomization methodology.
Synopsis Missing 
Data; 11.4.4 
Handling 
Missing Data
(Deleted text is struck-through and new text is in bold and underlined)
For the primary endpoint, subjects with missing data or meeting treatment failure criteria will 
be imputed as nonresponders. Sensitivity analyses will be performed and include (1) 
considering primary endpoint data for subjects meeting treatment failure criteria as missing and 
(2) using observed data regardless of whether the subject met treatment failure criteria. In both 
sensitivity analyses, missing response will be imputed by multiple imputation methods (eg, 
serial logistic regression) under the assumption of missing at random. Additional analyses 
using observed data without imputation may also be performed.If the missing data are not 
monotone, a Markov chain Monte Carlo method will be used first to effectively make the 
missing pattern monotone. For monotone missing data, a serial logistic regression method will 
be used. 
********************************************************************
For all other endpoints, observations after meeting treatment failure criteria will be set to 
missing for subjects who met the criteria. For binary endpoints, missing data will be imputed 
using multiple imputation methods (eg, serial logistic regression) under the assumption of 
missing at random. If the missing data are not monotone, a Markov chain Monte Carlo method 
will be used first to effectively make the missing pattern monotone. For monotone missing data, 
a serial logistic regression method will be used. For continuous endpoints, the statistical model 
(ie, MMRM) will adjust for missing data.
Rationale:  Corrections were made to indicate that subject diary cards are issued at Week 0 and not throughout the 
double-blind period and text was revised to clarify that AEs were not to be recorded in subject diaries.
Section 12
(Deleted text is struck-through)
Solicited Adverse Events
Solicited adverse events are predefined local and systemic events for which the subject is 
questioned specifically and which are noted by subjects in their diary (see Section 9.1.1, 
Overview)
Unsolicited Adverse Events
Unsolicited adverse events are all adverse events for which the subject is not questioned 
specifically in the subject diary.
Rationale: Minor errors were noted
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
22
Approved, Date: 23 January 2019
SYNOPSIS
A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Study of 
Ustekinumab in Subjects with Active Systemic Lupus Erythematosus
Ustekinumab (STELARA®) is a fully human monoclonal antibody that binds to the p40 protein subunit of 
human interleukin (IL)-12 and IL-23 cytokines with high affinity and specificity. The binding of 
ustekinumab to the IL-12/IL-23p40 subunit blocks the binding of IL-12 or IL-23 to the IL-12Rβ1 receptor 
on the surface of natural killer (NK) and clusters of differentiation (CD)4+ T cells. This inhibits the IL-12 
and IL-23 specific intracellular signaling and subsequent cytokine activation and production.
OBJECTIVES, ENDPOINTS, AND HYPOTHESES
Objectives
The primary objective is to evaluate the efficacy of ustekinumab in subjects with active systemic lupus 
erythematosus (SLE) who have not adequately responded to one or more standard-of-care treatments.
The secondary objectives are to evaluate the following in subjects with active SLE despite receiving one 
or more standard-of-care treatments:
1.
Reduction in SLE flares
2.
Improvement in global and organ-specific (mucocutaneous, musculoskeletal, etc) measures of SLE 
disease activity
3.
Glucocorticoid sparing
The additional objectives are to evaluate:
1.
Safety and tolerability
2.
Pharmacokinetics (PK) and immunogenicity
3.
Pharmacodynamic biomarkers and predictive biomarkers to identify subjects most likely to benefit 
from treatment with ustekinumab
4.
Measures of low disease activity state, remission, and organ damage 
5.
Effect on health-related quality of life, physical function, and work productivity
Endpoints
The primary endpoint is the proportion of subjects achieving an SLE Responder Index (SRI-4) composite 
response at Week 52.
The secondary endpoints are:
1.
Time to flare based on the proportion of subjects with a flare occurring at any time after the baseline 
visit through Week 52, with flare defined as either 1 or more new British Isles Lupus Assessment 
Group (BILAG) A or 2 or more new BILAG B domain scores
2.
The proportion of subjects with an SRI-4 composite response at Week 24
3.
The proportion of subjects achieving at least a 50% improvement in the number of joints with pain 
and signs of inflammation at Week 52 in subjects with at least 4 affected joints at baseline 
4.
The proportion of subjects receiving glucocorticoids at baseline who achieve reduction in 
glucocorticoid dose by Week 40 and sustain that reduction through Week 52 


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
23
Approved, Date: 23 January 2019
5.
The proportion of subjects achieving at least a 50% improvement in the Cutaneous Lupus 
Erythematosus Disease Area and Severity Index (CLASI) Activity Score at Week 52 in subjects with
a CLASI Activity Score of 4 or greater at baseline. 
6.
The proportion of subjects receiving glucocorticoids at baseline who achieve reduction in 
glucocorticoid dose by Week 40, sustain that reduction through Week 52, and achieve an SRI-4 
composite response at Week 52.   
Hypothesis
Treatment with ustekinumab is superior to placebo in subjects with active SLE despite receiving one or 
more standard-of-care treatments as measured by the proportion of subjects achieving an SRI-4 composite 
response at Week 52.
OVERVIEW OF STUDY DESIGN
CNTO1275SLE3001 is a multicenter, randomized, double-blind, placebo-controlled, parallel group, study 
to evaluate the efficacy, safety, and tolerability of ustekinumab in addition to standard-of-care 
background therapy in subjects between 16 (unless restricted by local requirements) and 75 years of age, 
inclusive, with active, autoantibody-positive SLE despite receiving one or more standard-of-care 
treatments.
The total duration of the study is up to 182 weeks, consisting of 3 study periods:  a ≤6-week screening
period (re-screening is permitted once per subject), a 52-week double-blind period, and a 124-week 
extension period.
Approximately 500 subjects will be randomly assigned in a 3:2 ratio to receive either ustekinumab or 
placebo with the following treatment administrations (see Section 6 for further details of study agent 
administration): 

Week 0: Body weight-range based intravenous (IV) administration of ustekinumab (~6 mg/kg) or 
placebo

Week 8 and every 8 weeks (q8w) thereafter through Week 48: subcutaneous (SC) administration of 
90 mg ustekinumab or placebo 

Subjects entering the extension period:  SC administration of 90 mg ustekinumab q8w through 
Week 160
A placebo comparator (in addition to standard-of-care background therapy) will be used in this study 
through Week 52 to allow for blinded, placebo-controlled evaluation of the long-term efficacy and safety 
of ustekinumab in subjects with SLE. 
Subjects will be stratified by race, presence of lupus nephritis, and baseline SLE medications and 
Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score (a combined factor), 
using permuted block central randomization. 
Clinical and laboratory evidence of disease activity will be evaluated and adjudicated by blinded external 
reviewers to verify that subjects are meeting inclusion/exclusion criteria and to ensure data quality 
throughout the study. 
The primary efficacy analysis will be performed after all subjects have completed Week 52 efficacy 
assessments (or discontinued) with additional secondary endpoints to be analyzed at Week 24 and 
Week 52. After Week 52, eligible subjects may enter the extension period.


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
24
Approved, Date: 23 January 2019
Every reasonable effort should be made to keep concomitant medications stable as defined in the 
protocol. Beginning at the screening visit, all concomitant therapies and all changes in concomitant 
therapies should be recorded throughout the study.
Subjects with cutaneous disease who provide consent will participate in medical photography to evaluate 
skin photographs at participating study sites. 
Database locks are planned at Week 52, Week 104, and at Week 176. The end of the study is defined as 
the last follow-up assessment (16 weeks after the last dose of study agent is administered at Week 160) 
for the last subject. 
An Independent Data Monitoring Committee (DMC) will be commissioned for this study.
A futility analysis will be carried out 24 weeks after approximately 50% of the planned subjects have
been randomized. The analysis will be performed in an unblinded fashion by the independent DMC based 
primarily on Week 24 efficacy data. Additional data available at the time of the futility analysis (eg, other 
endpoints, other time points) may also be considered. The details of the futility analysis will be included 
in the Statistical Analysis Plan (SAP).
SUBJECT POPULATION
The target population for this study is subjects between the ages of 16 and 75 years with active SLE 
according to Systemic Lupus International Collaborating Clinics (SLICC) criteria SLEDAI-2K score ≥6, 
despite receiving one or more standard-of-care treatments (eg, immunomodulators, antimalarial drugs, 
and/or glucocorticoids). The target population will include subjects with disease manifestations primarily 
affecting the skin and joints (most commonly observed disease manifestations in SLE), mucosal ulcers, 
renal, hematologic, or other disease features. In addition, subjects must have at least 1 positive 
autoantibody test (antinuclear antibodies [ANA], anti-double-stranded deoxyribonucleic acid 
(anti-dsDNA) antibodies, and/or anti-Smith antibodies) observed during screening, as well as a well-
documented positive autoantibody test in their medical history. Subjects must also have at least 1 BILAG 
A and/or 2 BILAG B domain scores observed during screening. Additionally, subjects must have a 
CLASI activity score of at least 4 (excluding diffuse non-inflammatory alopecia) or at least 4 joints with 
pain and signs of inflammation (active joints) at screening or at Week 0, or both. In addition, subjects 
must have a clinical SLEDAI-2K score (excluding laboratory results and lupus headache) ≥4 at Week 0, 
prior to first administration of study agent.
DOSAGE AND ADMINISTRATION
Following randomization at Week 0, subjects assigned to the active treatment group will receive an 
initial, body weight-range based IV dose approximating 6 mg/kg of ustekinumab (ustekinumab 260 mg 
weight ≤55 kg; ustekinumab 390 mg weight >55 kg and ≤85 kg; ustekinumab 520 mg weight >85 kg), 
and subjects who were randomized to placebo will receive the comparable placebo treatment. Starting at 
Week 8, subjects will receive SC dosing with either placebo or ustekinumab 90 mg q8w through 
Week 48. Subjects entering the extension period will receive ustekinumab 90 mg SC q8w through 
Week 160. 
For the double-blind study period, subjects will be administered 90 mg ustekinumab or placebo SC q8w 
at the study site. During the extension period beginning at Week 56 and continuing to Week 160 (and
after appropriate and documented training), subjects will be encouraged to self-administer study agent at 
home.


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
25
Approved, Date: 23 January 2019
DESCRIPTION OF STUDY AGENTS
Intravenous Administration
The ustekinumab supplied for this study is a single-use, sterile solution in 30 mL vials with 1 dose 
strength (ie, 130 mg in 26 mL nominal volume). In addition to ustekinumab, the solution contains 10 mM 
L-histidine, 8.5% (w/v) sucrose, 0.04% (w/v) polysorbate 80, 0.4 mg/mL L-methionine, and 20 µg/mL 
ethylenediaminetetraacetic acid (EDTA) disodium salt dihydrate at pH 6.0. No preservatives are present. 
Placebo study agent will have the same appearance as the respective ustekinumab agent. Except for 
ustekinumab, the placebo solution contains the same components as active drug. 
Subcutaneous Administration
Ustekinumab will also be supplied as a single-use prefilled syringe (PFS) in a strength of 90 mg in 1 mL 
nominal volume for SC administration. Each 1 mL of ustekinumab solution in the PFS contains 90 mg 
ustekinumab with nominal excipient concentrations of 6.7 mM L histidine, 7.6% (w/v) sucrose, 0.004% 
(w/v) polysorbate 80, at pH 6.0. No preservatives are present. The needle cover on the PFS contains dry 
natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex.
Except for ustekinumab, the placebo solution contains the same components as active drug.
EFFICACY EVALUATIONS
Efficacy will be evaluated by assessing the following:

Flares – using BILAG flare and the Modified Safety of Estrogens in Lupus Erythematosus National 
Assessment (SELENA) Flare Index (mSFI) definitions

Measures of global disease activity – SRI composite response, SLEDAI-2K, Physician’s Global 
Assessment of Disease Activity (PGA), BILAG, Lupus Foundation of America Rapid Evaluation of 
Activity in Lupus (LFA-REAL) Clinician-reported Outcome (ClinRO) score*

Glucocorticoid-sparing effects

Musculoskeletal disease – active, tender, and swollen joint count assessments 

Mucocutaneous disease – CLASI Activity Score 

Assessment of organ domain activity and damage – BILAG and SLEDAI-2K organ domains, CLASI 
Damage Score,*
Systemic Lupus International Collaborating Clinics/American College of 
Rheumatology (SLICC/ACR) damage index*

Low disease activity and remission – SLEDAI-2K score,* BILAG score,* Lupus Low Disease 
Activity State (LLDAS), Definitions of Remission in SLE (DORIS)*

Patient-reported outcomes (PROs) – Functional Assessment of Chronic Illness Therapy - Pain visual 
analogue scale (VAS),*
Fatigue (Functional Assessment of Chronic Illness Therapy 
[FACIT]-Fatigue), 36-Item Short Form Health Survey (SF-36v2; physical component score [PCS], 
mental component score [MCS], both PCS and MCS, individual domains), EuroQol 5-dimensional, 
5-level questionnaire (EQ-5D-5L) index score and VAS score,* Lupus Quality of Life (LupusQoL) 
domain scores,* Work Productivity and Activity Impairment Questionnaire–Lupus (WPAI-Lupus) 
total and domain scores, LFA-REAL PRO score*

Health economics and outcomes research – frequency of hospitalizations,* emergency/urgent care 
visits,* or unscheduled study visits*
*Results of these exploratory assessments will be summarized in a separate report.


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
26
Approved, Date: 23 January 2019
PHARMACOKINETIC and IMMUNOGENICITY EVALUATIONS

Summary of ustekinumab concentrations and immunogenicity 

Pharmacokinetics (PK)-efficacy relationships for primary and selected key secondary endpoints

If data allow, population PK and population PK-pharmacodynamics (PD) analysis on primary and/or 
selected key secondary efficacy endpoints
SAFETY EVALUATIONS
Safety evaluations will include assessment of adverse events (AEs), concomitant medications, pregnancy 
testing, administration reactions, chemistry, coagulation, hematology, and urinalysis laboratory tests, 
immunogenicity, vital signs, and general physical examination. In addition, electrocardiogram (ECG), 
chest x-ray (consistent with local regulations), human immunodeficiency virus (HIV), hepatitis B, 
hepatitis C, and tuberculosis (TB) testing will be required at screening.
STATISTICAL METHODS
Descriptive statistics (eg, mean, median, standard deviation, interquartile range, minimum, maximum) 
will be used to summarize continuous variables. Numbers and percentages will be used to summarize 
categorical variables. Median values will be reported for time to event variables. In addition, graphical 
data displays (eg, line plots) and subject listings may also be used to summarize/present the data.
Simple descriptive summary statistics, such as n, mean, standard deviation (SD), median, interquartile 
(IQ) range, minimum, and maximum for continuous variables, and counts and percentages for discrete 
variables will be used to summarize most data.
In general, all statistical tests will be performed at a 2-sided significance level of α=0.05.
Sample Size
The sample size calculation is based upon the primary endpoint, the proportion of SRI-4 composite 
responders at Week 52. A sample size of 300 subjects treated with ustekinumab and 200 subjects with 
placebo is projected to give approximately 98% power to detect a significant difference in response rate 
compared with placebo (assuming 35% and 53% response rates in placebo and ustekinumab, respectively, 
which translates to 18% absolute increase over placebo or an odds ratio of 2.09) with an alpha (α) level of 
0.05. The assumption of a 35% responder rate for placebo is based upon a previous study in which a 
similar SLE population was treated and is consistent with the results observed in CNTO1275SLE2001.
Additional considerations for powering the study include: (1) increasing the ability to have adequate 
numbers of subjects for subgroup analyses and (2) maintaining appropriate safety exposure in a pivotal 
study design.
Primary Efficacy Analyses
Analyses of the primary efficacy endpoint (SRI-4 composite response at Week 52) will include data from 
all randomized subjects who received at least 1 dose of study agent based on their assigned treatment 
group regardless of the actual treatment received. The primary analysis will be based upon the composite 
estimand where subjects meeting treatment failure criteria are assumed to be nonresponders from the 
point of treatment failure forward, and missing data are assumed as nonresponse. 
The SRI-4 composite response is defined as ≥4-point reduction from baseline in SLEDAI-2K score, no 
new BILAG A and no more than 1 new BILAG B domain score, and no worsening from baseline in the 
PGA. Subjects who meet 1 or more treatment failure criteria prior to Week 52 will be considered SRI-4 
nonresponders at Week 52 regardless of the observed SRI-4 response status.


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
27
Approved, Date: 23 January 2019
Logistic regression, adjusting for baseline stratification factors, region, and baseline SLEDAI-2K, will be 
used to analyze the primary endpoint. The logistic regression model will include treatment group and 
stratification factors. The baseline SLEDAI-2K value will be defined as the closest nonmissing 
measurement taken prior to the Week 0 infusion.
Secondary Efficacy Analyses
With the order specified above, each of the secondary endpoints will be tested at a 2 sided α level of 0.05 
if significance is achieved for the preceding hypothesis. If a given comparison is not significant at the 2-
sided α level of 0.05, the remaining treatment group comparisons will be considered supportive analysis.
Other Efficacy Analyses
The consistency of efficacy for SRI-4 composite response at Week 52 may be examined in subgroups 
defined by age, race, baseline SLE Medications and SLEDAI-2K (combined) Score, baseline lupus 
nephritis, weight, body mass index, and region. Other planned analyses include analysis of additional
endpoints.
Missing Data
For the primary endpoint, subjects with missing data or meeting treatment failure criteria will be imputed 
as nonresponders. Sensitivity analyses will be performed and include (1) considering primary endpoint 
data for subjects meeting treatment failure criteria as missing and (2) using observed data regardless of 
whether the subject met treatment failure criteria. In both sensitivity analyses, missing response will be 
imputed by multiple imputation methods (eg, serial logistic regression) under the assumption of missing 
at random. Additional analyses using observed data without imputation may also be performed.
For binary major secondary endpoints, analyses will be similar to the analysis of the primary endpoint:  
subjects with missing data or meeting treatment failure criteria will be imputed as nonresponders. For 
other secondary endpoints, observations after meeting treatment failure criteria will be set to missing for 
subjects who met the criteria. No imputation will be performed for missing postbaseline continuous 
values; the statistical model (ie, mixed-model repeated measures [MMRM]) will adjust for missing data.
For all other endpoints, observations after meeting treatment failure criteria will be set to missing for 
subjects who met the criteria. For binary endpoints, missing data will be imputed using multiple 
imputation methods (eg, serial logistic regression) under the assumption of missing at random. For 
continuous endpoints, the statistical model (ie, MMRM) will adjust for missing data.  
Pharmacokinetic Analyses
Serum ustekinumab concentrations will be summarized over time. Descriptive statistics, including 
arithmetic mean, standard deviation, median, interquartile range, minimum, and maximum will be 
calculated at each sampling time point. All concentrations below the lowest quantifiable sample 
concentration of the assay (BQL) or missing data will be labeled as such in the concentration data listing 
or statistical analysis system (SAS) dataset. The BQL concentrations will be treated as zero in the 
summary statistics.
Immunogenicity Analyses
The incidence and titers of anti-ustekinumab antibodies will be summarized for all subjects who receive 
at least 1 dose of ustekinumab and have appropriate samples for detection of antibodies to ustekinumab 
(ie, subjects with at least 1 sample obtained after their first dose of ustekinumab).
A listing of subjects who are positive for antibodies to ustekinumab will be provided. The maximum titers 
of antibodies to ustekinumab will be summarized for subjects who are positive for antibodies to 
ustekinumab.


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
28
Approved, Date: 23 January 2019
The incidence of neutralizing antibodies (NAbs) to ustekinumab will be summarized for subjects who are 
positive for antibodies to ustekinumab and have samples evaluable for NAbs to ustekinumab
Pharmacodynamic and Biomarker Analyses
Biomarker analyses may be performed, including serum analysis for levels of interferon (IFN) as well as 
molecular pathway profiling for evidence of IL-12 and IL-23 pathway modulation. The biomarkers 
analyzed may include inflammatory markers, RNA, auto-antibodies, T, B, and NK cell 
immunophenotyping, and other categories of biomarkers potentially involved in the development and the 
progression of SLE. Biomarker results will be summarized in a separate technical report. 
Genetic (DNA) analyses will be conducted only in subjects who sign the optional DNA consent form. 
These analyses will be summarized in a separate technical report.
Safety Analyses
Safety analyses will include summaries of discontinuations, deaths, AEs, serious adverse events, and
clinical laboratory tests. Targeted safety events in SLE, based on mechanistic plausibility (eg, serious 
infections, opportunistic infections, TB, hypersensitivity reactions) or potential population risks (eg, 
worsening of renal or central nervous system [CNS] disease) will also be summarized.


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
29
Approved, Date: 23 January 2019
TIME AND EVENTS SCHEDULE:  SCREENING PERIOD AND 52-WEEK DOUBLE-BLIND PERIOD 
Table 1:
TIME AND EVENTS SCHEDULE - Screening Period and 52-Week Double-blind Period
Double-blind Period
Follow-up
Week
Screeninga
(≤6 Weeks)
0
4
8
12
16
20
24
28
32
36
40
44
48
52
64 or
EOTb, c
Study Proceduresd
Screening/Administrative
Informed consente
X
Subject assent (if applicable)f
X
Inclusion/exclusion criteriaa
X
X
SLE classification by SLICC 
criteria
X
Medical history and 
demographics
X
Study Agent Administration
Randomizationg
X
Study agent administration (at 
study site)h
X
X
X
X
X
X
X
Issue subject diary cards
X
Subject diary cards returned to 
clinic
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety Assessments
Full-body physical 
examination
X
X
X
X
X
Targeted physical examination
X
X
X
X
X
X
X
X
X
X
X
Electrocardiogrami
X
Chest x-rayj
X
HIV, HBV, and HCV 
screening
X
QuantiFERON®-TB test
X
Tuberculin skin testk
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TB evaluationl
X
X
X
X
X
X
X
X
X
Urine pregnancy testm
X
X
X
X
X
X
X
X
X


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
30
Approved, Date: 23 January 2019
Table 1:
TIME AND EVENTS SCHEDULE - Screening Period and 52-Week Double-blind Period
Double-blind Period
Follow-up
Week
Screeninga
(≤6 Weeks)
0
4
8
12
16
20
24
28
32
36
40
44
48
52
64 or
EOTb, c
Review concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Glucocorticoid taperingn
←   Weeks 24 to 40   →
Medical resource utilizationo
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Infusion or injection-site 
reaction evaluationp
X
X
X
X
X
X
X
Efficacy Assessmentsq
ClinROs
BILAG
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SLEDAI-2K (S2K RI-50 
Baseline and Screening)r
X
X
SLEDAI-2K (S2K RI-50 
Follow-up)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Modified SELENA Flare Index
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physician’s Global 
Assessment of Disease Activity
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Joint count assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CLASI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
LFA – REAL ClinROs
X
X
X
X
X
SLICC/ACR Damage Index
X
X
PROs
Patient Assessment of Pain 
Intensity (VAS)
X
X
X
X
X
X
FACIT Fatigue 
X
X
X
X
X
SF-36 Standard (4-week 
recall) v2 
X
X
X
EQ-5D-5L
X
X
X
LupusQoL
X
X
X
WPAI-Lupus
X
X
X
LFA – REAL PROs
X
X
X
X
X
Medical photographyt
X
X
X
X


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
31
Approved, Date: 23 January 2019
Table 1:
TIME AND EVENTS SCHEDULE - Screening Period and 52-Week Double-blind Period
Double-blind Period
Follow-up
Week
Screeninga
(≤6 Weeks)
0
4
8
12
16
20
24
28
32
36
40
44
48
52
64 or
EOTb, c
Clinical Laboratory 
Assessmentsu
Chemistry 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Flow cytometryv
X
Coagulation 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
C3, C4 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coombs direct test (local lab)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Rheumatoid factor and 
anti-CCPg
X
Anti-Smith 
X
Antinuclear antibodies 
X
X
X
X
X
Anti-dsDNA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Other autoantibodiesw
X
X
X
X
Anti-phospholipid antibodiesx
X
X
X
X
Ig isotype profile  
X
X
X
X
Urine Analyses (spot urine)u
Urinalysis (dipstick, all 
subjects)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine sample for biomarkers 
(all subjects)
X
X
X
X
X
X
X
Urine protein/creatinine ratio
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine sediment analysis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacokinetics/
Immunogenicity
Serum ustekinumab 
concentrationsy
2Xz
X
X
X
X
X
X
X
X
X
X
X
Population PKaa
← X →
(Weeks 0 to 8)
← X →
(Weeks 12 to 20)
Antibodies to study agenty
X
X
X
X
X
X
X


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
32
Approved, Date: 23 January 2019
Table 1:
TIME AND EVENTS SCHEDULE - Screening Period and 52-Week Double-blind Period
Double-blind Period
Follow-up
Week
Screeninga
(≤6 Weeks)
0
4
8
12
16
20
24
28
32
36
40
44
48
52
64 or
EOTb, c
Biomarkers
Serum biomarkers
X
X
X
X
X
X
X
X
Whole blood (RNA)
X
X
X
X
X
X
X
X
PBMC (cellular analysis)bb  
X
X
X
X
X
X
Whole blood (DNA)cc
X
a.
Screening visit must be performed no more than 6 weeks prior to the randomization visit (Week 0). Lupus-specific assessments relating to Inclusion/Exclusion criteria 
(See Section 4.1) must be reviewed and approved by the Sponsor and/or Sponsor-selected independent reviewer(s) to determine subject eligibility before randomization.
b.
It is strongly recommended that subjects who permanently discontinue study agent, but do not withdraw from study participation, be followed at all subsequent study 
visits through Week 52. At a minimum, subjects who permanently discontinue study agent, but do not withdraw from study participation, should return for a follow-up 
visit 16 weeks after the last study agent administration to undergo procedures as outlined for the end-of-treatment (EOT) visit. Subjects remaining on study agent and 
completing the Week 52 visit who do not enter the extension period should return for a follow-up visit 16 weeks after the last study agent administration to undergo 
Week 64 (EOT visit) procedures. 
c.
Mandatory at-site visit for subjects who enter the study extension.
d.
Administration of study agent and visit window should be within ±7 days of the scheduled visit date. Unless otherwise specified, all assessments (except for injection-
site evaluation) are to be completed prior to study agent administration. 
e.
Subjects who are considered to be adults legally (per local requirements) or parents or legal representatives of subjects who are not considered to be adults (per local 
requirements) will sign informed consent forms for participation in the main study, CNTO1275SLE3001, and may additionally consent for the following: (a) whole 
blood DNA collection for genetic factors, (b) medical photography at selected sites.
f.
Assent for participation in the main study is also required of subjects who are not considered to be adults legally (per local requirements) as described in Section 16.2.3, 
Informed Consent. Assent may additionally be obtained for the following: (a) whole blood DNA collection for genetic factors, (b) medical photography.
g.
At screening, rheumatoid factor and anti-CCP auto-antibodies will be used to assess for co-existing rheumatoid arthritis (RA)/lupus. Before a subject will be approved 
for randomization, the Investigator must affirm that subjects with positive rheumatoid factor or anti-CCP autoantibodies do not have coexistence of SLE and RA 
according to the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for RA.4  
h.
Intravenous administration of study agent at Week 0, all other doses will be subcutaneous (SC) to be administered at the clinic through Week 48.
i.
A 12-lead electrocardiogram (ECG) will be performed locally at screening. Subjects should rest in a supine position for at least 5 minutes before ECG recording and 
should refrain from talking or moving arms or legs.
j.
Chest x-ray posterior/anterior and lateral views (or consistent with local regulations) must be taken within 3 months prior to the first administration of study agent for 
tuberculosis (TB) detection.
k.
Only required if QuantiFERON®-TB test is not registered/approved locally or the tuberculin skin test (TST) is mandated by local health authorities.


STELARA® (ustekinumab)
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Approved, Date: 23 January 2019
l.
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 (performed locally, consistent with local regulations), and QuantiFERON®-
TB test should be performed. A TST is additionally required if the QuantiFERON®-TB test is not registered/approved locally or the TST is mandated by local health 
authorities. Additional safety procedures may be performed if clinically indicated or mandated by local standards of practice.
m. In addition to the urine screening evaluation, a serum pregnancy test may be conducted at any time at the discretion of Investigator or subject. Urine pregnancy tests 
may be conducted more frequently (eg, monthly basis) if required by local regulations.
n.
See Section 8.1.2 for information on glucocorticoid tapering.
o.
Medical resource utilization data (Section 9.3.7), such as hospitalizations, emergency/urgent care visits, or unscheduled visits, will be collected for all subjects 
throughout the study. 
p.
Subjects should be monitored for the occurrence of infusion reactions for at least 1 hour after intravenous (IV) infusion and injection-site reactions for at least 
30 minutes following SC injection. 
q.
Whenever possible, patient-reported outcome assessments should be conducted before any tests, procedures, or other consultations for that visit to prevent influencing 
subjects’ perceptions. It is recommended that PROs be performed in the following sequence:  Patient Assessment of Pain Intensity (VAS), FACIT-Fatigue, SF-36, 
EQ-5D-5L, LupusQoL, WPAI-Lupus, and LFA-REAL PRO. It is recommended that ClinRO procedures be performed in the following sequence:  BILAG, 
SLEDAI-2K, mSFI, PGA, joint count assessment, CLASI, LFA-REAL ClinRO, and SLICC/ACR Damage Index. ClinRO assessments should be performed by an 
adequately trained assessor (see Section 9.2 for details).
r.
Complete SLEDAI-2K (baseline) will be evaluated during screening and at Week 0. At Week 0, to be eligible for study participation, subjects must have SLEDAI-2K 
score 4 for clinical features (excluding laboratory results and lupus headache) as assessed by the Investigator. 
s.
ClinRO portion to be completed by the Investigator at all sites. PRO portion to be performed at selected sites in certain English-speaking countries. 
t.
Medical photography of skin lesions will be performed at selected sites in subjects with cutaneous disease activity present at baseline who give specific consent.
u.
Assessments must be performed by the central laboratory unless otherwise indicated.
v.
Perform clinical B-cell flow cytometry analyses at screening for subjects previously exposed to B-cell depleting therapies (such as rituximab and epratuzumab). 
w.
Other autoantibodies include testing for anti-Smith, anti-Sjögren’s-syndrome-related antigen A (SSA anti-Ro) and B (SSB anti-La), anti-ribonucleoprotein (anti-RNP).
x.
If an abnormal test result is not obtained at Week 0, no additional follow up testing is required. However, additional testing may be performed if clinically indicated.
y.
The same blood draw will be used for the measurement of ustekinumab concentration and detection of antibodies to ustekinumab. For visits with study agent 
administration, all blood samples for assessing pre-dose ustekinumab concentration and antibodies to ustekinumab MUST be collected BEFORE the administration of 
the study agent. Residual sample may be used to evaluate antibodies to ustekinumab at unspecified visits or other biomarker analysis.
z.
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 subjects.
aa. Additional venous blood sample collection for population PK analysis should occur on any day in each of the 2 designated time periods except on the days of scheduled 
study visits. Additionally, this blood sample should be collected at least 24 hours prior to or after the actual time of study agent administration.
bb. Whole blood will be collected and processed for peripheral blood mononuclear cell (PBMC) cryopreservation.
cc. Whole blood for genetic analyses will be collected only from subjects who sign a separate informed consent form to participate in the DNA substudy


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
34
Approved, Date: 23 January 2019
TIME AND EVENTS SCHEDULE:  EXTENSION PERIOD
Table 2:
TIME AND EVENTS SCHEDULE – Extension Period (Week 56 Through Week 176)
Extension Period
Follow-
upa
Week
56b
64b
80b
112b
136b
160b
176 or
EOS 
Study Proceduresc
Study Agent Administration
Study agent dispensed
X
X
X
X
X
X
SC study agent administration trainingd
X
X
Study agent administratione
←-- Every 8 weeks SC from Weeks 56-160 --→
Glucocorticoid tapering
←---------------- Per Investigator Discretion ----------------→
Issue subject diaries
X
X
X
X
X
X
Subject diaries returned
X
X
X
X
X
X
Safety Assessments
Full-body physical examination
X
X
Targeted physical examination
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
TB evaluationf
X
X
X
X
X
X
X
Urine pregnancy testg
X
X
X
X
X
X
X
Review concomitant therapy
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
Medical resource utilizationh
X
X
X
X
X
X
X
Efficacy Assessmentsi
ClinROs
BILAG
X
X
X
X
X
X
X
SLEDAI-2K (S2K-RI-50 Follow-up)
X
X
X
X
X
X
X
Physician’s Global Assessment of Disease Activity
X
X
X
X
X
X
X
Joint count assessment
X
X
X
X
X
X
X
CLASI
X
X
X
X
X
X
X
SLICC ACR Damage Index
X
X
PROs
FACIT-Fatigue
X
X
X
SF-36 Standard (4-week recall) v2
X
X
X
WPAI – Lupus
X
X


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
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Approved, Date: 23 January 2019
Table 2:
TIME AND EVENTS SCHEDULE – Extension Period (Week 56 Through Week 176)
Extension Period
Follow-
upa
Week
56b
64b
80b
112b
136b
160b
176 or
EOS 
Study Proceduresc
Clinical Laboratory Assessments
Chemistry
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
C3, C4 
X
X
X
X
X
X
X
Coombs direct test (local lab)
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
Anti-dsDNA
X
X
X
X
X
X
X
Ig isotype profile
X
X
Urine Analyses (spot urine) 
Urinalysis (dipstick, all subjects)
X
X
X
X
X
X
X
Urine protein/creatinine ratio
X
X
X
X
X
X
X
Urine sediment analysis
X
X
X
X
X
X
X
Pharmacokinetics/Immunogenicityj
Serum ustekinumab concentrations
X
X
X
X
X
X
X
Antibodies to study agent
X
X
X
X
X
X
X
a.
Subjects who complete all scheduled doses or discontinue study agent administration before the end of the study extension should return 
approximately 16 weeks after last study agent administration to undergo Week 176 (End of Study [EOS] visit) procedures.
b.
Mandatory at-site visit for subjects who enter the study extension. 
c.
All assessments are to be completed prior to study agent administration.
d.
Additional visits are permitted for training subjects in study agent self-administration.
e.
Following training on study agent administration, study agent may be administered by the subject (or trained designee) at home via SC 
injection every 8 weeks. Subjects will be required to document administered doses in their subject diaries. Subjects who are unwilling or 
unable to self-administer study agent at home (eg, because they are following standard practice in their country or because recommended 
storage conditions are not feasible) are permitted to receive SC injections by a trained designee at the study site or at home.
f.
Tuberculosis (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 
(local, consistent with local regulations), and QuantiFERON®-TB test should be performed. A TST is additionally required if the 
QuantiFERON®-TB test is not registered/approved locally or the TST is mandated by local health authorities.


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
36
Approved, Date: 23 January 2019
Table 2:
TIME AND EVENTS SCHEDULE – Extension Period (Week 56 Through Week 176)
Extension Period
Follow-
upa
Week
56b
64b
80b
112b
136b
160b
176 or
EOS 
Study Proceduresc
g.
A urine or serum pregnancy test may be conducted at any time at the discretion of Investigator or subject, or if required by local 
regulations.
h.
Medical resource utilization data (Section 9.3.7), such as hospitalizations, emergency/urgent care visits, or unscheduled visits, will be 
collected throughout the study. 
i.
Whenever possible, patient-reported outcome assessments should be conducted before any tests, procedures, or other consultations for that 
visit to prevent influencing subjects’ perceptions. It is recommended that PROs be performed in the following sequence:  FACIT-Fatigue, 
SF-36, and WPAI-Lupus. It is recommended that ClinRO procedures be performed in the following sequence:  BILAG, SLEDAI-2K, 
PGA, joint count assessment, CLASI, and SLICC/ACR Damage Index. ClinRO assessments should be performed by an adequately trained 
assessor (see Section 9.2 for details).
j.
The same blood draw will be used for the measurement of ustekinumab concentration and detection of antibodies to ustekinumab. All 
blood samples collected for assessing predose ustekinumab concentration and antibodies to ustekinumab MUST be collected BEFORE the 
administration of the study agent. Subjects must be instructed to not administer study agent before coming for site visit.


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
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Approved, Date: 23 January 2019
ABBREVIATIONS
ACE
angiotensin-converting enzyme
ACR
American College of Rheumatology
ACTH
adrenocorticotropic hormone 
AE
adverse event
ANA
antinuclear antibodies
APS
antiphospholipid syndrome 
anti-dsDNA
anti-double-stranded deoxyribonucleic acid
anti-HBc total 
HBV core antibody total
anti-HBs
HBV surface antibody
anti-SSA/Ro
anti-Sjögren’s-syndrome-related antigen A (also known as anti-Ro)
anti-SSB/La
anti-Sjögren’s-syndrome-related antigen B (also known as anti-La)
ARB
angiotensin II receptor blocker
AZA /6 MP
azathioprine/6-mercaptopurine
BAFF
B-cell activating factor, also known as B-lymphocyte stimulator (BLyS)
BCG
Bacille Calmette-Guérin
-hCG
-human chorionic gonadotropin
BILAG
British Isles Lupus Assessment Group 
BLyS
B-lymphocyte stimulator, also known as B-cell activating factor (BAFF)
CD
clusters of differentiation 
CLASI
Cutaneous Lupus Erythematosus Disease Area and Severity Index 
ClinRO
clinician-reported outcome
CNS
central nervous system
cSFI
classic Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) flare index 
CTCAE
Common Terminology Criteria for Adverse Events 
DBL
Database lock
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid
DORIS
definitions of remission in systemic lupus erythematosus 
ECG
electrocardiogram
eCRF
electronic case report form
eDC
electronic data capture 
EDTA
ethylenediaminetetraacetic acid
ELISA
enzyme-linked immunosorbent assay 
EQ-5D-5L
EuroQol 5-dimensional, 5-level questionnaire 
FACIT
Functional Assessment of Chronic Illness Therapy
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone 
GCP
Good Clinical Practice 
HBsAg
HBV surface antigen
HBV
hepatitis B virus 
HCV
hepatitis C virus
HIV
human immunodeficiency virus 
HRQoL
health-related quality of life 
IA
intra-articular
ICF
Informed Consent Form
ICH
International Conference on Harmonisation 
IEC
Independent Ethics Committee
IFN
interferon
Ig
immunoglobulin
IL
interleukin
IM
intramuscular
IP
investigational product 
IRB
Institutional Review Board 
IV
intravenous
IWRS
interactive web response system 


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
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Approved, Date: 23 January 2019
LFA-REAL
Lupus Foundation of America Rapid Evaluation of Activity in Lupus
LLDAS
lupus low disease activity state 
LupusQoL
Lupus Quality of Life 
MCS
mental component score 
MMF
mycophenolate mofetil 
MMRM
mixed-model repeated measures
MPA
mycophenolic acid 
mSFI
modified SELENA flare Index 
MTX
methotrexate
NAbs
neutralizing antibodies 
NSAIDs
nonsteroidal anti-inflammatory drugs 
PBMC
peripheral blood mononuclear cells
PCS
physical component score 
PD
pharmacodynamic(s)
PFS
prefilled syringe 
PGA
Physician’s Global Assessment of Disease Activity 
PK
pharmacokinetic
PQC
product quality complaint 
PRO
patient-reported outcome
PsA
psoriatic arthritis
q8w
every 8 weeks
RA
rheumatoid arthritis
RNA
ribonucleic acid
RNP
ribonucleoprotein
S2K RI-50
SLEDAI-2K Responder Index
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SF-36
36-Item Short Form Health Survey 
SLE
systemic lupus erythematosus
SLEDAI
Systemic Lupus Erythematosus Disease Activity Index
SLEDAI-2K
Systemic Lupus Erythematosus Disease Activity Index 2000 
SELENA
Safety of Estrogens in Lupus Erythematosus National Assessment
SLICC
Systemic Lupus International Collaborating Clinics
SRI-4
SLE Responder Index
SUSAR
suspected unexpected serious adverse reaction
TB
tuberculosis
Th
T helper
TNF
tumor necrosis factor alpha
US
United States
VAS
visual analogue scale 
WBC
white blood cells 
WPAI-Lupus
Work Productivity and Activity Impairment Questionnaire–Lupus


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
39
Approved, Date: 23 January 2019
DEFINITIONS OF TERMS
Clinical outcome 
assessment (COA)
Includes PROs, Clinician-Reported Outcomes (ClinROs), Observer Reported Outcomes 
(ObsRO) and Performance Reported Outcomes (PerfRO)
Lupus low disease 
activity state 
(LLDAS)
Defined as: 1) SLEDAI-2K ≤4, with no activity in major organ systems (renal, CNS, 
cardiopulmonary, vasculitis, fever) and no hemolytic anemia or gastrointestinal activity; 2) 
no new lupus disease activity compared with the previous assessment; 3) a PGA score 
(scale 0–3) ≤1; 4) a current prednisone (or equivalent) dose ≤7.5 mg daily; and 5) well 
tolerated standard maintenance doses of immunosuppressive drugs and approved biological 
agents)


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
40
Approved, Date: 23 January 2019
1.
INTRODUCTION
Systemic lupus erythematosus (SLE) is a complex, immune-mediated inflammatory disorder of 
unknown etiology that can affect almost any organ system and follows a waxing and waning
disease course. The estimated annual incidence of lupus varies from 1.8 to 7.6 cases per 100,000 
people and the worldwide prevalence ranges from 14 to 172 cases per 100,000.56 It is more 
prevalent in Afro-Caribbean, Asian, or Hispanic populations and occurs up to 9 times more 
frequently in women than in men. The highest prevalence of SLE is among women of 
childbearing age. 
In patients with SLE, the immune system attacks the body's cells and tissues and the resulting 
inflammation and tissue damage can harm the heart, joints, skin, lungs, blood vessels, liver, 
kidneys, and nervous system. Approximately half of the patients diagnosed with SLE present 
with organ-threatening disease, but it can take several years to diagnose patients who do not 
present with organ involvement. Some of the primary complaints of newly diagnosed lupus 
patients are arthralgia (62%) and cutaneous symptoms (new photosensitivity; 20%), followed by 
persistent fever and malaise.56 Patients with mild disease typically have skin rashes and joint 
pain and require less aggressive treatment. With more severe disease, patients may experience a 
variety of serious conditions depending on the organ-systems involved, including lupus nephritis 
with potential renal failure, endocarditis or myocarditis, pneumonitis, pregnancy complications, 
stroke, and neurological complications, vasculitis, and cytopenias with associated risks of 
bleeding or infection. Those with severe SLE have a life expectancy that is shortened by 10 to 
30 years, largely due to the complications of their disease and/or associated with SLE therapy 
and accelerated atherosclerosis. The long-term outcome for patients with lupus depends on a 
variety of factors including whether they have organ involvement, the presence of certain 
laboratory measures (such as anti-phospholipid antibodies), race, gender, age of onset, access to 
health care, adherence to treatment, education, and comorbidities. Only about 5% of patients 
who are diagnosed with SLE will demonstrate a spontaneous remission without treatment.
It is estimated that 10% to 20% of patients experience SLE onset prior to adulthood. The most 
frequently cited maximum age at diagnosis used to define pediatric-onset SLE is 16 years. 
Studies that provide direct comparisons of patients with pediatric and adult-onset SLE reveal that 
pediatric-onset SLE often presents with more acute and severe disease features than adult-onset 
SLE. Many reports suggest that at the time of diagnosis, there is a higher frequency of renal, 
neurological, and hematological involvement with pediatric-onset SLE compared with 
adult-onset SLE. Despite a general lack of comorbid conditions, children and adolescents have 
higher mortality rates than adults with SLE. Further, a Lupus in Minorities (LUMINA) study 
showed that there appeared to be more active disease during the disease course in 
adolescent-onset SLE (SLE onset between age 13 and 18 years) than in those with adult-onset 
SLE. Almost all children with SLE require treatment with glucocorticoids during the disease
course, and many are treated with immunosuppressive agents.32
Existing therapies for SLE are generally either cytotoxic or immunomodulatory and may have 
notable safety risks. Thus, there is a large unmet need for new alternative treatments that can 
provide significant benefit in this disease without incurring a high safety risk. In the past 


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
41
Approved, Date: 23 January 2019
fifty years, only one drug with a new mechanism of action has been approved by the European 
Medicines Agency or the United States (US) Food and Drug Administration (FDA) for treatment 
of adult SLE. In 2011, the B-lymphocyte stimulator-specific inhibitor belimumab was approved 
as add-on therapy for the treatment of adult patients with active, autoantibody-positive SLE with 
a high degree of disease activity despite standard-of-care therapy.34,54 A variety of new 
therapeutic agents are being evaluated for the treatment of subjects with refractory lupus; 
however, to date very few have succeeded in late stage clinical testing or demonstrated notable 
clinical efficacy beyond those medications currently considered standard of care for patients with 
this disease.
For the most comprehensive nonclinical and clinical information regarding ustekinumab, refer to 
the latest version of the Investigator's Brochure25 and addenda.
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
1.1.
Background
To date, ustekinumab has received marketing authorization globally, for the treatment of adult 
and pediatric patients (age ≥12 to <18 years) with chronic moderate to severe plaque psoriasis, 
adult patients with active psoriatic arthritis (PsA), and adult patients with moderate to severe 
Crohn’s disease. The cumulative global exposure (through 31 December 2016) has been 
estimated as 777,478 person-years. Based on completed clinical studies alone, 7,837 subjects 
have been exposed to ustekinumab across all indications. In Phase 2 and Phase 3 clinical studies, 
subjects have been exposed to ustekinumab for 6 months, 1 year and some subjects have had 5 or
more years of exposure to the drug. The overall safety profile of ustekinumab was similar for 
patients regardless of indication and the most common adverse reactions (>5%) in controlled 
periods of clinical studies were nasopharyngitis and headache. Most adverse events (AEs) were 
considered mild and did not necessitate drug discontinuation. A Phase 2 clinical study of 
ustekinumab in SLE demonstrated clinical efficacy with no new safety signals compared with
previous studies in other indications. The exposure and safety profiles in the SLE Phase 2 study 
were similar to registrational studies in Crohn’s disease using the same dose regimen
(Section 1.2.2). Refer to the latest version of the Investigator's Brochure25 for further details.
1.2.
Overall Rationale for the Study
1.2.1.
Scientific Rationale for Use of Anti-IL-12/23p40 Therapy in Systemic 
Lupus Erythematosus
Chronic immune activation in SLE leads to increased production of inflammatory cytokines that 
contribute actively to local inflammation and to processes that mediate tissue damage. Interferon 
(IFN) signatures, an increased expression of type I IFN-regulated genes, have been observed to
occur more frequently in lupus families and may be a risk factor for development of SLE.2,35
Several studies have reported an elevation of interleukin (IL)-12, IL-6, and IL-23 in both serum 
and tissues of patients with SLE, suggesting that the inflammatory environment in SLE is prone
to induce T helper (Th)1 and Th17 cells.7,30,36,42,47,61 Interleukin-12 is produced primarily by 


STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001 Amendment 2
42
Approved, Date: 23 January 2019
antigen-presenting cells as a secreted heterodimeric cytokine comprising 2 protein subunits, 
designated p35 and p40 for their approximate molecular weights. In patients with active SLE, 
messenger ribonucleic acid (RNA) levels of p35 and p40 were significantly higher compared 
with those in the inactive SLE patients.23 For clusters of differentiation (CD)4+ T cells, IL-12 
signaling concurrent with antigen presentation is thought to invoke differentiation towards the 
Th1 phenotype, which produces a robust proinflammatory cytokine, interferon gamma (IFNγ). 
Clear evidence for a genetic link between the IL-23/Th17 pathways in SLE is lacking,28,44,46
although genome-wide association studies in SLE have identiﬁed signal transducer and activator 
of transcription 4 (STAT4), which mediates Type I IFN, IL-12, and IL-23 signaling, as a 
susceptibility gene in Asian, Caucasian, and African-American populations.20,24,45  
Ustekinumab (STELARA®) is a fully human monoclonal antibody that binds to the p40 protein 
subunit of human IL-12 and IL-23 cytokines with high affinity and specificity. The binding of 
ustekinumab to the IL-12/IL-23p40 subunit blocks the binding of IL-12 or IL-23 to the IL-12Rβ1 
receptor on the surface of natural killer (NK) and CD4+ T cells. This inhibits IL-12- and 
IL-23-specific intracellular signaling and subsequent cytokine activation and production. This is 
also supported by preclinical studies implicating IL-12 and IL-23 in animal models and human 
SLE tissues, limited evidence based on experimental, off-label use of ustekinumab in SLE 
patients, and its favorable safety profile in several disease indications.
Taken together, these data and investigations from the Alliance for Lupus Research and the 
Lupus Research Institute, which highlighted ustekinumab as the most prominent drug candidate 
for repurposing in SLE,18 strongly support the scientific rationale for further evaluation of the 
efficacy and safety of ustekinumab in subjects with active SLE.
1.2.2.
Results of CNTO1275SLE2001 Phase 2 Study 
CNTO1275SLE2001 is a Phase 2, proof-of-concept study of the efficacy and safety of 
ustekinumab added to standard-of-care background in subjects with active SLE. All subjects in 
the study were receiving background standard-of-care therapy with glucocorticoids and/or 
immunomodulators. A total of 102 subjects were randomly assigned to receive either 
ustekinumab (n=60) or placebo (n=42) through Week 24. Subjects randomized to active drug 
received an initial body weight-range-based intravenous (IV) dose approximating 6 mg/kg of 
ustekinumab (ie, 260 mg for subjects ≥35 kg to ≤55 kg; 390 mg for subjects >55 to ≤85 kg; and 
520 mg for subjects >85 kg). Subjects randomized to placebo received matching placebo. The IV 
dose was followed by 90 mg subcutaneous (SC) ustekinumab or matching placebo every 8 weeks 
(q8w) starting from Week 8. At Week 24, subjects who received placebo crossed-over and all 
subjects received ustekinumab 90 mg SC q8w without an IV dose. The primary endpoint of the 
study was the proportion of subjects with a composite measure of SLE disease activity (SRI-4 
[SLE Responder Index] composite response) at Week 24.
Subjects were randomized at 36 sites across 5 regions, including Asia Pacific (Taiwan and 
Australia), Eastern Europe (Hungary and Poland), Western Europe (Spain and Germany), Latin 
America (Mexico and Argentina), and the US.


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All randomized subjects received at least a partial initial IV infusion dose of study agent. Of the 
42 subjects in the placebo group and the 60 in the ustekinumab group, 33 subjects in the placebo 
group and 56 in the ustekinumab group completed their Week 24 visit. Nine subjects in the 
placebo group and 4 in the ustekinumab group prematurely discontinued study agent.
Efficacy
The primary endpoint of the study was met. At Week 24, a significantly greater proportion of 
subjects in the ustekinumab treatment group (60.0%; p=0.0046) achieved an SRI-4 composite 
response than did subjects in the placebo group (31.0%). Sensitivity analyses showed similar 
treatment effects supporting the robustness of the primary analysis. Ustekinumab also 
demonstrated greater clinical efficacy versus placebo in measures of SLE disease activity,
including systemic features (Systemic Lupus Erythematosus Disease Activity Index 2000 
[SLEDAI-2K] and physician’s global assessment [PGA]), musculoskeletal disease (active joint 
counts), mucocutaneous disease (Cutaneous Lupus Erythematosus Disease Area and Severity 
Index [CLASI]), time to British Isles Lupus Assessment Group (BILAG) flare, and levels of 
circulating complement C3 and anti-double-stranded deoxyribonucleic acid (anti-dsDNA)
autoantibodies.53
Safety
The safety analysis set included a total of 102 subjects, with 42 in the placebo group and 60 in 
the ustekinumab group. Treatment with ustekinumab was generally well tolerated in subjects 
with SLE, with similar safety profiles observed in the placebo and ustekinumab groups. Through 
the Week 24 database lock (DBL), no deaths, serious opportunistic infections, active tuberculosis 
(TB), or malignancies were reported. Key safety results through Week 24 from study 
CNTO1275SLE2001 are summarized in Table 3. Refer to the current version of the 
Investigator’s Brochure for further details. 


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Table 3:
Overall Summary of Adverse Events Through Week 24; Safety Analysis Set 
(Study CNTO1275SLE2001)
Placebo 
Ustekinumab 
Treated subjects 
42
60
Avg duration of follow-up (weeks)
23.3
24.3
Subjects who discontinued study agent because of 1 or more adverse 
events
4 (44.4%)a
3 (75.0%)a
Subjects with 1 or more treatment emergent adverse events
28 (66.7%)
47 (78.3%)
Subjects with 1 or more serious treatment emergent adverse events
4 (9.5%)
5 (8.3%)
Deaths
0
0
Subjects with 1 or more infections
21 (50.0%)
26 (43.3%)
Subjects with 1 or more serious infections
0
2 (3.3%)
Subjects with 1 or more malignancies
0
0
Subjects with 1 or more injection-site reactions
0
1 (1.7%)
Subjects with a treatment emergent infusion reaction
1 (2.4%)
2 (3.3%)
a
Denominator = number of subjects who discontinued study agent for any reason: 9 in the placebo group and 4 in 
the ustekinumab group.
Note: Percentage calculated with the number of randomized, treated subjects in each study phase as the denominator. 
Incidence is based on the number of subjects experiencing at least one adverse event, not the number of events.
Adapted from: [TSIDS01.RTF] [\\\\\TSIDS01.SAS] 24JUL2017, 09:01; [TSFAE01.RTF] [\\\\\TSFAE01.SAS] 24JUL2017, 09:01; 
[TSFAE02.RTF] [\\\\\TSFAE02.SAS] 24JUL2017, 09:01[TSFAE05.RTF] [\\\\\TSFAE05.SAS] 26JUL2017, 02:11; [TSFAE06.RTF] 
[\\\\\TSFAE06.SAS] 26JUL2017, 02:11; [TSFAE09.RTF] [\\\\\TSFAE09.SAS] 26JUL2017, 02:11; [TSFAE08.RTF] 
[\\\\\TSFAE08.SAS] 26JUL2017, 02:11
Pharmacokinetics
Following a single IV administration of weight-range based ~ 6mg/kg ustekinumab (ie, 260 mg
for subjects ≥35 kg to ≤55 kg; 390 mg for subjects >55 to ≤85 kg; and 520 mg for subjects 
>85 kg) at Week 0, median peak concentration at 1 hour post-dose was 143 µg/mL and median 
serum concentration at Week 8 was 8.85 µg/mL. Following 90 mg SC q8w administration 
starting at Week 8, steady state was achieved approximately by Week 24 with a median steady 
state trough concentration of 2.67 µg/mL. Serum ustekinumab concentrations over time in 
subjects with SLE were similar to those observed in subjects with Crohn’s disease, who received 
the same dose regimen.9
Following the weight-range based IV dose, median serum ustekinumab concentrations were
generally similar across the 3 weight categories at the end of Week 8. Following 90 mg SC q8w 
administration, comparable serum ustekinumab concentrations were generally attained regardless 
of body weight category through Week 24. The median steady-state trough serum ustekinumab 
concentrations at Week 24 in subjects with baseline body weight >85 kg (1.49 μg/mL) were 
slightly lower than in subjects with baseline body weight ≥35 kg to ≤55 kg and >55 kg to ≤85 kg
(3.20 and 2.92 μg/mL respectively). However, this did not impact SRI-4 composite response
rates in the highest body weight group.


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Overall, following treatment with ustekinumab at the dose regimen evaluated in the Phase 2
study, no apparent exposure-response trends were observed between serum ustekinumab 
concentrations and clinical efficacy measurements. However, these results should be interpreted 
with caution, given the small number of subjects in each quartile and the relatively narrow drug 
exposure range following a single-dose regimen of ustekinumab.
Immunogenicity
The overall incidence of antibodies to ustekinumab in the ustekinumab treatment group through 
Week 24 was 8.5% (5 of 59 subjects with evaluable serum samples). Antibody responses to 
ustekinumab were generally of low titer; the highest peak titer was ≤1:1600 in one subject.
Comparable median serum ustekinumab concentrations were observed between subjects with 
and without development of antibodies to ustekinumab through Week 24. Thus, development of 
antidrug antibodies to ustekinumab did not appear to be associated with a reduction in efficacy. 
However, these results should be interpreted with caution, given the small number of subjects 
who were positive for antibodies to ustekinumab in the ustekinumab treatment group.
Phase 2 Study Conclusions

Study CNTO1275SLE2001 has shown that treatment with ustekinumab, administered as an 
~6 mg/kg IV dose followed by 90 mg SC at Week 8 and then every 8 weeks thereafter was 
efficacious and generally well tolerated in subjects with SLE.53

The safety,
PK, and anti-drug antibody
profile of this dose regimen in the 
CNTO1275SLE2001 study was consistent with the well-established profile observed in 
three large-scale Phase 3 Crohn’s disease studies using the same dose regimen.9  
1.2.3.
Justification for Dosing Regimen
In the Phase 2 CNTO1275SLE2001 study, greater efficacy compared with placebo was observed 
across clinical and laboratory measures of disease activity with IV administration of ustekinumab
~6 mg/kg followed by 90 mg SC ustekinumab q8w beginning at Week 8. No new safety signals 
for ustekinumab administered on a background of standard-of-care therapy were observed in 
subjects with SLE compared with previous studies in other indications.25
The same dosing regimen is proposed for this Phase 3 study of ustekinumab in SLE, and is based 
on findings from the CNTO1275SLE2001 study as well as the Sponsor’s longstanding 
experience and understanding of the safety and PK-pharmacodynamic (PD) relationships of 
ustekinumab. PK parameters of ustekinumab have, in general, been similar across multiple 
indications, including psoriasis, PsA, Crohn’s disease, and SLE after correcting for body 
weight-related PK differences. 
Elevation of total circulating IL-12/23p40 has been consistently observed in previous studies of 
ustekinumab due to the stabilization of p40 by binding of ustekinumab, and has been a reliable 
measure of target engagement in clinical studies. In the CNTO1275SLE2001 study, the elevated 
levels of total IL-12/23p40 in SLE subjects observed were similar to those seen in Crohn’s 
disease studies.


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Given the multi-organ systemic involvement of SLE, and the high IL-12/23p40 and Th1 cell 
burden present at baseline in the circulation and tissue, respectively, an IV dose was tested. It 
was believed that the higher initial exposures enabled by IV administration and the resultant 
more rapid onset of action, might be important in inducing response and establishing a durable
reduction in active signs and symptoms of SLE. In the CNTO1275SLE2001 study, 
administration of a ~6 mg/kg IV dose of ustekinumab resulted in increased levels of C3 and 
reduced titers of anti-dsDNA autoantibodies as early as Week 4, suggesting a rapid PD response 
for clinically relevant markers of disease activity. Further, evidence of a treatment effect of 
ustekinumab over placebo was observed by Week 12 in most clinical efficacy measures, 
including SRI-4 composite response.  
Most subjects receiving ustekinumab in the CNTO1275SLE2001 study maintained steady-state 
trough concentrations above 0.8-1.4 µg/mL, an exposure threshold that has been shown to 
correlate with greater efficacy in subjects with Crohn’s disease. Following treatment with SC 
ustekinumab 90 mg q8w in subjects with SLE, approximately 80% of subjects are predicted to 
achieve steady‑state trough ustekinumab concentrations 1 μg/mL. Given the multi-organ 
system involvement in SLE, maintenance dosing regimens lower than 90 mg q8w would not be 
expected to produce optimal efficacy in the SLE population. 
Study CNTO1275SLE2001 has shown that treatment with ustekinumab administered as an 
~6 mg/kg IV dose following by 90 mg SC dose at Week 8 and then every 8 weeks thereafter was 
efficacious and generally well tolerated in subjects with SLE.53 The safety profile of this dose 
regimen in the CNTO1275SLE2001 study was consistent with the well-established profile 
observed in several large-scale Phase 3 Crohn’s disease studies.9 Therefore, this dosing regimen 
was selected for further evaluation in this Phase 3 SLE study.
1.2.4.
Benefit/Risk Assessment
To date, ustekinumab has received marketing authorization globally for the treatment of adult 
and pediatric patients (age ≥12 to <18 years) with chronic moderate to severe plaque psoriasis, 
adult patients with active PsA, and adult patients with moderate to severe Crohn’s disease. The 
overall safety profile of ustekinumab was similar for patients regardless of indication. Refer to 
the latest version of the Investigator's Brochure25 for further details.
Ustekinumab is being evaluated in patients with SLE in a Phase 2 clinical study 
CNTO1275SLE2001. The results of that study through 24 weeks (see Section 1.2.2) indicate that 
ustekinumab, administered as an initial body weight-range-based IV dose approximating 
6 mg/kg of ustekinumab followed by 90 mg SC ustekinumab every 8 weeks starting from 
Week 8, is an effective therapy in SLE beyond standard-of-care background therapy. The same 
dosing regimen is proposed for this Phase 3 study of ustekinumab in SLE.
In the CNTO1275SLE2001 study through the Week 24 DBL, treatment with ustekinumab was 
generally well tolerated in subjects with SLE, with similar safety profiles observed in the placebo 
and ustekinumab groups. No deaths, serious opportunistic infections, active TB, or malignancies 


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were reported. Further, no new safety signals were identified in the SLE study compared with 
previous studies in other indications.
In this Phase 3 study, potential risks of treatment with ustekinumab (eg, serious infections, 
including TB and hypersensitivity reactions), as well as the potential risks inherent in patients 
with SLE (severe disease flares, lupus nephritis, central nervous system [CNS] disease, 
vasculitis, cytopenias, serious infections, and opportunistic infections), are being addressed in 
multiple ways:

Inclusion/exclusion criteria (Section 4.1) set limits regarding, for example, history of 
unstable or progressive organ-threatening disease, infections or predisposition to infections, 
history of reactions to biologic agents, and baseline laboratory abnormalities.

Comprehensive medical monitoring of data by the sponsor during the conduct of this study 
includes regular assessment of AEs and serious adverse events (SAEs), vital signs, physical 
examination, and laboratory results (Table 1 and Table 2 Time and Events Schedules) to 
evaluate individual cases as well as potential emerging safety trends. In addition, as 
discussed in Section 11.10, an external, independent Data Monitoring Committee (DMC) 
will provide oversight and will conduct independent evaluation of the safety data accrued in 
this protocol.

Certain concomitant medications (Section 8) have been prohibited and limitations set on 
dose levels of permitted concomitant medications, such as high dose glucocorticoids, 
cytotoxic agents, and use of multiple biologics simultaneously, that could introduce safety 
risks due to oversuppression of the immune system.

Lastly, the steroid-sparing effects of ustekinumab are being evaluated by implementing a
glucocorticoid taper from Week 24-40 during the double-blind period and throughout the 
extension period. This may add benefit by reducing risk of infection and other 
glucocorticoid-related complications. However, should a subject experience worsening of
disease activity, rescue therapy is permitted per medical necessity as outlined in Table 5 and 
Table 6.
Based on the available safety data in SLE and other disease indications, efficacy data in the SLE 
Phase 2 study, and proposed safety measures, the overall risk/benefit assessment of ustekinumab 
in this protocol is acceptable.
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1.
Objectives
2.1.1.
Primary Objective
The primary objective is to evaluate the efficacy of ustekinumab in subjects with active SLE who 
have not adequately responded to one or more standard-of-care treatments.
2.1.2.
Secondary Objectives
The secondary objectives are to evaluate the following in subjects with active SLE despite 
receiving one or more standard-of-care treatments:


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1.
Reduction in SLE flares
2.
Improvement in global and organ-specific (mucocutaneous, musculoskeletal, etc) measures 
of SLE disease activity
3.
Glucocorticoid sparing
2.1.3.
Additional Objectives
The additional objectives are to evaluate:
1.
Safety and tolerability
2.
Pharmacokinetics and immunogenicity
3.
Pharmacodynamic biomarkers and predictive biomarkers to identify subjects most likely to 
benefit from treatment with ustekinumab
4.
Measures of low disease activity state, remission, and organ damage
5.
Effect on health-related quality of life, physical function, and work productivity
2.2.
Endpoints
Refer to Section 9, Study Evaluations for assessments related to endpoints.
2.2.1.
Primary Endpoint
The primary endpoint is the proportion of subjects achieving an SRI-4 composite response at 
Week 52.
2.2.2.
Secondary Endpoints
The secondary endpoints are:
1.
Time to flare based on the proportion of subjects with a flare occurring at any time after the 
baseline visit through Week 52, with flare defined as either 1 or more new BILAG A or 2 or 
more new BILAG B domain scores
2.
The proportion of subjects with an SRI-4 composite response at Week 24
3.
The proportion of subjects achieving at least a 50% improvement in the number of joints 
with pain and signs of inflammation at Week 52 in subjects with at least 4 affected joints at 
baseline 
4.
The proportion of subjects receiving glucocorticoids at baseline who achieve reduction in 
glucocorticoid dose by Week 40 and sustain that reduction through Week 52 (See 
Section 9.3.5 for definitions of reduction of glucocorticoid dose and sustained reduction of 
glucocorticoid dose.)
5.
The proportion of subjects achieving at least a 50% improvement in the CLASI Activity 
Score at Week 52 in subjects with a CLASI Activity Score of 4 or greater at baseline
6.
The proportion of subjects receiving glucocorticoids at baseline who achieve reduction in 
glucocorticoid dose by Week 40, sustain that reduction through Week 52, and achieve an 
SRI-4 composite response at Week 52 


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2.2.3.
Additional Endpoints
Measures of Improvement in Global Disease Activity

The proportion of subjects with an SRI-4 composite response in the subpopulation who was 
unable to taper glucocorticoids 

The proportions of subjects with SRI-4, SRI-5, SRI-6, SRI-7, and SRI-8 composite 
responses over time

The proportions of subjects with at least a 4-, 5-, 6-, 7-, or 8-point improvement compared 
with baseline in SLEDAI-2K over time

The proportions of subjects with at least a 4-, 5-, 6-, 7-, or 8-point improvement compared 
with baseline in SLEDAI-2K excluding serologic activity (C3, C4, anti-dsDNA 
autoantibodies) over time

The proportion of subjects with an SRI-4 composite response at ≥50% of the study visits 
from baseline to Week 52

The proportion of subjects with at least a 4-point improvement compared with baseline in 
S2K RI-50 over time

The proportion of subjects with no worsening, improvement* in PGA over time

Lupus Foundation of America Rapid Evaluation of Activity in Lupus (LFA-REAL) 
clinician-reported outcome (ClinRO)*
Flare

Annualized flare rate, total number of flares, proportion of subjects with flares, and time to 
flare analysis of BILAG flares, severe BILAG flares (defined as at least 1 new BILAG A 
domain score compared with baseline), moderate BILAG flares (defined as at least 2 new 
BILAG B domain scores compared with baseline) 

Annualized flare rate, total number of flares, proportion of subjects with flares, and time to 
flare analysis of modified Safety of Estrogens in Lupus Erythematosus National Assessment 
(SELENA) flare Index (mSFI) flares, severe mSFI flares (Section 9.2.4), mild/moderate 
mSFI flares (Section 9.2.4) compared with baseline
Glucocorticoid Sparing

The proportion of subjects receiving glucocorticoids at baseline who achieve an average 
daily glucocorticoid dosage reduction of at least 25% (relative to the baseline dose) to a 
glucocorticoid dose level ≤7.5 mg/day by Week 40 and sustain that reduction through 
Week 52

The proportion of subjects receiving glucocorticoids at baseline who achieve an average 
daily glucocorticoid dose reduction of at least 50% compared with the baseline dose level by 
Week 40 and sustain that reduction through Week 52

The proportion of subjects who require increases in glucocorticoid dose above the baseline 
dose level over time

Cumulative average daily
glucocorticoid
dose over time
in subjects receiving 
glucocorticoids at baseline


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Musculoskeletal Disease

The proportion of subjects achieving at least a 20% or 50% improvement in the number of
active joints (defined as joints with pain and signs of inflammation), tender joints (defined as 
joints with pain on examination), swollen joints (defined as joints with signs of 
inflammation) over time in subjects with at least 4 active joints at baseline

Change from baseline in the number of active, tender, swollen joints over time in subjects 
with at least 4 active joints at baseline
Mucocutaneous Disease

The proportion of subjects who achieve a 20% or 50% reduction from baseline in CLASI 
activity score over time in those with a baseline CLASI activity score of at least 4 

The proportion of subjects who achieve a 20% or 50% reduction from baseline in CLASI 
activity score over time in those with a baseline CLASI activity score of at least 8 

Change from baseline in the CLASI activity score over time in those with a baseline CLASI 
activity score of at least 4 
Assessment of Organ Domain Activity and Damage

The proportion of subjects with no BILAG worsening compared with baseline over time 

Time to first Systemic Lupus International Collaborating Clinics/American College of 
Rheumatology (SLICC/ACR) damage index worsening (defined as SLICC/ACR damage 
index damage score >0) over time in those subjects with SLICC/ACR damage index 
score = 0 at baseline*

Proportion of subjects who remain free of SLICC/ACR damage index progression (defined 
as SLICC/ACR damage index damage score = 0) over time*

Proportion of subjects with SLICC/ACR damage index accrual (defined as change from 
baseline in SLICC/ACR damage index score >0) over time*
Low Disease Activity and Remission

The proportion of subjects with SLEDAI-2K score of 0, ≤2 over time*

The proportion of subjects who achieve lupus low disease activity state (LLDAS) over time

The proportion of subjects with BILAG major clinical response over time*

The proportion of subjects who achieve clinical remission on treatment according to 
definitions of remission in SLE (DORIS) over time*
Disease-specific Clinical Biomarkers

The change from baseline in serological activity (eg, levels of anti-dsDNA and other 
autoantibodies, C3 and C4 levels) over time in subjects with abnormal levels of that 
serologic marker at baseline

The proportions of subjects with normalization, improvement of anti-dsDNA and other 
autoantibodies, C3, C4 levels over time in subjects with abnormal levels of that serologic 
marker at baseline*


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Patient-reported Outcomes/ Health Economics and Outcomes Research

Frequency of total and SLE-related hospitalizations, emergency/urgent care visits, or
unscheduled visits*

The proportion of subjects with clinically meaningful improvement in patient-reported 
outcomes (PROs) over time: pain visual analogue scale (VAS),* Functional Assessment of
Chronic Illness Therapy - Fatigue (FACIT-Fatigue), 36-Item Short Form Health Survey 
(SF-36v2; physical component score [PCS], mental component score [MCS], both PCS and 
MCS, individual domains), Lupus Quality of Life (LupusQoL) domain scores,*

Change from baseline in PROs over time: EuroQol 5-dimensional, 5-level questionnaire 
(EQ-5D-5L) index score and VAS score,* Work Productivity and Activity Impairment 
Questionnaire–Lupus (WPAI-Lupus) total and domain scores, LFA-REAL PRO*

Proportion of subjects with no worsening (defined as <10% worsening compared with
baseline) in Patient's Assessment of Pain VAS over time*
Pharmacokinetics and Immunogenicity 

Summary of ustekinumab concentrations and immunogenicity 

PK-efficacy relationships for primary and selected key secondary endpoints

If data allow, population PK and population PK-PD analysis on primary and/or selected key 
secondary efficacy endpoints
Biomarkers

Predictive biomarkers of treatment response over time
Refer to Section 9 for evaluations and definitions related to study endpoints.
* Results of these exploratory assessments will be summarized in a separate report.
2.3.
Hypothesis
Treatment with ustekinumab is superior to placebo in subjects with active SLE despite receiving 
one or more standard-of-care treatments as measured by the proportion of subjects achieving an 
SRI-4 composite response at Week 52.  
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
CNTO1275SLE3001
is 
a 
multicenter,
randomized, 
double-blind, 
placebo-controlled, 
parallel-group, study to evaluate the efficacy, safety, and tolerability of ustekinumab in subjects 
between 16 (unless restricted by local requirements) and 75 years of age, inclusive, with active, 
autoantibody-positive SLE despite receiving one or more standard-of-care treatments (ie, 
immunomodulators, antimalarial drugs, and glucocorticoids; see Section 8). The total duration of 
the study is up to 182 weeks, consisting of 3 study periods: a ≤6-week screening period 
(re-screening is permitted once per subject), a 52-week double-blind period, and a 124-week
extension period.


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Unscheduled visits are permitted for cause, such as safety events, worsening SLE disease activity
or flare, or to receive SC study agent during the extension period for those subjects who cannot 
self-administer at home.
Approximately 500 subjects will be randomly assigned in a 3:2 ratio to receive either 
ustekinumab or placebo with the following treatment administrations (see Section 6 for further 
details of study agent administration):

Week 0: Body weight-range based IV administration of ustekinumab (~6 mg/kg) or placebo

Week 8 and every 8 weeks (q8w) thereafter through Week 48: SC administration of 90 mg
ustekinumab or placebo

Subjects entering the extension period:
SC administration of 90 mg ustekinumab q8w 
through Week 160
A placebo comparator (in addition to standard-of-care background therapy) will be used in this 
study through Week 52 to allow for blinded, placebo-controlled evaluation of the long-term 
efficacy and safety of ustekinumab in subjects with SLE. 
Subjects will be stratified by race, presence of lupus nephritis, and baseline SLE medications and 
SLEDAI-2K score (a combined factor), using permuted block central randomization. Baseline 
SLE medications and SLEDAI-2K score will be stratified as follows: 

High dose medications and SLEDAI-2K ≥10 

High dose medications and SLEDAI-2K <10  

Medium dose medications and SLEDAI-2K ≥10 

Medium dose medications and SLEDAI-2K <10 
High dose medications are defined as:  ≥15 mg/wk methotrexate (MTX), or ≥1.5 mg/kg/day 
azathioprine/6 mercaptopurine (AZA/6-MP), or ≥1.5 g/day mycophenolate mofetil (MMF)/
≥1.125 g/day mycophenolic acid (MPA), and/or ≥15 mg/day prednisone or equivalent.
Medium dose medications are defined as:  <15 mg/wk MTX, or <1.5 mg/kg/day AZA/6-MP, or 
<1.5 g/day MMF/<1.125 g/day MPA, and/or <15 mg/day prednisone or equivalent. 
Diagnosis of lupus nephritis will be considered valid if based upon the opinion of a nephrologist 
or rheumatologist who has excluded other potential causes of renal disease. For stratification 
purposes, presence of lupus nephritis will be defined as clinical evidence that is consistent with 
lupus nephritis, including one or more of the following:
a.
Proteinuria defined as: >0.5 grams protein or greater than 3+ protein by dipstick. A spot 
urine creatinine/protein ratio > 0.5 can be substituted for the 24-hour protein measurement.


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OR
b. The presence of cellular casts on microscopic analysis of spun urine (including red blood 
cells, hemoglobin, granular, tubular, or mixed casts). Active urinary sediment (>5 red blood 
cells/high-power field [RBC/hpf]) in the absence of menstruation or infection, or >5 white 
blood cells [WBC]/hpf in the absence of infection, or cellular casts limited to RBC or WBC 
casts) can be substituted for cellular casts.
OR
c.
Histologic evidence compatible with lupus nephritis on renal biopsy demonstrating immune 
complex-mediated glomerulonephritis as defined by International Society of Nephrology 
(ISN) and the Renal Pathology Society (RPS) 2003 Classification Criteria as follows:

Class I – Minimal mesangial lupus nephritis

Class II – Mesangial proliferative lupus nephritis

Class III – Focal lupus nephritis (active and chronic; proliferative and sclerosing)

Class IV – Diffuse lupus nephritis (active and chronic; proliferative and sclerosing; 
segmental and global)

Class V – Membranous lupus nephritis

Class VI – Advanced sclerosing lupus nephritis
Clinical and laboratory evidence of disease activity will be evaluated and adjudicated by blinded
external reviewers to verify that subjects are meeting inclusion/exclusion criteria and to ensure 
data quality throughout the study. 
The primary efficacy analysis will be performed after all subjects have completed Week 52 
efficacy assessments (or discontinued) with additional secondary endpoints to be analyzed at 
Week 24 and Week 52. After Week 52, eligible subjects (see Section 9.1.4) may enter the 
extension period.
Every reasonable effort should be made to keep concomitant medications stable as defined in the 
protocol (see Section 3.2.4 for information on glucocorticoid tapering). Beginning at the 
screening visit, all concomitant therapies and all changes in concomitant therapies should be 
recorded throughout the study.
Subjects with cutaneous disease who provide consent will participate in medical photography to
evaluate skin photographs at participating study sites.
Database locks are planned at Week 52, Week 104, and at Week 176. The end of the study is 
defined as the last follow-up assessment (16 weeks after the last dose of study agent is 
administered at Week 160) for the last subject. 
An external, independent DMC will be commissioned for this study. Refer to Section 11.11 for 
further details.


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A futility analysis will be carried out 24 weeks after approximately 50% of the planned subjects 
have been randomized. The analysis will be performed in an unblinded fashion by the
independent DMC based primarily on Week 24 efficacy data. Additional data available at the 
time of the futility analysis (eg, other endpoints, other time points) may also be considered. The 
details of the futility analysis will be included in the Statistical Analysis Plan (SAP).
A diagram of the study design is provided in Figure 1.


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Figure 1:
Schematic Overview of the Study
Study agent administered at study site
Double-Blind Period
Extension Period
Ustekinumab self-administered
DBL
DBL                               
DBL
Week
0
4
8
12
16    20
24    28    32    36   40    44    48    52    56    64    72    80
88    96    104    112    120    128    136    144    152    160       176 
Screen
≤ 6 wk
Study Agent 
Administration
R
Placebo (N=200)  IV Wk 0, SC q8 Wks
Safety FP
Ustekinumab (N=300)  IV Wk 0, 90 mg SC q8 Wks
Safety FP
Wk 52                                                
Primary Endpoint:        
SRI-4 Response
GC Tapering
GC and Immunosuppressant Tapering Permitted
Ustekinumab 90 mg SC q8 Wks
Ustekinumab 90 mg SC q8 Wks
= Randomization        = SC Study Agent Administration        = ~ 6 mg/kg IV Load       
= Study Visit     GC = Glucocorticoids      FP = Follow-up Period      DBL = Database Lock
R
Wk 176                                    
End of Study


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3.2.
Study Design Rationale
3.2.1.
Study Population
The target population for this study is subjects between the ages of 16 and 75 years with active 
SLE according to SLICC criteria SLEDAI-2K13 score ≥6, despite receiving one or more 
standard-of-care treatments (eg, immunomodulators, antimalarial drugs, and/or glucocorticoids).
The target population will include subjects with disease manifestations primarily affecting the 
skin and joints (most commonly observed disease manifestations in SLE), mucosal ulcers, renal, 
hematologic, or other disease features. Subjects with less common disease manifestations such as 
nonprogressive and stable, renal and neuropsychiatric disease will also be permitted to enroll. In 
addition, subjects must have at least 1 positive autoantibody test (antinuclear antibodies [ANA], 
anti-dsDNA antibodies, and/or anti-Smith antibodies) observed during screening, as well as a 
well-documented positive autoantibody test in their medical history. Subjects must also have at 
least 1 BILAG A and/or 2 BILAG B domain scores observed during screening. Additionally,
subjects must have a CLASI activity score of at least 4 (excluding diffuse non-inflammatory 
alopecia) or at least 4 joints with pain and signs of inflammation (active joints) at screening, or at
Week 0, or both. In addition, subjects must have a clinical SLEDAI-2K score (excluding 
laboratory results and lupus headache) ≥4 at Week 0, prior to first administration of study agent. 
Adolescent subjects 16 to <18 years of age will be permitted to enroll. Within the adolescent 
SLE disease population, there is a large unmet need for new, alternative treatments that can 
provide significant benefit without incurring a high safety risk. Adolescent SLE subjects will 
therefore undergo study assessments similar to those for the adult study population since they are 
generally “adult-like” in their clinical presentation and treatment paradigm. One notable 
exception is that both parental (or legal representative) consent and subject assent will be 
obtained in subjects who are not considered to be adults (per local requirements) (Section 4.1.1). 
Of note, ustekinumab has been evaluated in the pediatric population for various indications (a 
total of 110 subjects ≥12 to <18 years old). Ustekinumab was safe and well tolerated in this
population, which had exposure similar to the adult population, and the safety profile was similar 
to that seen in studies in adults. Ustekinumab has been approved by the US FDA for the 
treatment of adolescent patients with moderately to severely active plaque psoriasis (CADMUS 
study).
The safety and efficacy of ustekinumab has also been evaluated in 310 subjects who were 
65 years or older. No major age-related differences in ustekinumab PK were observed in clinical 
studies that included geriatric subjects. In addition, no differences in safety or efficacy were 
observed between subjects older than 65 years and those younger than 65 years.25 However, 
subjects older than 75 years are excluded because the benefit/risk ratio is less favorable in this 
population:  serious infections, including sepsis, are a major cause of morbidity and mortality in 
older SLE patients17,48 and, in many older SLE patients, symptoms are related to the 
accumulation of chronic damage rather than active disease, which has often resolved.17


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The incidence and prevalence of SLE varies globally and in certain subpopulations (eg, Asians, 
those of African descent, and Hispanics are disproportionately affected by the disease compared
with those of European descent).27 In addition, treatment response to certain background 
medications and potentially investigational agents may differ between different racial and ethnic 
groups. Thus, this study will investigate the safety and efficacy of ustekinumab in a racially and 
ethnically diverse population with SLE. In order to evaluate the safety and efficacy of 
ustekinumab in a broad study population, the target population will include subjects from across 
the globe (eg, Asia-Pacific region, North America, Europe, Latin America).
3.2.2.
Blinding, Control, Study Phase/Periods, Treatment Groups
Treatment groups are outlined in Section 3.1. A placebo comparator (in addition to standard-of-
care background therapy) will be used in a 52-week, placebo-controlled period in order to 
comply with health authority guidance regarding appropriate testing of new compounds in the 
treatment of SLE, as well as to allow for controlled evaluation of long-term endpoints such as 
sustained response, disease flares, evaluation of organ systems that may take longer to manifest 
change, and measures of low disease activity and remission, and reductions in glucocorticoid 
dose (see Sections 3.2.4 and 8.1.2 for guidelines on glucocorticoid tapering). 
Permuted block allocation will be used to minimize bias in the assignment of subjects to 
treatment groups, to increase the likelihood that known and unknown subject attributes 
(eg, demographic and baseline disease characteristics; Section 5.1) are evenly balanced across 
treatment groups, and to enhance the validity of statistical comparisons across treatment groups. 
Blinded treatment through Week 52, will be used to reduce potential bias during data collection 
and evaluation of clinical endpoints. See Section 5 for further details on randomization and 
blinding.
3.2.3.
Biomarker Collection
Biomarker samples will be collected at selected sites to evaluate the mechanism of action of 
ustekinumab to help explain interindividual variability in clinical outcomes, or to help identify 
population subgroups that respond differently to ustekinumab. The biomarker analyses will also 
evaluate the PD of ustekinumab in SLE and will aid in evaluating the drug-clinical response 
relationship.
Biomarker samples may be used to enable the development of safer, more effective, and 
ultimately individualized therapies for SLE.
3.2.4.
Glucocorticoid Tapering
Gradual tapering of oral glucocorticoid dosing after Week 24 and through Week 40 will be used 
to evaluate the steroid-sparing potential of ustekinumab. Stabilizing the glucocorticoid dose 
between Weeks 40 and 52 will allow evaluation of maintained reductions in glucocorticoid
therapy on SLE disease activity (see Section 8.1.2, Glucocorticoid Therapy).


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3.2.5.
Patient-Reported Outcomes
Patient-reported outcomes on pain, fatigue, lupus disease-specific and general health-related 
quality of life, and work productivity (WPAI) will be assessed. In addition, evaluation of a subset 
of subjects using a novel VAS-based assessment tool (LFA-REAL; Section 9.2.13) is planned. 
4.
SUBJECT POPULATION
Screening for eligible subjects must be performed no more than 6 weeks prior to the 
randomization visit (Week 0). Approximately 500 subjects with disease manifestations primarily 
involving the skin and joints who may also have renal, hematologic or other disease features will
be enrolled.
The inclusion and exclusion criteria for enrolling subjects in this study are described in
Sections 4.1.1 and 4.1.2, respectively. If there is a question about the inclusion or exclusion 
criteria below, the Investigator must consult with the appropriate sponsor representative and 
resolve any issues before enrolling a subject in the study. Waivers are not allowed.
4.1.
Main Study
4.1.1.
Inclusion Criteria
Each potential subject must satisfy all the following criteria to be enrolled in the study:
1.
Be male or female (according to their reproductive organs and functions assigned by 
chromosomal complement)
2.
Subjects who are considered to be adults legally (per local requirements) must sign an 
informed consent form (ICF) indicating that he or she understands the purpose of, and 
procedures required for, the study and is willing to participate in the study. Subjects 
who are not considered to be adults legally (per local requirements) must have 
parent(s) (preferably both if available or as per local requirements) (or their legally 
acceptable representative) sign an ICF indicating that he or she understands the purpose 
of, and procedures required for, the study and is willing to allow the child to participate 
in the study. Assent is also required of children capable of understanding the nature of 
the study as described in Section 16.2.3, Informed Consent.
3.
Be willing and able to adhere to the prohibitions and restrictions specified in this 
protocol.
4.
Be between 16 (unless restricted by local requirements) and 75 years of age, inclusive.
5.
Had a diagnosis of SLE made or confirmed by a physician (such as a rheumatologist, 
nephrologist, internal medicine specialist, or dermatologist) experienced in the 
treatment of SLE.
6.
Criterion modified per Amendment 2:


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6.1
Had a documented medical history (ie, met at least 1 of the bulleted criteria 
below) that subject met the SLICC classification criteria for SLE41 at least 
3 months prior to first dose of study agent:
o
Met a total of at least 4 SLICC criteria, including at least 1 clinical and at 
least 1 immunologic (Attachment 1).
o
Had a diagnosis of lupus nephritis, confirmed by renal biopsy and at least 1 
of the following autoantibodies: ANA or anti-dsDNA.
7.
Have at least 1 well-documented (subject file, referring physician letter, or laboratory 
result) unequivocally positive test in medical history for at least 1 of the following 
autoantibodies:  ANA, anti-dsDNA, and/or anti-Smith
8.
Have at least 1 unequivocally positive autoantibody test including ANA (≥1:80 titer by 
Central Lab test) and/or anti-dsDNA antibodies and/or anti-Smith antibodies detected 
during screening.
9.
Have at least 1 BILAG A and/or 2 BILAG B domain scores observed during screening.
10.
Have a CLASI activity score of at least 4 (excluding diffuse non-inflammatory 
alopecia) or at least 4 joints with pain and signs of inflammation (active joints) at 
screening or at Week 0, or both.
11.
Demonstrate active disease based on SLEDAI-2K score ≥6 observed during screening. 
Must also have SLEDAI-2K ≥4 for clinical features (ie, SLEDAI-2K score excluding 
headache, and laboratory abnormalities) present at Week 0 prior to randomization.
12.
Must be receiving one or more of the following protocol-permitted, systemic standard-
of-care treatments:
a)
Oral glucocorticoids (average daily dose ≤20 mg of prednisone or equivalent) 
for ≥6 weeks and at a stable dose ≥4 weeks prior to first dose of study agent
o
If currently not using oral glucocorticoids, must not have received them 
for ≥6 weeks prior to the first dose of study agent.
b)
Antimalarials (≤250 mg/day chloroquine, ≤400 mg/day hydroxychloroquine, 
and/or ≤100 mg/day quinacrine) for ≥12 weeks and at a stable dose for 
≥6 weeks prior to first dose of study agent
c)
If using one or more of the following immunomodulatory drugs, must be 
receiving for ≥12 weeks and be on a stable dose for ≥6 weeks prior to first 
dose of study agent:
o
MMF ≤2 g/day


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o
MPA ≤1.5 g/day
o
AZA /6-MP ≤2 mg/kg/day; up to 100 mg/day for subjects weighing 
≤50 kg 
o
Oral 
MTX 
≤25 mg/Week or 
SC 
or 
intramuscular
(IM)
MTX 
≤20 mg/Week with concomitant folic acid or folinic acid
If the subject is using concomitantly 2 or more of the immunomodulatory 
drugs listed above (MMF, MPA, AZA, 6-MP, MTX), the suitability of the 
subject to participate in the study must be discussed with the medical 
monitor and/or sponsor before the subject is randomized.
13.
Regular or as needed treatment with the following agents with no changes in dose or 
frequency is permitted as follows:
a)
Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor 
blockers (ARBs) for ≥2 weeks prior to first dose of study agent
b)
Nonsteroidal anti-inflammatory drugs (NSAIDs) or other analgesics for 
≥2 weeks prior to first dose of study agent
c)
Permitted topical medications for cutaneous disease (Section 8.1.6) for 
≥4 weeks prior to first dose of study agent
o
Must not be using any prohibited topical medications (such as tacrolimus, 
pimecrolimus, dapsone, thalidomide), with the exception of cyclosporine 
A for ophthalmic use 
14.
Contraceptive use by men or women should be consistent with local regulations 
regarding the use of contraceptive methods for subjects participating in clinical studies.
Typical use failure rates may differ from those when used consistently and correctly. 
Use should be consistent with local regulations regarding the use of contraceptive 
methods for subjects in clinical studies.
Before randomization, a woman must be either:
a.
Not of childbearing potential, defined as:
1)
Premenarchal: A premenarchal state is one in which menarche has not yet 
occurred.
2)
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; however, in the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.


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3)
Permanently sterile: Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, bilateral tubal occlusion/ligation procedures, and 
bilateral oophorectomy.
or
b. Of childbearing potential:
1)
Practicing a highly effective method of contraception (failure rate of <1% per 
year when used consistently and correctly) consistent with local regulations 
regarding the use of birth control methods for subjects participating in clinical 
studies: eg, hormone contraception associated with inhibition of ovulation; 
intrauterine device (IUD); intrauterine hormone-releasing system (IUS);
bilateral tubal occlusion; vasectomized partner; 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 agent. 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 subject.
2)
Agrees to remain on a highly effective method of contraception throughout 
the study and for at least 16 weeks after the last dose of study agent.
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.
15.
A woman of childbearing potential must have a negative urine pregnancy tests
(-human chorionic gonadotropin [-hCG]) obtained during screening and at Week 0 
before the first dose of study agent.
16.
A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during the study and for 4 months after receiving the last dose of study 
agent.
17.
A man who is sexually active with a woman of childbearing potential and has not had a 
vasectomy must agree to use a barrier method of birth control eg, either condom with 
spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm 
or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository. A man who 
is sexually active with a woman who is pregnant must use a condom and all men must 
not donate sperm during the study and for 20 weeks after receiving the last dose of 
study agent.


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18.
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 subjects who have a history of latent TB and are currently receiving 
treatment for latent TB, will initiate treatment for latent TB prior to first 
administration of study agent, or have documentation of having completed 
appropriate treatment for latent TB within 3 years prior to the first 
administration of study agent. It is the responsibility of the Investigator to 
verify the adequacy of previous anti-tuberculous treatment and provide 
appropriate documentation.
b. Have no signs or symptoms suggestive of active TB upon medical history 
and/or physical examination.
c.
Have had no recent close contact with a person with active TB or, if there has 
been such contact, will be referred to a physician specializing in TB to undergo 
additional evaluation and, if warranted, receive appropriate treatment for latent 
TB prior to the first administration of study agent.
d. Within 6 weeks prior to the first administration of study agent, has a negative 
QuantiFERON®-TB test result, or have
a newly identified positive 
QuantiFERON®-TB test result in which active TB has been ruled out and for 
which appropriate treatment for latent TB has been initiated prior to the first 
administration of study agent. Within 6 weeks prior to the first administration 
of study agent, a negative tuberculin skin test (Attachment 2), or a newly 
identified positive tuberculin skin test in which active TB has been ruled out 
and for which appropriate treatment for latent TB has been initiated prior to the 
first administration of study agent, is additionally required if the 
QuantiFERON®-TB test is not approved/registered in that country or the 
tuberculin skin test is mandated by local health authorities.
i.
A subject whose first QuantiFERON®-TB test result is indeterminate 
should have the test repeated. If the second QuantiFERON®-TB test 
result is also indeterminate, the subject may be enrolled without 
treatment for latent TB, if active TB is ruled out, their chest radiograph 
shows no abnormality suggestive of TB (active or old, inactive TB), and 
the subject has no additional risk factors for TB as determined by the 
Investigator. This determination must be promptly reported to the 
Sponsor’s medical monitor and recorded in the subject's source 
documents and initialed by the Investigator.
ii.
The QuantiFERON®-TB test and the tuberculin skin test are not 
required at screening for subjects with a history of latent TB and 
ongoing treatment for latent TB or documentation of having completed 
adequate treatment as described above; Subjects with documentation of 


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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 (consistent 
with local regulations), taken within 3 months prior to the first administration of 
study agent and read by a qualified radiologist or pulmonologist, with no 
evidence of current, active TB or old, inactive TB.
19.
Criterion modified per Amendment 2:
19.1
Subjects must have laboratory test results within the following parameters at 
screening:
Hemoglobin
≥8.0 g/dL
(SI: 80 g/L)
Lymphocytes
≥0.5 x 103/L
(SI: ≥0.5 GI/L)
Neutrophils
≥1.0 x 103/L
(SI: 1.0 GI/L)
Platelets
≥75 x 103/L
(SI: 75 GI/L)
Serum creatinine
≤1.8 mg/dL
(SI: 159 mol/L)
In addition, the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
levels must be within 3 x the upper limit of normal (ULN) range for the laboratory 
conducting the test. 
A one-time repeat of these screening laboratory tests (eg, hemoglobin, lymphocytes, 
neutrophils, platelets, serum creatinine, AST, ALT, ANA, anti-dsDNA, anti-Smith) is 
allowed during the 6-week screening period and the Investigator may consider the 
subject eligible if the previously exclusionary laboratory test result is within an 
acceptable range per eligibility criteria on repeat testing at the central laboratory. A 
screening laboratory test(s) 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.
Subjects 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 subject’s source documents 
and initialed by the Investigator. Subjects with Common Terminology Criteria for 
Adverse Events (CTCAE) Grade 3 or 4 laboratory abnormalities must be discussed 
with the medical monitor and/or sponsor to determine eligibility for enrollment.


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4.1.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study:
1.
Criterion modified per Amendment 2
1.1
Has any unstable or progressive manifestation of SLE (lupus cerebritis, optic 
neuritis, transverse myelitis, psychosis, uncontrolled seizures, systemic 
vasculitis, end-stage renal disease, severe or rapidly progressive Class III or IV 
glomerulonephritis, isolated Class V lupus nephritis [ie, without coexistent 
Class I, II, III, or IV nephritis], Class VI lupus nephritis, pulmonary 
hemorrhage, myocarditis) that is likely to warrant escalation in therapy beyond 
permitted background medications. Subjects requiring renal hemodialysis or 
peritoneal dialysis are also excluded.
2.
Has other inflammatory diseases that might confound the evaluations of efficacy, 
including but not limited to rheumatoid arthritis (RA), PsA, RA/lupus overlap, 
psoriasis, Crohn’s disease, or active Lyme disease.
3.
Is pregnant, nursing, or planning a pregnancy or planning to father a child while 
enrolled in the study or within 4 months after receiving the last administration of study 
agent.
4.
Is an employee of the Investigator or study site (ie, personnel to whom the 
Investigator has delegated a role or responsibility for conducting the study), 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.
5.
Lives in an institution on court or authority order, unless permitted by local 
regulations.
Concomitant or previous medical therapies received:
6.
Has received systemic immunomodulatory agents (eg, leflunomide, tacrolimus, 
sirolimus, mizoribine) other than those described in inclusion criteria within 3 months 
prior to the first dose of study agent (Section 8.1.7). Glucocorticoids are not included 
in this criterion; see Section 8.1.2 regarding glucocorticoid use.
7.
Has used oral cyclophosphamide within 90 days or IV cyclophosphamide within 
180 days of starting screening.


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8.
Criterion modified per Amendment 2:
8.1
Exclusions for treatment with B-cell targeted therapies (eg, belimumab, 
rituximab, epratuzumab)* are as follows:
a.
Treatment with a single B-cell targeted therapy within 3 months prior to first 
dose of study agent.
b. Treatment with >1 previous B-cell targeted therapy within 6 months prior to 
first dose of study agent.
c.
Treatment with B-cell depleting therapy (eg, rituximab, epratuzumab) within 
12 months prior to first dose of study agent or have evidence of continued 
B-cell depletion following such therapy.
*If a subject has received one or more B-cell targeted therapies, the length of time 
required before administering the first dose of study agent should be whichever is 
the longest applicable washout period.
9.
Has ever received ustekinumab.
10. Has received prior immunomodulatory biologic therapy not described in Section 8.1.7
such as
tocilizumab, alefacept, efalizumab, natalizumab, abatacept, anakinra,
brodalumab, secukinumab, ixekizumab, or agents whose mechanism of action targets 
tumor necrosis factor alpha (TNFα), IL-1, IL-2, IL-6, IL-17, or IFN pathways, less 
than 5 half-lives or 3 months, whichever is longer, prior to first dose of the study 
agent.
11. Has received adrenocorticotropic hormone (ACTH) administered by injection within 
1 month prior to the first administration of study agent.
12. Criterion modified per Amendment 2:
12.1
Has received topical cream/ointment preparations of cyclosporine A (except 
for ophthalmic use), high-potency topical glucocorticoids (World Health 
Organization 
[WHO] 
encoding 
dictionary), 
or 
other 
topical 
immunomodulatory agents (such as tacrolimus, pimecrolimus) within 4 weeks 
prior to the first administration of study agent.
13. Has received an investigational drug that is not previously defined in other exclusion 
criteria (including investigational vaccines or other medications specified in 
Section 4.2) within 5 half-lives or 3 months, whichever is longer, or used an invasive 
investigational medical device within 3 months before the planned first dose of study 
agent, or is currently enrolled in an interventional study.


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14. Is currently receiving venom immunotherapy (honeybee, wasp, yellow jacket, hornet, 
or fire ant).
15. Subjects likely to require multiple courses of systemic steroids (eg, uncontrolled 
asthma, uncontrolled chronic obstructive pulmonary disease) for reasons other than 
SLE should be excluded from study participation.
16. Has received epidural, IV, IM, intra-articular (IA), intrabursal, or intralesional 
administration of glucocorticoids within 6 weeks prior to the first administration of 
study agent.
17. Use of complementary therapies, including traditional/Chinese medicines, herbs, 
ointments, or procedures (eg, acupuncture), that have the potential to activate (eg, 
echinacea) or inhibit (eg, Tripterygium wilfordii Hook F) the immune system is 
prohibited within 6 weeks of the first administration of study agent. In addition, use of 
complementary therapies, including traditional/Chinese medicines and herbs, that 
have the potential to interact with antithrombotic agents (eg, St. John’s Wort) is 
prohibited within 6 weeks of the first administration of study agent in those taking 
antithrombotic agents. Any questions or concerns with the use of these therapies 
should be discussed with the study sponsor and/or medical monitor.  
NOTE:  See also Exclusion 43 and Exclusion 44.
Infections or predisposition to infections:
18. Has had a Bacille Calmette-Guérin (BCG) vaccination within 12 months of screening.
19. Has received a live virus or live bacterial vaccination within 16 weeks prior to the first 
administration of study agent.
20. Has a history of active granulomatous infection, including histoplasmosis, or 
coccidioidomycosis. Refer to Section 4.1 for information regarding eligibility with a 
history of latent TB.
21. Has a chest radiograph within 3 months prior to the first administration of study agent
that shows an abnormality suggestive of a malignancy or current active infection, 
including TB. Radiographic findings such as pulmonary nodules should be evaluated 
by an experienced radiologist and/or pulmonologist to determine whether the 
presentation is suggestive of active infection or malignancy and final assessment 
documented by the Investigator prior to randomization.
22. Has had a nontuberculous mycobacterial infection or opportunistic infection (eg, 
cytomegalovirus, pneumocystosis, aspergillosis).


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23. 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.
24. Has a history of human immunodeficiency virus (HIV) antibody positive, or tests 
positive for HIV at screening.
25. Has a hepatitis B infection. Subjects must undergo screening for hepatitis B virus 
(HBV; Attachment 4). At a minimum, this includes testing for HBsAg (HBV surface 
antigen), anti-HBs (HBV surface antibody), and anti-HBc total (HBV core antibody 
total).
26. Is seropositive for antibodies to hepatitis C virus (HCV), unless has 2 negative HCV 
RNA test results 6 months apart prior to screening and has a third negative HCV RNA 
test result at screening. 
27. 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 CNS zoster infection.
28. Within 2 months prior to first administration of study agent, 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.
Concurrent medical conditions or past medical history and procedures:
29. Has a history or suspected occurrence of drug-induced lupus.
30. Has inherited complement deficiency or combined variable immunodeficiency.
31. Has urinary protein level of >4 g/day or protein/creatinine ratio estimating >4g/day 
equivalent proteinuria.
32. Has a history of catastrophic antiphospholipid syndrome (APS). Subjects with a 
history of non-catastrophic APS must be adequately controlled with anticoagulation 
and/or anti-platelet therapy in accordance with local guidelines. The suitability of the 
subject to participate in the study must be discussed with the medical monitor and/or 
sponsor before the subject is randomized
33. Has a known hypersensitivity to human immunoglobulin (Ig) proteins (eg, IV Ig).


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34. Has known allergies, hypersensitivity, or intolerance to ustekinumab or its excipients 
(see Section 14.1 and the ustekinumab Investigator’s Brochure).
35. Any major illness/condition or evidence of an unstable clinical condition (eg, renal, 
hepatic, 
hematologic, 
gastrointestinal, 
endocrine, 
pulmonary, 
immunologic, 
psychiatric), 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. 
36. Has had major surgery, (eg, requiring general anesthesia) within 1 month before 
screening, or will not have fully recovered from surgery, or has major surgery (eg, 
requiring general anesthesia) planned during the time the subject is expected to 
participate in the study or within 1 month after the last dose of study agent 
administration.
Note: Subjects with planned minor surgical procedures to be conducted under local 
anesthesia may participate after discussion with the medical monitor and/or sponsor.
37. Has a transplanted organ (except for a corneal transplant performed >3 months prior 
to first administration of study agent).
38. Uses semipermanently attached wigs that would interfere with scoring of cutaneous 
disease.
39. Has or has had a substance abuse (drug or alcohol) problem within the previous 
3 years.
40. Is unwilling or unable to undergo multiple venipunctures because of poor tolerability 
or lack of easy venous access.
Malignancy or increased potential for malignancy:
41. 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 agent administration and 
carcinoma in situ of the cervix that has been documented to be surgically cured). 
42. 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, or 
history of monoclonal gammopathy of undetermined significance.


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Additional concomitant or previous medical therapies received:
43. Use of IV gamma globulin, apheresis therapy (including but not limited to 
plasmapheresis, photopheresis, leukocytapheresis), or immunoadsorption is prohibited 
within 6 months prior to the first administration of study agent and within 4 months 
after receiving the last administration of study agent.
44. Has ever received stem cell transplantation (including hematopoietic stem cell 
transplantation and mesenchymal stem cell transplantation).
45. Has undergone a splenectomy.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
A subject’s eligibility for study entry, with respect to SLE-related features, will be reviewed by 
independent medical reviewers in addition to the study sponsor before a subject will be approved 
for randomization. If a subject's clinical status changes (including any available laboratory 
results or receipt of additional medical records) after screening but before the first dose of study 
agent is given such that he or she no longer meets all eligibility criteria, then the subject should 
be excluded from participation in the study. Section 17.4 describes the required documentation to 
support meeting the enrollment criteria. The Sponsor reserves the right to discontinue the subject 
for any operational or safety reasons.
4.2.
Prohibitions and Restrictions 
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions to be eligible for participation:
1.
Refer to Section 8 PRESTUDY AND CONCOMITANT THERAPY for additional 
details regarding therapies that are prohibited and restricted during the study.
2.
Agree to follow all requirements that must be followed during the study as described 
in the Inclusion and Exclusion Criteria, Sections 4.1 and 4.1.2 (eg, contraceptive 
requirements).
3.
Agree to avoid excess exposure to natural or artificial (tanning beds, phototherapy, 
etc) sunlight. In addition, it is advised that subjects maintain their typical use of sun 
protective measures (such as a hat, sunglasses, protective clothing, sunscreen). The 
time period for this requirement is from the start of screening until the last dose of 
study agent has been received.
4.
Use of additional immunosuppressants or immunomodulators, other than those 
explicitly allowed in the inclusion/exclusion criteria (Section 4.1 and 4.1.2), are 
prohibited including but not limited to those listed in Section 8.1.7.


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5.
Must agree not to receive a live virus or live bacterial vaccination during the study. 
Subjects must also agree not to receive BCG vaccination for 12 months after last dose 
of study agent, or any other live vaccine for 16 weeks after receiving the last 
administration of study agent.
6.
Must agree not to receive an investigational medical device or an investigational drug 
other than study agent for the duration of this study.
7.
Skin concealers or topical tan preparations or nonpermanent tattoos should be avoided 
within 48 hours before a study visit due to their potential to obscure skin disease 
activity.
8.
Subjects should avoid use of any wigs or hair attachments that cannot be readily 
removed for scalp examination. 
5.
TREATMENT ALLOCATION AND BLINDING
5.1.
Treatment Allocation
Procedures for Randomization and Stratification
Permuted block central randomization will be implemented in this study using an interactive web 
response system (IWRS). Subjects will be randomly assigned to 1 of 2 treatment groups based on 
a computer-generated randomization schedule prepared before the study under the supervision of 
the sponsor; however, the sponsor will not be privy to the actual randomization schedule.
Permuted block randomization with the following stratification factors will be used:

race (white, black, all other categories combined)

presence of lupus nephritis at baseline (Y/N)

composite of baseline SLE medications and SLEDAI score (high medications and SLEDAI 
≥10, high medications and SLEDAI <10, medium medications and SLEDAI ≥10, medium 
medications and SLEDAI <10)

Subjects will be defined as receiving high medications if they are receiving any of the 
following: ≥15 mg/wk MTX, or ≥1.5 mg/kg/day AZA/6-MP, or ≥1.5 g/day 
MMF/1.125 g/day MPA, and/or ≥15 mg/day prednisolone or equivalent. 

Subjects receiving baseline medication(s) for SLE that do not meet the criteria above 
for the category of “high” medications would be included in the “medium” medication 
category.   
Based on the computer-generated randomization schedule, the IWRS will assign a unique 
treatment code, which will dictate the treatment assignment and matching study agent kit for 
each subject. A detailed description of the permuted block allocation will be included in the 
SAP.


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5.2.
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 subject in emergency situations where unblinding is deemed necessary.
Data that may potentially unblind the treatment
assignment
(eg, study agent
serum 
concentrations, anti-ustekinumab antibodies, treatment 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 database lock and unblinding.
The blind will be maintained during the extension period until the last subject completes the 
Week 52 evaluations and the 52-week database is locked. (The DMC will review unblinded data 
and interim analysis results; see Section 11.10 and Section 11.11). At the Week 52 DBL, the data 
will be unblinded for analysis to some sponsor personnel while subjects are still participating in 
the study. Identification of sponsor personnel who will have access to the unblinded subject-level 
data will be documented prior to unblinding. Investigative study sites and subjects will remain 
blinded to initial treatment assignment until after the final database is locked.
Under normal circumstances, the blind should not be broken until all subjects have completed 
the study and the database is finalized. The Investigator may in an emergency determine the 
identity of the study agent by contacting the IWRS. While the responsibility to break the
treatment assignment 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 and reason for the unblinding must be 
documented by the IWRS, in the appropriate section of the electronic case report form (eCRF), 
and in the source document. The documentation received from the IWRS indicating the code 
break must be retained with the subject's source documents in a secure manner.
Subjects who have had their treatment assignment unblinded should continue to return for 
scheduled evaluations.
6.
DOSAGE AND ADMINISTRATION
Following randomization at Week 0, subjects assigned to the active treatment group will receive 
an initial, body weight-range based IV dose approximating 6 mg/kg of ustekinumab 
(ustekinumab 260 mg weight ≤55 kg; ustekinumab 390 mg weight >55 kg and ≤85 kg; 
ustekinumab 520 mg weight >85 kg), and subjects who were randomized to placebo will receive 
the comparable placebo treatment. Starting at Week 8, subjects will receive SC dosing with 
either placebo or ustekinumab 90 mg q8w through Week 48. Subjects entering the extension 
period will receive open-label ustekinumab 90 mg SC every 8 weeks through Week 160. 
Subjects and Investigators will be aware (open-label) that ustekinumab is the only study agent to 


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be administered during the extension period. However, subjects and Investigators will remain 
blinded to initial treatment assignment during the double-blind period for the duration of the 
study through the final DBL.
During the double-blind study period, subjects will be administered study agent at the study site. 
Subjects (or their designee) should be trained to administer study agent during the Week 56 and 
the Week 64 visit of the extension period. Additional training sessions are permitted per 
Investigator discretion. During the extension period beginning at Week 56 and continuing to 
Week 160 (and after appropriate and documented training), subjects will be encouraged to 
administer study agent at home; study agent will be provided to subjects for at-home 
administration. Subjects who are unwilling or unable to self-administer study agent at home (eg, 
because they are following standard practice in their country or because recommended storage 
conditions are not feasible) are permitted to receive SC injections at the study site or at home by 
a trained designee. See Section 14 for further instructions on the IV and SC administration of the 
study agent. Additional details may be provided in a pharmacy manual/study site investigational 
product (IP) and procedures manual that is provided separately (Section 15).
7.
TREATMENT COMPLIANCE
Study site personnel will maintain a log of all study agent administered. Drug supplies for each 
subject will be inventoried and accounted for. Study agent will be administered as an IV infusion 
by qualified study site personnel and the details of each administration will be recorded in the 
eCRF (including date, start and stop times of the IV infusion, and volume infused).
During the extension period, if a study visit occurs on the same day that a subject is due to 
receive his or her next dose, ustekinumab may be administered at the study site. Subjects who are 
unwilling or unable to self-administer ustekinumab (eg, because they are following standard 
practice in their country or because recommended storage conditions are not feasible) may return 
to the study side for additional visits to have study agent administered. Additional visits to the 
study site should be documented. Subjects will be required to document in their diaries study 
agent administered at home (see Section 6).
Additional details may be provided in a pharmacy manual/study site IP and procedures manual 
that is provided separately (Section 15).
8.
PRESTUDY AND CONCOMITANT THERAPY
Prestudy SLE therapies administered before the screening visit must be recorded at screening. 
Detailed information of prestudy topical and systemic SLE therapies including dosage and 
frequency of administration must be recorded. For any therapies that were discontinued, the 
reason for discontinuation (eg, non-response, loss of response, intolerance, safety concern, etc) 
should be documented. Modification of an effective preexisting therapy must not be made for the 
explicit purpose of entering a subject into the study.
Concomitant SLE therapies (and non-SLE concomitant therapies) must be recorded throughout 
the study beginning at Screening to 16 weeks after the last dose of study agent (any changes 


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must be recorded throughout the study). Concomitant therapies should also be recorded beyond 
16 weeks after the last dose of study agent only in conjunction with new or worsening AEs or
SAEs that meet the criteria outlined in Section 12.3.2.
All therapies (such as prescription or over-the-counter medications, including vaccines, vitamins, 
herbal supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, 
special diets, exercise regimens) different from the study agent must be recorded in the eCRF. 
Recorded information will include a description of the type of therapy, duration of use, dosing 
regimen, route of administration, and indication.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
Every reasonable effort should be made to keep concomitant medications stable to avoid 
introducing non-protocol medications for SLE disease activity through Week 52, or as specified 
in the following sections. Dose stabilization of all concomitant medications is required prior to 
randomization (Section 8.1). All medications must meet study protocol guidelines (see 
Sections 4.1 and 4.1.2, and Table 4 and Table 5, which outline permitted concomitant medication 
use and dose stabilization requirements prior to randomization and during the blinded study 
period). It is recommended that all other concomitant medications be maintained at stable doses 
through the 16-week safety follow-up for those discontinuing the study prematurely, or for those 
who do not enter the extension period. 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 subject’s medical record. Adjustments in 
concomitant therapies that do not comply with the study protocol guidelines may cause a subject 
to be considered a treatment failure for the primary and secondary endpoints through Week 52.
For subjects entering the extension period, concomitant therapy, including glucocorticoids, may 
be decreased per the Investigator's discretion. Permitted medications and medication adjustments 
during the extension period are outlined in Section 8.2 and Table 6. 
During the entire study, Investigators should consider whether increases in permitted background 
therapy due to increased SLE disease activity warrant discontinuation of study agent. This should 
be 
discussed 
with 
the 
medical 
monitor 
and/or 
sponsor.
If 
protocol-prohibited 
immunosuppressants (such as cyclosporine or tacrolimus), biologics (such as belimumab or 
rituximab), cytotoxic agents (such as cyclophosphamide), IV glucocorticoids, or average daily 
doses of oral glucocorticoids >40 mg (prednisone or equivalent) are initiated for severe, 
progressive, or unstable SLE disease activity, the subject should be discontinued from the study.
See Section 3.2.4 and Section 8.1.2 for management of glucocorticoid therapy during the blinded 
treatment period and the extension period.


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8.1.
Prestudy and Concomitant Medications Through Week 52
Table 4 outlines permitted concomitant medication use and dose stabilization requirements prior 
to randomization.
Table 4:
Permitted Concomitant Medications for SLE, the Minimum Stabilization Period before 
Randomization, and the Maximum Allowed Doses at Study Randomization 
Permitted Concomitant 
Medications for SLEa
Stabilization Period Prior 
to First Administration of 
Study Agent
Maximum Allowable Dose
Antimalarials (chloroquine, 
hydroxychloroquine, or 
quinacrine)
Treated for ≥12 weeks with 
stable dosing for ≥6 weeks
≤250 mg/day chloroquine (≤3 mg/kg/day)
≤400 mg/day hydroxychloroquine 
≤100 mg/day quinacrine
Oral glucocorticoids
Treated for ≥6 weeks with 
stable dosing ≥4 weeks
before the first dose of 
study agent. 
If not currently using oral 
glucocorticoids, must not 
have received them or any 
IV or IM glucocorticoid for 
≥6 weeks prior to the first 
administration of study 
agent
Equivalent to average daily dose of ≤20 mg
prednisone
NSAIDs and other analgesics
At least 2 weeks
No more than the usual marketed doses
approved in the country where the study is 
being conducted
Anti-hypertensive medications 
(ARBs or ACE inhibitors)
At least 2 weeks
No more than the usual marketed doses
approved in the country where the study is 
being conducted. 
Non-biologic immunomodulators:
Treated for ≥12 weeks with 
stable dosing for ≥6 weeks
Mycophenolate mofetil 
(MMF)
≤2 g/day
Mycophenolic acid (MPA)
≤1.5 g/day
Azathioprine (AZA)/
6-mercaptopurine (6-MP)
≤2 mg/kg/day (up to 100 mg/day for 
subjects weighing ≤50 kg)
Methotrexate (MTX)a
≤25 mg/week, oral; ≤20 mg/Week IM or SC
a
It is recommended that all subjects taking MTX in this study receive concomitant folate or folinic acid. 
Subjects receiving concomitant folate or folinic acid should have been treated with stable dosing for 
≥6 weeks before the first dose of study agent.
Table 5 summarizes the protocol requirements and any allowed changes in dosing for 
study-permitted SLE medications during the double-blind study period.


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Table 5:
Blinded Study Period - Protocol Requirements for Permitted Concomitant SLE Medications 
Permitted Concomitant 
Medications for SLEa
Study Dose at Entry 
Maximum Allowable Dose During Study
Antimalarials (chloroquine, 
hydroxychloroquine, or 
quinacrine; Section 8.1.1)
≤250 mg/day chloroquine (≤3 mg/kg/day)
≤400 mg/day hydroxychloroquine 
≤100 mg/day quinacrine 
Initiation of new antimalarial treatment is not permitted through Week 52.
Oral glucocorticoids 
(Section 8.1.2)b
Stable dosing equivalent to 
average daily dose of ≤20 mg
prednisone 
Through Week 6 - Dose adjustment 
(increase or decrease) of no more than 5 mg 
prednisone (or equivalent/day) to a 
maximum average daily dose of 25 mg is 
allowed
Week 6 through Week 12 - No increases 
in glucocorticoid dose are permitted. 
Decreases in glucocorticoid dose of no 
more than 5 mg prednisone (or 
equivalent/day) are permitted. Dose 
reduction to at or below the baseline dose is 
required in those subjects who increased 
glucocorticoid dose through Week 6. 
Week 12 through Week 24 - no 
adjustments in glucocorticoid dose are 
permitted.
Week 24 through 
Week 40 - glucocorticoid dose reductions 
not exceeding 10-20% of the current dose 
per week are strongly encouraged. 
Reason(s) for not tapering glucocorticoids 
should be documented. If possible, 
glucocorticoids should be tapered to an 
average daily dose of ≤7.5 mg prednisone 
(or equivalent) or at least a 50% reduction 
from baseline dose by Week 40
(Section 8.1.2).
Week 40 through Week 52 - no further 
adjustment of glucocorticoid dose is 
permitted
NSAIDs and other analgesics 
(Section 8.1.3)
Stable dosing no more than the usual marketed doses approved in the 
country where the study is being conducted. Notable changes in NSAID 
dosing to be recorded in concomitant medications. 
Anti-hypertensive medications 
(ARBs or ACE inhibitors) 
(Section 8.1.4)
No more than the usual marketed doses approved in the country where the 
study is being conducted. Initiation of new ARBs or ACE inhibitors is not 
permitted through Week 52. Substitution of ACE inhibitors for ARBs or 
ARBs for ACE inhibitors is permitted if medically necessary.


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Table 5:
Blinded Study Period - Protocol Requirements for Permitted Concomitant SLE Medications 
Permitted Concomitant 
Medications for SLEa
Study Dose at Entry 
Maximum Allowable Dose During Study
Non-biologic 
immunomodulators 
(Section 8.1.5):
Stable dosing through Week 52. Initiation 
of a new immunomodulator is not permitted 
through Week 52.
Mycophenolate mofetil 
(MMF)
≤2 g/day
Mycophenolic acid 
(MPA)
≤1.5 g/day
Azathioprine (AZA)/6-
mercaptopurine (6-MP)
≤2 mg/kg/day (up to 100 mg/
day for subjects weighing 
≤50 kg)
Methotrexate (MTX)c
≤25 mg/week (oral) or 
≤20 mg/week (IM or SC)
a
Permitted concomitant medications are not supplied by the sponsor.
b
Between Weeks 12 and 52, subjects requiring average daily doses of glucocorticoids for SLE disease activity 
that exceed their baseline dose at Week 0 will be categorized as treatment failures. While these subjects will 
be permitted to remain in the study, the Investigator must consider whether glucocorticoid dose increases to 
an average daily dose ≥40 mg prednisone or equivalent for more than 7 consecutive days or whether a 
requirement for multiple rescues with glucocorticoid therapy between Weeks 12 and 52 should result in 
discontinuation of study agent administration.
c
It is recommended that all subjects taking MTX in this study receive concomitant folate or folinic acid. 
Guidelines for dose adjustment in the event of MTX toxicity are included in the Trial Center File.
8.1.1.
Antimalarial Medications
Stable treatment with hydroxychloroquine, chloroquine, or quinacrine is permitted through 
Week 52 as shown in Table 4 and Table 5. It is not permitted to introduce or adjust dosing of 
antimalarials through Week 52; however, if necessary, one antimalarial may be substituted for 
another. Antimalarials produced by a licensed compounding pharmacy (eg, quinacrine) in the 
country of administration and using pharmaceutical grade components are allowed. It is 
recommended that subjects receiving antimalarials receive screening for retinal toxicity 
according to local guidelines.
8.1.2.
Glucocorticoid Therapy
Subjects likely to require multiple courses of glucocorticoids for reasons other than SLE (eg,
history of uncontrolled asthma, uncontrolled chronic obstructive pulmonary disease, etc) should 
be excluded from study participation. However, subjects may receive short courses (2 weeks or 
less) of oral glucocorticoids for reasons such as prophylactic therapy before surgery (stress-dose 
glucocorticoids), therapy for certain infections, acute exacerbation of asthma or chronic 
obstructive pulmonary disease, or other condition (eg, contact dermatitis) not related to increased 
SLE disease activity. Dosage, duration, and reason for glucocorticoid use in these instances must 
be documented.


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Unnecessary changes in glucocorticoid dose are discouraged, and any dose adjustments are 
recommended to be made in small amounts. Changes in glucocorticoid dosing other than those 
described in this section of the protocol are allowed only for medical necessity. The degree and 
timing of any unspecified glucocorticoid adjustments should be carefully considered as this may 
have a significant impact on the study results and upon continuation of study agent.
Oral Glucocorticoids
If using oral glucocorticoids, subjects must be receiving this medication for at least 6 weeks prior
to the first study agent administration and be on a stable dose equivalent to an average daily dose
of ≤20 mg prednisone (or equivalent) for at least 4 weeks prior to the first study agent dose. 
A summary of allowed glucocorticoid dosing at randomization and any permitted changes during 
the study are shown in Table 4 and in Table 5 and Table 6, respectively. A suggested gradual 
glucocorticoid tapering schedule (not exceeding 10%-20% reduction in current average daily 
dose per week) is recommended. Between Weeks 24 and 40, glucocorticoid tapering is strongly 
encouraged for all subjects who in the Investigator’s judgment have stable or improving disease 
activity and have not met any criterion for treatment failure (specific details will be provided in 
the SAP). Reason(s) for not tapering glucocorticoids should be documented.
Glucocorticoid tapering is also strongly encouraged during the extension period between 
Weeks 52 and 176 (see Section 8.2 and Table 6).
Additional considerations of oral glucocorticoid use during the study are as follows: 

If a subject experiences worsening disease activity while tapering glucocorticoids, further 
dose decreases may be suspended, and/or their oral glucocorticoid dose may be temporarily 
increased (ie, glucocorticoid rescue) if deemed necessary by the Investigator. 

Increases in average daily glucocorticoid dose that exceed the baseline dose will result in a 
subject being considered a treatment failure. If glucocorticoid tapering is interrupted, 
Investigators are encouraged to resume tapering within 4 weeks.

Tapering is not recommended if, in the opinion of the Investigator, it would pose a significant 
risk to the subject. 

It is recommended that subjects be educated about and monitored for symptoms of steroid 
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 steroid tapering, as appropriate.


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
While subjects meeting treatment failure criteria for increases in glucocorticoid dose may be 
permitted to remain in the study, the Investigator must consider whether oral glucocorticoid
dose increases to an average daily dose ≥40 mg/day prednisone or equivalent for more than
7 consecutive days or whether a requirement for multiple rescues with glucocorticoid therapy 
after Week 12 should result in discontinuation of study agent administration and/or 
potentially require withdrawal from the study.
Epidural, Intravenous, Intramuscular, Intra-articular, Intrabursal injection, and 
Intralesional Glucocorticoids
Epidural, IV, IM, IA, intrabursal, or intralesional administration of glucocorticoids is strongly 
discouraged within 6 weeks prior to the first administration of study agent.
Up to the Week 12 visit, short-term (≤2 weeks) epidural, IV, IM, intrabursal, or intralesional 
glucocorticoid use should be limited to situations where, in the opinion of the Investigator, there 
are no adequate alternatives. After Week 12, epidural, IV, IM, intrabursal, or intralesional 
glucocorticoid use may cause subjects to be considered treatment failures. In addition, it should 
be noted that subjects will be considered treatment failures if at any time during the study, an IV 
glucocorticoid dose of >625 mg prednisone equivalent/day for 2 or more days total is 
administered.
If clinically necessary, a total of 1 or 2 IA injections may be permitted for SLE up to Week 12 
and should be recorded as a medical procedure; however, joints treated with IA injections will be 
imputed as “active” in all subsequent assessments. After Week 12, IA glucocorticoid use may 
also cause subjects to be considered treatment failures.
ACTH administered by injection is not allowed within 1 month prior to the first administration 
of study agent and throughout the study.
Rectal Administration
Rectal administration of glucocorticoids, if necessary, should be short-term and topical
preparations should be used.
Inhalation Glucocorticoids
Glucocorticoids administered by bronchial or nasal inhalation for treatment of conditions other
than SLE may be given as needed.
8.1.3.
Nonsteroidal Anti-inflammatory Drugs
Prescriptions of NSAIDs and other regularly administered analgesics should not be adjusted for 
at least 2 weeks prior to the first administration of the study agent and through Week 52, and 
may be changed only if the subject develops unacceptable side effects. Subjects are permitted to
receive the usual marketed doses approved in the country in which the study is being conducted.
NSAIDs, including aspirin or selective cyclooxygenase-2 (COX-2) inhibitors, and other 
analgesics (including topical or injectable NSAIDs, analgesics or other pain-relieving agents 


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such as capsaicin) that are used on an “as needed” basis should not be used within 48 hours
before a study visit. 
8.1.4.
Anti-hypertensive Medications
Subjects are permitted to receive stable doses of ARB or ACE inhibitors for the treatment of 
hypertension, cardiovascular disease, kidney disease, and lupus nephritis. If receiving regular 
treatment with ACE inhibitors or ARBs, subjects must be receiving stable dosing for at least 2 
weeks prior to first administration of study agent. If necessary, subjects are permitted to switch 
between ARB and ACE inhibitors or vice versa. Effort should be made to ensure that the 
effective doses of the switched drugs are comparable. Subjects should not initiate ARB- or ACE-
inhibitor therapy between randomization and Week 52. 
8.1.5.
Non-biologic Immunomodulators 
If receiving immunomodulators, subjects should be receiving stable dosing from screening 
through Week 52. Subjects can be receiving MMF/MPA, AZA/6-MP, and/or MTX with 
recommended concomitant folic or folinic acid (Table 5). A reduction in immunomodulators is 
allowed only if the subject develops unacceptable side effects, with the implication that this may 
affect interpretation of the subject’s clinical data. A higher dose of an immunomodulator 
(relative to the baseline dose) or the addition of a new immunomodulator to the existing 
treatment regimen will cause subjects to be considered a treatment failure. Any increase in dose 
of immunomodulator (relative to baseline) must be discussed with the study sponsor and/or 
medical monitor to determine whether it may require discontinuation of study agent. 
8.1.6.
Topical Medications
Regular use of topical medications is permitted. However, topical compounds cannot include a 
prohibited medication. For example, topical ointments or creams that include cyclosporine A, 
tacrolimus, pimecrolimus, dapsone, or thalidomide are prohibited through Week 52; however, 
ophthalmic use of cyclosporine A is permitted. “As needed” use of topical NSAIDs, analgesics,
or other pain-relieving agents such as capsaicin is permitted, but not within 48 hours prior to 
study visit. “As needed” use of topical low (Class VI, VII) to moderate (Class IV, Class V) 
potency glucocorticoids (according to the World Health Organization classification of topical 
glucocorticoids) is permitted, but not within 48 hours prior to a study visit. High potency topical 
glucocorticoids are not allowed through Week 52 for all subjects with cutaneous involvement.
8.1.7.
Prohibited Therapies
Use of additional immunosuppressants or immunomodulators, other than those explicitly 
allowed in the inclusion/exclusion criteria (Section 4.1 and 4.1.2), are prohibited including, but
not limited to, the following:

Agents targeted at reducing TNF(eg, infliximab, golimumab, certolizumab pegol, 
etanercept, CT-P13, and adalimumab) 


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
B-cell targeted agents (anti-CD20 eg, rituximab, anti-B-cell activating factor [BAFF], also 
known as B lymphocyte stimulator [BLyS], eg, belimumab, or anti-CD22 eg, epratuzumab, 
or other B-cell targeted therapies, such as tabalumab, atacicept, daratumumab)

Interleukin-1 inhibitors (eg, canakinumab)

Interleukin-2 inhibitors or exogenous IL-2 therapy

Interferon inhibitors or exogenous IFN therapy

IL-1 receptor antagonist (eg, anakinra)

Tocilizumab or any other biologic targeting IL-6 or IL-6 receptor

Tofacitinib or any other janus kinase (JAK) inhibitor

Abatacept

Anti-IL-17 agents (eg, brodalumab, secukinumab, and ixekizumab) 

Leflunomide

Cyclosporine A (oral or topical ointment/cream preparations) except for ophthalmic use 

Tacrolimus or pimecrolimus, or other immunomodulatory oral or topical preparations (see 
Section 8.1.6)

Toll-like receptor inhibitors

Thalidomide or lenalidomide

Dapsone

Adrenocorticotropic hormone (ACTH) by injection

IV glucocorticoids (see Section 4.2)
Use of cytotoxic drugs is prohibited including, but not limited to, cyclophosphamide, 
chlorambucil, nitrogen mustard, or other alkylating agents. 
Multiple administrations of high doses of oral glucocorticoids (average daily dose ≥40 mg), or 
initiation of high potency topical glucocorticoids, are prohibited during the study as defined in 
Section 8.1.2.
Sulfa-based antibiotics, where reasonable, should generally be avoided.
The use of complementary therapies (eg, herbs, ointments, traditional Chinese medicine, 
acupuncture) that have the potential to activate or inhibit the immune system is prohibited (see 
Section 4.1.2). In addition, use of complementary therapies that have the potential to interact 
with antithrombotic agents is prohibited in those taking antithrombotic agents.
The use of other complementary therapies is strongly discouraged; in individual cases, use may 
be permitted following discussion with the study sponsor and/or medical monitor.


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8.2.
Concomitant Medications Use and Rescue Therapy During the Extension 
Period
Increases in doses of current medications or addition of new protocol-permitted medications for 
SLE disease activity, such as NSAIDs, ACE inhibitors, ARBs, immunomodulators 
(antimalarials, MTX, MMF/MPA, AZA/6-MP) and, potentially, topically applied or locally 
injected therapies (if clinically indicated) are permitted but should be discussed with the medical 
monitor and/or sponsor. 
Severe, progressive, or unstable worsening of SLE disease activity that requires escalation in 
therapy, including biologics such as belimumab or rituximab, systemic immunomodulators such 
as cyclosporine or tacrolimus, sustained high doses of oral glucocorticoids, use of IV
glucocorticoids, or
use of cytotoxic agents such as cyclophosphamide
will require 
discontinuation from the study (see Section 8). 
Glucocorticoid dose reductions not exceeding 10-20% of the current dose per week are strongly 
recommended during the extension period (Table 6). If possible, glucocorticoids may be 
completely tapered off by the end of study visit.
Reductions in dose or discontinuation of existing background medications is permitted during the 
extension period per Investigator discretion. Subjects will be issued diary cards to record use of 
background SLE medications between study visits. All medication changes during the extension 
period should be recorded in the concomitant therapy section of the eCRF.
Table 6 summarizes the protocol requirements and any allowed changes in dosing for 
study-permitted SLE medications during the extension period.
Table 6:
Extension Period- Protocol Requirements for Permitted Concomitant SLE Medications 
Permitted Concomitant 
Medications
for SLEa
Study Dosing at Entry 
Maximum Allowable Dose During Study
Antimalarials (chloroquine, 
hydroxychloroquine or 
quinacrine) (Section 8.1.1)
≤250 mg/day chloroquine (≤3 mg/kg/day)
≤400 mg/day hydroxychloroquine 
≤100 mg/day quinacrine
Oral glucocorticoids 
(Section 8.1.2)
Stable dosing equivalent to 
average daily dose of ≤20 mg
prednisone 
Glucocorticoid dose reductions not 
exceeding 10-20% of the current dose per 
week are recommended. If possible, 
glucocorticoids may be completely tapered 
off by the end-of-study visit.
NSAIDs and other analgesics 
(Section 8.1.3)
No more than the usual marketed doses approved in the country where the 
study is being conducted. Notable changes in NSAID dosing to be recorded 
in concomitant medications. 


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Table 6:
Extension Period- Protocol Requirements for Permitted Concomitant SLE Medications 
Permitted Concomitant 
Medications
for SLEa
Study Dosing at Entry 
Maximum Allowable Dose During Study
Anti-hypertensive medications 
(ARBs or ACE inhibitors) 
(Section 8.1.4)
No more than the usual marketed doses approved in the country where the 
study is being conducted. Substitution of ACE inhibitors for ARBs or ARBs
for ACE inhibitors is permitted if medically necessary. Addition of a new
ARB or ACE inhibitor may be permitted during the extension period after 
discussion with the medical monitor and/or sponsor.
Non-biologic 
Immunomodulators 
(Section 8.1.5):
Addition of a new permitted 
immunomodulator or increases in dose of a 
current immunomodulator should be 
discussed with the medical monitor and/or 
sponsor.
Mycophenolate mofetil 
(MMF)
≤2 g/day
Mycophenolic acid (MPA)
≤1.5 g/day
Azathioprine (AZA)/6-
mercaptopurine (6-MP)
≤2 mg/kg/day (up to 100 mg/
day for subjects weighing 
≤50 kg)
Methotrexate (MTX)b
≤25 mg/Week (oral) or 
≤20 mg/Week (IM or SC)
Topical agents (eg, cyclosporine 
A, tacrolimus, pimecrolimus) 
(Section 8.1.6), 
Should be discussed with the medical 
monitor prior to administration, and should 
be clearly documented
Locally administered therapies 
(eg, intramuscular, intra-
articular, intrabursal, or
intralesional glucocorticoids; 
Section 8.1.2) 
Should be discussed with the medical 
monitor prior to administration, and should 
be clearly documented
a
Permitted concomitant medications are not supplied by the sponsor.
b
It is recommended that all subjects taking MTX in this study receive concomitant folate or folinic acid. 
Guidelines for dose adjustment in the event of MTX toxicity are included in the Trial Center File.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
Table 1 (TIME AND EVENTS SCHEDULE:  Screening Period and 52-Week Treatment Period)
and Table 2 (TIME AND EVENTS SCHEDULE:  Extension Period) summarize the frequency 
and timing of measurements and sample collection applicable to this study.
Whenever possible PRO assessments should be conducted/completed before any tests, 
procedures, or other consultations to prevent influencing subject perceptions. Urine and blood 
collections for PK and PD assessments should be kept as close to the specified time as possible


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and are to be collected prior to study agent administration unless otherwise specified (eg,
population PK sample). Other measurements may be done earlier than specified timepoints if 
needed.
It is recommended that PROs be performed in the following sequence:  Patient Assessment of 
Pain Intensity (VAS), FACIT-Fatigue, SF-36, EQ-5D-5L, LupusQoL, WPAI-Lupus, and LFA-
REAL PRO. It is recommended that ClinRO procedures be performed in the following sequence: 
BILAG, SLEDAI-2K, mSFI, PGA, joint count assessment, CLASI, LFA-REAL ClinRO, and 
SLICC/ACR Damage Index. ClinRO assessments should be performed by an adequately trained 
assessor (see Section 9.2 for details).
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
Investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the subject's participation in the study and

At 8-week intervals starting at Week 0 through Week 52 and at the end-of-treatment or the 
end-of-study visit.

Pregnancy testing will be performed at every visit during the extension period, and 
additional pregnancy testing may be performed as necessary.

If experiencing a delayed menstrual period (over 1 month between menstruations) or 
infrequent or irregular menstrual cycles to confirm absence of pregnancy
Subjects who consent to participate in medical photography, will have photographs of target 
cutaneous lesions or areas of active disease as noted in Table 1 and Section 9.8.
The total blood volume to be collected from each subject over the course of the double-blind
portion of the study through Week 64 follow-up will be approximately 730 mL. The total blood 
volume to be collected in the extension period from Week 56 to Week 176 will be approximately
140 mL. Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
9.1.2.
Screening Phase
Written informed consent (and written informed assent for subjects who are not considered to be 
adults legally per local requirements) must be obtained and reviewed by the Investigator before 
any screening data are collected.
Screening procedures will be performed as indicated in Table 1. The screening visit must be 
performed no more than 6 weeks prior to the randomization visit (Week 0).

Subjects must undergo testing for TB and their medical history assessment must include 
specific questions about a history of TB or known occupational or other personal exposure 
to individuals with active TB. The subject should be asked about past testing for TB, 
including chest radiograph results and responses to tuberculin skin or other TB testing. 
Investigators have the option to use both the QuantiFERON®-TB test and the tuberculin skin 
test (Attachment 2) to screen for latent TB if they believe, based on their judgment, that the
use of both tests is clinically indicated in order to evaluate a subject who has high risk of 


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having latent TB. If either the QuantiFERON®-TB test or the tuberculin skin test is positive, 
the subject is considered to have latent TB infection for the purposes of eligibility for this 
study.
Women of childbearing potential must have a negative urine pregnancy test at screening and at 
Week 0 before randomization. In addition to the urine pregnancy screening evaluation, a serum 
β-hCG pregnancy test may be conducted at any time at the discretion of Investigator or subject. 
Women of childbearing potential and men must consent to use highly effective methods of
contraception (see Section 4.1) and continue to use contraception for the duration of the study 
and for 4 months after the last dose of study agent. The method(s) of contraception used by each 
subject must be documented.
All screening evaluations establishing subject eligibility will be performed and reviewed by the 
Investigator before a subject can be randomized. Subjects must have received approval for study 
randomization following review of screening lupus assessments by the sponsor and/or sponsor-
selected independent reviewer(s). A data review committee will consist of a team of sponsor 
and/or sponsor-selected independent reviewer(s) who will evaluate suitability of subjects for 
randomization based on scoring of clinical assessment tools (eg, SLEDAI-2K, BILAG, joint 
count assessments, CLASI) performed at screening. Details of the data review process will be 
provided in a separate manual. 
Documentation (historical or local laboratory testing) of unequivocally positive values (as 
defined in the laboratory’s reference range) should be provided for the following:  ANA (eg, 
ANA by human epithelial type 2 cells [HEp-2] titer, ANA by enzyme-linked immunosorbent 
assay [ELISA]), or anti-dsDNA (eg, anti-dsDNA by Farr assay or ELISA), or anti-Smith. To 
establish subject eligibility, these results must be confirmed through central laboratory testing.
9.1.2.1.
Retesting/Rescreening
A one-time repeat of screening laboratory tests (eg, hemoglobin, lymphocytes, neutrophils, 
platelets, serum creatinine, AST, ALT, ANA, anti-dsDNA, anti-Smith) is allowed during the 
6-week screening period and the Investigator may consider the subject eligible if the previously 
exclusionary laboratory test result is within an acceptable range per eligibility criteria on repeat 
testing at the central laboratory. A screening laboratory test(s) 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.
The goal of the retest procedure is to assess if the subject is eligible for randomization within the 
screening window or is a screen failure. Subjects who have laboratory values that do not meet 
entry criteria following the retest or do not meet disease activity criteria following the repeat 
procedure are to be deemed screen failures. Exceptions to this are positive QuantiFERON®-TB,
hepatitis C or B, or HIV tests; unless there is a suspected error in sample collection or analysis 
performance, these tests may not be repeated to meet eligibility criteria.
If the investigator wishes to rescreen a subject who has failed screening, the investigator should 
discuss it with the study sponsor and/or their designee. Only 1 rescreening is allowed per subject. 


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Subjects who are rescreened will be assigned a new subject number, undergo the informed 
consent process again, and start a new screening phase.
9.1.3.
Double-blind Treatment Phase
9.1.3.1.
Day of Randomization
Eligible subjects will be randomly assigned by the IWRS in a 3:2 ratio to receive either 
ustekinumab or placebo in a blinded manner. Assessments will be performed as indicated in the 
Time and Events Schedule (Table 1). Subjects will be administered blinded IV study agent.
Subjects participating in the cutaneous lupus substudy will have baseline, pretreatment 
photographs taken. 
9.1.3.2.
Double-blind, Placebo-controlled Treatment Period 
After randomization and the first administration of study agent by IV infusion, subjects will have 
SC blinded study agent administration 8 weeks after the IV dose and q8w thereafter through the 
Week 48 visit. Assessments will be performed as indicated in Table 1.
Subjects participating in medical photography will have posttreatment photographs taken at 
Weeks 12, 24, and 52 (see Section 9.8).
To aid in the early detection of TB reactivation or new TB infection during study participation, 
subjects must be evaluated for signs and symptoms of active TB at scheduled visits (refer to 
Time and Events Schedule) or by telephone contact approximately every 8 to 12 weeks. The 
following series of questions is suggested for use during the evaluation: 
“Have you/Has your child had a new cough of > 14 days’ duration or a change in a chronic 
cough?”
“Have you/Has your child had any of the following symptoms:
o
Persistent fever?
o
Unintentional weight loss?
o
Night sweats?”
“Have you/Has your child had close contact with an individual with active TB?”  (If there is 
uncertainty as to whether a contact should be considered “close,” a physician specializing in TB 
should be consulted.) 
If the evaluation raises suspicion that a subject may have TB reactivation or new TB infection, 
an immediate and thorough investigation should be undertaken, including, where possible, 
consultation with a physician specializing in TB. 
Investigators should be aware that TB reactivation in immunocompromised subjects may present 
as disseminated disease or with extrapulmonary features.  Subjects with evidence of active TB 
should be referred for appropriate treatment.


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Subjects who experience close contact with an individual with active TB during the conduct of 
the study must have a repeat chest radiograph, a repeat QuantiFERON® TB test, a repeat 
tuberculin skin test in countries in which the QuantiFERON®-TB test is not approved/registered 
or the tuberculin skin test is mandated by local health authorities, and, if possible, referral to a 
physician specializing in TB to determine the subject’s risk of developing active TB and whether 
treatment for latent TB is warranted. If the QuantiFERON®-TB test result is indeterminate, the 
test should be repeated as outlined in Section 4.1.1.  Subjects should be encouraged to return for 
all subsequent scheduled study visits according to the protocol.
9.1.4.
Extension Period
Subjects will be eligible to participate in the extension period when they have completed 
participation in the main study through the Week 52 visit; subjects who do not complete the 
Week 52 visit are not eligible to enter the extension. The purpose of the extension is to evaluate 
the safety, efficacy, and pharmacologic effects of ustekinumab in SLE for a maximum total 
duration of approximately 2 years beyond the 52-week main study period. Eligible subjects will 
enter the extension at Week 56. Any subject who does not enter the extension period should 
follow the Time and Events schedule for the main study (Table 1), and have a safety follow-up
visit conducted 16 weeks after their last dose of study agent.
See Section 8.2 and Table 6 for concomitant medication use and rescue therapy during the 
extension period. The timing and procedures for the extension period are presented in Table 2.
9.1.4.1.
Subject Selection
To be eligible to enter the extension study, subjects must meet the following criteria:

Have completed the Week 52 visit. Subjects who withdraw consent and/or have permanently 
discontinued study agent administration prior to the Week 52 visit will be not be eligible to 
enter the extension period. 

In the judgment of the study Investigator, the potential benefit of continuing long-term 
treatment with study agent outweighs the potential risks for the subject.
9.1.4.2.
Dosing Regimen
Subjects (or their designee) should be trained to administer study agent during the Week 56 and 
the Week 64 visit of the extension period. Additional training sessions are permitted per 
Investigator discretion. 
Subjects who received ustekinumab 90 mg SC q8w during the double-blind period will continue 
to do so during the extension period. Subjects who received placebo during the double-blind
study period will cross over to receive ustekinumab 90 mg q8w beginning at Week 56. IWRS 
will be preprogrammed to coordinate the crossover of study agent while maintaining the blind. A 
safety follow-up visit will occur 16-weeks after the final administration of study agent.


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9.1.5.
End of Study/Early Withdrawal
Subjects who discontinue study agent or active participation in the study will no longer receive 
study agent. Subjects who withdraw early from study participation will be required to return for 
follow-up assessments. When a subject withdraws from the study, the reason(s) for withdrawal,
if available, should be recorded by the Investigator on the relevant page of the eCRF. Whenever 
possible, all subjects who discontinue study agent or withdraw from the study prematurely will 
undergo all end of study assessments as shown in Table 1 and Table 2. 
9.1.6.
Posttreatment Phase (Follow-Up) 
It is strongly recommended that subjects who permanently discontinue study agent, but do not 
withdraw from study participation, be followed at all subsequent study visits through Week 52. 
At a minimum, subjects who permanently discontinue study agent, but do not withdraw from 
study participation, should return for a follow-up visit 16 weeks after the last study agent 
administration to undergo procedures as outlined for the end-of-treatment (EOT) visit (Table 1). 
Subjects remaining on study agent and completing the Week 52 visit who do not enter the 
extension period should return for a follow-up visit 16 weeks after the last study agent 
administration to undergo Week 64 (EOT visit) procedures.
Every effort should be made to record the reason for study agent and/or study discontinuation. If 
the information on reasons for discontinuation is obtained via telephone contact, written 
documentation of the communication must be available for review in the source documents. If 
the subject has died, the date and cause of death will be collected and documented on the eCRF.
Investigators may recontact the subject to obtain long-term follow-up information regarding the 
subject's safety or survival status as noted in the informed consent form (refer to Section 16.2.3, 
Informed Consent).
9.2.
Efficacy Evaluations
All efficacy evaluations should be performed consistently by the same study Investigator or 
subinvestigator at every visit to achieve comparable measures over time. It is recommended that 
the designated assessor identify an appropriate backup in case the designated assessor is 
unavailable.  
ClinROs, including joint assessments, should be performed by an adequately trained assessor, 
preferably a rheumatologist. If a rheumatologist is not available, the assessor should be a health 
care provider with at least 1 year of experience in scoring these instruments. A health care 
provider with less than 1 year of experience may serve as a ClinRO assessor only with the 
approval of the sponsor. It is recommended that the designated assessor identify an appropriate 
backup.
Independent data review by the sponsor or sponsor-designated independent reviewer(s) will be 
performed throughout the study for key SLE assessments (eg, SLEDAI-2K, BILAG, joint count 
assessments, mSFI, and CLASI). These data will be reviewed at every visit that these data are 
collected and may require reconciliation of inconsistencies across assessments.


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9.2.1.
SLE Disease Activity Index 2000
The SLE disease activity index 2000 (SLEDAI-2K) is an established, validated SLE activity 
index. It is based on the presence of 24 features in 9 organ systems and measures disease activity 
in SLE patients in the previous 30 days; the index is weighted according to the feature. Features 
are scored by the assessing physician if present within the last 30 days, with more severe features 
having higher scores, and then simply added to determine the total SLEDAI-2K score, which 
ranges from 0 to 105.50,51 The baseline measurement for the SLEDAI-2K is defined as the closest 
measurement taken prior to the initiation of the Week 0 study agent administration.
SLEDAI improvement is defined as a reduction from baseline in total SLEDAI-2K score. No 
worsening of total SLEDAI-2K from baseline is defined as a change ≤0 in SLEDAI-2K score. At 
baseline, the features assessed in the SLEDAI-2K are used for comparison to the SLEDAI-2K
RI-50 [Follow-up] described below.
The SLEDAI-2K has been adapted and developed into the SLEDAI-2K RI-50, a measure that 
can document partial improvement in the 24 disease features between SLEDAI-2K assessments. 
A threshold of 50% improvement was judged to reflect clinically significant improvement and is 
scored as half the weight for the feature. “When a descriptor is recorded as present at the initial 
visit, 1 of 3 situations can follow: (1) the descriptor achieves complete remission at follow-up, in 
which case the score would be “0”; (2) the descriptor does not achieve a minimum of 50% 
improvement at follow-up, in which case the score would be identical to its corresponding 
SLEDAI-2K value; or (3) the descriptor improves by ≥50% (according to the SLEDAI-2K RI-50 
definition) but has not achieved complete remission, in which case the score is evaluated as one-
half the score that would be assigned for SLEDAI-2K.” The SLEDAI-2K RI-50 score is the sum 
of the 24 scored items, which ranges from 0 to 105.49,52  
9.2.2.
British Isles Lupus Assessment Group
The BILAG index21,26 scores subjects based on the need for alterations or intensification of 
therapy. The assessing physician will evaluate 97 items divided into 9 organ system domains. 
The physician considers presence of each item in the past 4 weeks and answers 0=not present, 
1=improving, 2=same, 3=worse, or 4=new. Each organ/system domain is classified 
programmatically or by data reviewers as BILAG A, B, C, D, or E based upon criteria specific to 
the domain.26 The BILAG index was designed to give practicing physicians a tool to help in 
decision-making based on amount of activity in each organ/system. The baseline measurement 
for the BILAG is defined as the closest measurement taken during the study and prior to 
administration of study agent at Week 0.

BILAG Improvement is defined as (1) all BILAG A scores at baseline improved to either 
B, C or D and (2) all BILAG B scores at baseline improved to C or D and (3) no worsening 
in disease activity defined as no new BILAG A scores and ≤ 1 new BILAG B score.

Major Clinical Response in BILAG is defined as BILAG C score or better in all organ 
domains.

No worsening in BILAG disease activity is defined as no new BILAG A scores and ≤1 
new BILAG B score.


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9.2.3.
Physician’s Global Assessment of Disease Activity
The PGA38,39 independent of subjects’ assessment is recorded on a 10-cm VAS with responses 
ranging from 0-3, and verbal anchors “No Lupus Activity” (0) on the far-left side of the scale 
and “Extremely Active Lupus” (3) on the far right of the scale. Disease activity can range from 0 
representing no disease activity, 1 representing mild disease activity, 2 representing moderate 
disease activity, to 3 representing extremely active disease. The baseline measurement for the 
PGA is defined as the closest measurement taken prior to the initiation of the Week 0 
administration.

No worsening in PGA defined as no significant deterioration (<10% increase from 
baseline) using a 10-cm visual analogue scale.12
9.2.4.
Modified SELENA Flare Index (mSFI)
The classic Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) flare 
index (cSFI) was originally developed for the SELENA study.3,40 The index was designed to 
capture flares of all types as well as distinguishing severe flares from mild-to-moderate flares. 
The cSFI is a composite index that includes the following components: 

Assessment of change from baseline in global and organ-specific disease activity measures 
using the SELENA-SLEDAI instrument 

Increase from baseline in the Physician’s Global Assessment (PGA) of disease activity 

Increase in dose or addition of new oral glucocorticoid therapy for SLE activity 

Addition of new NSAID, antimalarial, or immunomodulatory therapy for SLE activity 

Hospitalization for SLE activity 
The cSFI was modified in this study (mSFI) for use with the SLEDAI-2K. Further modifications 
included:

An expanded list of background therapies (MMF, belimumab, rituximab, or other 
immunosuppressant therapy) for SLE activity 

A modification in the definition of severe flare to ensure that at least one additional mSFI 
component (eg, organ-specific disease activity, added background therapy) is present if the 
change in SLEDAI-2K instrument score to “greater than 12” box was checked
9.2.5.
Joint Count Assessments
Assessment of active joints (defined as joints demonstrating pain and signs of inflammation), 
tender joints, and swollen joints will be performed at visits indicated in Table 1 and Table 2. To 
be considered an active joint, an affected joint must be painful as reported by the subject and 
must demonstrate tenderness and at least one additional sign of inflammation (eg, observed 
swelling such as edema or effusion) on physical examination as determined by the joint assessor. 
Each of 64 joints will be evaluated for tenderness and 62 joints for swelling (hips are excluded 
for swelling).


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The joint assessment should be performed by an adequately trained joint assessor. The joint 
assessor should preferably be a rheumatologist, but if a rheumatologist is not available, it should 
be a health care provider with at least 1 year of experience in performing joint assessments. A 
health care provider with less than 1 year of experience may serve as a joint assessor based upon 
the approval of the sponsor. It is strongly recommended that the same joint assessor perform
these assessments at every visit. It is recommended that the designated assessor identify an 
appropriate back-up joint assessor in case the designated joint assessor is unavailable.
9.2.6.
Cutaneous Lupus Erythematosus Disease Area and Severity Index
Cutaneous lupus disease activity and severity will be measured by the Cutaneous Lupus 
Erythematosus Disease Area and Severity Index (CLASI). The CLASI is an instrument to assess 
the disease activity and damage caused to the skin for cutaneous lupus erythematosus patients 
with or without systemic involvement.1 The CLASI consists of 2 scores; the first summarizes the 
activity of the disease while the second is a measure of the damage caused by the disease 
(CLASI Activity and CLASI Damage scores). Activity is scored by the Investigator based on 
erythema, scale/hyperkeratosis, mucous membrane involvement, acute hair loss, and non-
scarring alopecia. Damage is scored in terms of dyspigmentation and scarring, including scarring 
alopecia. The scores are calculated by simple addition based on the extent of the symptoms.1

CLASI scores range from 0-70 for activity and 0-56 for damage, with higher scores 
indicating worse disease activity.
9.2.7.
Patient Assessment of Pain Intensity
The subject will be asked to report his or her average pain during the past Week on a 10-cm VAS 
with anchors 0 to represent “no pain” and 10 to represent “the worst possible pain.”
9.2.8.
Lupus Quality of Life Measure 
The Lupus Quality of Life (LupusQoL) is a validated SLE-specific health-related quality of life 
(HRQoL) instrument consisting of 34 items across 8 domains (Physical health, Emotional health, 
Body image, Pain, Planning, Fatigue, Intimate relationships, and Burden to others). The 
LupusQoL has a 5-point Likert response format, where 0 = all the time, 1 = most of the time, 
2 = a good bit of the time, 3 = occasionally, and 4 = never, and uses a 4-week recall period. The 
mean raw domain score is transformed to scores ranging from 0 (worst HRQoL) to 100 (best 
HRQoL) by dividing by 4 and then multiplying by 100. A higher score reflects better HRQoL.31
9.2.9.
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.8,29 A study using a combination of approaches, 
including both anchor-based estimates derived from statistically significant cross-sectional and 


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longitudinal differences and distribution-based estimates concluded that the minimal clinically 
important difference in patients with SLE for the FACIT-Fatigue is between 3 and 4 points.6 This 
range is similar to that which has been reported in other disease areas.5,6,37  
9.2.10.
Short-form Health Survey-36 Standard (4-Week Recall) v2 
The 36-item Short-form Health Survey (SF-36) questionnaire is a self-administered generic 
measure of HRQoL comprising 36 items over 8 domains that cover a range of functioning: 

Limitations in physical function

Limitations in usual role activities

Bodily pain

General mental health (psychological distress and well-being)

Vitality (energy and fatigue)

Limitations in social functioning due to physical or mental health problems

Limitations in usual role activities due to personal or emotional problems

General health perception
The Standard version uses a 4-week recall period and 5-point Likert response options ranging 
from “Excellent” to “Poor” (with the exception of the General Health item, which uses a 
one-year recall period, and Likert response options ranging from “Much better” to “Much 
worse”). The scoring yields a PCS score and an MCS score, and 8 subscale scores. The scale 
scores and summary scores are converted into 0-100 using a norm-based system where linear 
transformations are performed to transform scores to a mean of 50 and standard deviations of 10, 
based upon general US population norms.57 Higher scores represent better outcomes. SF-36 can 
be completed in 5 to 10 minutes. The instrument has undergone extensive linguistic and cultural 
validation.
The concepts measured by the SF-36 are not specific to any age, disease, or treatment group, 
allowing comparison of relative burden of different diseases and the benefit of different 
treatments.57 A change of 2.5 points in any of the subscales or 5 points for the component score 
is associated with clinically meaningful change.43,58,59
9.2.11.
EuroQol EQ-5D-5L Descriptive System
The EuroQol EQ-5D-5L Descriptive System (EQ-5D-5L) is a general health-related quality of 
life measure comprising a descriptive system and the EQ VAS.19
The descriptive system comprises five dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression, with 5-point Likert response options ranging from “I 
have no problems in...” to “I am unable to…”. Subjects will be asked to rate their current health 
and functional status for each of the 5 domains. Individual patient responses to the 5 questions 
are collected, and responses are converted into an overall quality of life score via a preference-
based statistical mapping algorithm. The scores on these five dimensions can be presented as a 


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health profile or can be converted to a single summary index number (utility) reflecting 
preferability compared to other health profiles.
Additionally, EQ-5D-5L also includes a 20-cm visual analog scale (EQ-VAS) that ranges from 
100 for "best imaginable health state" to 0 for "worst imaginable health state," respectively. 
Respondents are asked to indicate how they rate their own health by drawing a line from an 
anchor box to that point on the EQ-VAS which best represents their own health on that day. This 
can be used as a quantitative measure of health outcome that reflects the patient’s own 
judgement. 
9.2.12.
Work Productivity and Activity Impairment Scale – Lupus
The Work Productivity and Activity Impairment (WPAI) scale consists of 6 questions intended 
to evaluate work hours lost due to lupus disease and to assess the impact of lupus disease on 
work productivity and on regular daily activities. The WPAI scoring is evaluated over the prior 
7 calendar days. Outcomes for each domain are expressed as impairment percentages, with 
higher numbers indicating greater impairment and less productivity. The WPAI-Lupus reflects 
the impairments due to lupus.16
9.2.13.
Lupus Foundation of America Rapid Evaluation of Activity in Lupus
(LFA-REAL)
The Lupus Foundation of America Rapid Evaluation of Activity in Lupus (LFA-REAL™) is a 
novel 2-part disease assessment system, based on a series of simple questions and observations, 
to determine a treatment’s impact on the patient’s health and daily life. One set of questions and 
observations, known as a ClinRO, is designed for clinicians; and the other set of questions, 
known as a PRO is designed for subjects. Both the ClinRO and PRO portions consist of 
anchored, landmarked VAS with a range of scores from 0-3. Domains in the ClinRO portion 
include 
mucocutaneous, 
musculoskeletal, 
cardiorespiratory, 
neuropsychiatric, 
renal, 
hematologic, constitutional, vasculitis, and rare other (to be filled in by the clinician). Domains 
in the PRO portion include symptom-based measures, including rash, arthritis, muscle 
symptoms, fatigue, hair loss, fever, and other body symptoms. Higher scores denote worse 
disease. This tool is intended to make evidence-based and targeted treatment decisions, allowing 
for overall as well as organ-specific disease assessment, and for comparisons between physician 
and patient evaluation of ongoing disease activity.22
9.2.14.
SLICC/ACR Damage Index
The SLICC/ACR Damage Index is a validated, reliable instrument to measure organ damage 
after the diagnosis of lupus. The SLICC/ACR damage index evaluates 12 systems which are 
assessed by 41 items for damage, which is defined as non-reversible change that is not related to 
active inflammation and that has occurred since the onset of lupus and present for at least 6 
months. Items are scored based upon evidence of damage with a maximum possible score of 47. 
Scores can only increase with time. If evidence of damage is noted for an item, it is given a score 
of 1.14


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9.3.
Efficacy Endpoint Definitions
9.3.1.
SRI Composite Response
SRI-4 response is defined as ≥4-point reduction from baseline in SLEDAI-2K score, no new 
BILAG A and no more than 1 new BILAG B domain score, and no worsening from baseline in 
the PGA (<10% worsening from baseline).13 For the primary endpoint analysis, SRI-4 composite 
response is the proportion of subjects who achieve a SLEDAI-2K SRI-4 response at Week 52 
and do not meet the treatment failure criteria prior to Week 52. SRI-5, SRI-6, SRI-7, and SRI-8 
response are defined similarly, except the SLEDAI-2K improvement from baseline is to be at 
least 5, 6, 7, or 8 points, respectively.
9.3.2.
Lupus Low Disease Activity State 
Lupus Low Disease Activity State (LLDAS) was initially developed in a single-center SLE 
cohort11 to predict the non-accrual of irreversible organ damage, measured using the SLICC 
damage index. It was later investigated in a multi-national multi-ethnic cohort.15 A modified 
definition of LLDAS is used in this study and is defined as meeting all the following 
conditions33:

SLEDAI-2K ≤4, with no activity in major organ systems (renal, CNS, cardiopulmonary, 
vasculitis), and no reported fever, hemolytic anemia, or gastrointestinal activity)

No new disease activity compared with the previous assessment

PGA ≤1 on a 0-3 scale VAS

A current prednisone (or equivalent) dose of ≤7.5 mg daily

Well-tolerated standard maintenance doses of permitted immunosuppressive drugs and 
approved biological agents
9.3.3.
Definitions of Remission in Systemic Lupus Erythematosus 
The on-treatment definitions of remission in systemic lupus erythematosus (DORIS) defines 
clinical SLE remission as determined by clinical SLEDAI-2K = 0, BILAG D or E for all 
systems, or clinical European consensus lupus outcome measure (ECLAM) 0, including routine 
laboratory assessments and PGA.55,60 A distinction is made between remission off and on 
therapy. Remission can be categorized as Clinical Remission or Complete Remission (requiring 
negative serologies) and separately as Clinical Remission on treatment and Complete Remission 
on treatment. A modified definition of DORIS Clinical Remission on treatment is used in this 
study and is defined as meeting all the following conditions: 

SLEDAI-2K score = 0 (excluding anti-dsDNA, C3, and C4 components)

PGA score <0.5 cm on a 10 cm, 0-3 VAS scale

Prednisone (or equivalent) dose ≤5 mg/day

Antimalarial, immunosuppressant, or study agent use is permitted


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9.3.4.
SLE Flare
For this study, SLE flares will be defined as follows:

SLEDAI-2K flare is defined as at least 1 new SLEDAI-2K mild/moderate or severe flare 
compared with baseline as assessed using mSFI.

Severe SLEDAI-2K flare is defined as presence of one or more of the following: 

Increase in SLEDAI-2K score to greater than 12. If this is the only criteria met, at least 
one additional criterion below must also be present to be considered a severe 
SLEDAI-2K flare

New/Worse SLE activity (CNS, vasculitis, nephritis, myositis, thrombocytopenia 
(<60,000/mm3), hemolytic anemia (hemoglobin <7 g/dL or decrease in hemoglobin 
>3 g/dL) requiring one or more of the following: (1) increase in prednisone (or 
equivalent) dose to >0.5 mg/kg/day, (2) a doubling or greater of prednisone (or 
equivalent) dose, (3)
addition of a new systemic immunosuppressant agent 
(cyclophosphamide, AZA, MTX, MMF, belimumab, rituximab, or other systemic 
immunosuppressant therapy), or (4) hospitalization for SLE activity

Increase in prednisone (or equivalent) to >0.5 mg/kg/day for SLE activity

New cyclophosphamide, AZA, MTX, MMF, belimumab, rituximab (or other systemic 
immunosuppressant therapy) for SLE activity

Hospitalization for SLE activity

Increase in the 0-3 VAS anchored PGA score to >2.5

Mild/moderate SLEDAI-2K flare is defined as presence of one or more of the following: 

Increase in SLEDAI-2K score of 3 points or more (but not to more than 12)

New/worse SLE activity (discoid, photosensitive, profundus, cutaneous vasculitis, 
bullous lupus, nasopharyngeal ulcers, pleuritis, pericarditis, arthritis, fever due to SLE)

Increase in prednisone (or equivalent), but not to >0.5 mg/kg/day, for SLE activity

Added NSAID or hydroxychloroquine (or other antimalarial therapy) for SLE activity

Increase in the 0-3 VAS anchored PGA score by ≥1, but not to more than 2.5

BILAG flare is defined as at least 1 new BILAG A or 2 new BILAG B domain scores not 
present at baseline:

Severe BILAG flare is defined as at least 1 new BILAG A domain score not present at 
baseline

Moderate BILAG flare is defined as at least 2 new BILAG B domain scores not present at 
baseline
The following definitions will be applied to both SLEDAI-2K and BILAG Flares:

A flare-free visit is defined as any postbaseline visit where none of the flare criteria above 
are met. If a subject has any of the flare criteria listed above, he or she will not be counted as 
being flare free at the specific visit. 


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
Time to first flare is defined as the time (in days) after baseline when a given subject 
experiences his or her first flare. Time to first flare is calculated as the date of the first flare 
minus the date of randomization day + 1.

The annualized flare rate is the number of flares per year.
9.3.5.
Reduction of Glucocorticoid Dose
For this study, reduction of glucocorticoid dose is defined as:

A reduction in average daily oral glucocorticoid dose by at least 50% (relative to the 
baseline dose) 
or

Reduction of average daily oral glucocorticoid dose by at least 25% (relative to the baseline 
dose) so that the average daily dose is reduced to ≤7.5 mg (prednisone or equivalent) 
For this study, sustained reduction of glucocorticoid dose is defined as:
Achieving average daily oral glucocorticoid dose reduction (as described above) between 
Weeks 24 and 40, and sustaining that reduction through Week 52, in those subjects who, at 
baseline, were receiving oral glucocorticoids. 
9.3.6.
Major Clinical Response
Major clinical response is defined as BILAG C score or better in all organ domains.
9.3.7.
Medical Resource Utilization
Medical resource utilization data associated with medical encounters will be collected by the 
Investigator and staff for subjects throughout the study. Protocol-mandated procedures, tests, and 
encounters are excluded. The data collected may be used to conduct economic analyses for both 
total and SLE-related encounters on hospitalizations, emergency room/urgent care visits, and 
unscheduled visits to health-care providers.
9.4.
Pharmacokinetics and Immunogenicity
Serum samples will be collected for measurement of serum concentrations of ustekinumab and 
anti-ustekinumab antibodies at the timepoints specified in Table 1.
Additional information about the collection, handling, and shipment of biological samples can be 
found in the Laboratory Manual.
9.4.1.
Evaluations 
Serum samples will be used to evaluate the PK of ustekinumab, as well as the anti-ustekinumab
antibodies. Serum collected for PK and immunogenicity analyses may additionally be used to 
evaluate safety or efficacy aspects that address concerns arising during or after the study period. 
Genetic analyses will not be performed on these serum samples. Subject confidentiality will be 
maintained.


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9.4.2.
Procedures and Analyses 
9.4.2.1.
Pharmacokinetics
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. The
Sponsor, or its designee, under conditions in which the subjects’ identity remains blinded, will 
assay these samples.
9.4.2.2.
Immunogenicity
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 
detection of anti-ustekinumab antibodies will also be evaluated for ustekinumab serum 
concentration to enable interpretation of the antibody data. Anti-ustekinumab antibodies will be 
evaluated in serum samples collected from all subjects according to Table 1 and Table 2. Serum 
samples will be screened for antibodies binding to ustekinumab and the titer of confirmed 
positive samples will be reported. Other analyses may be performed to further characterize the 
immunogenicity of ustekinumab.  Serum samples that test positive for antibodies to ustekinumab 
will be further characterized to determine if antibodies to ustekinumab could neutralize the 
biological effects of ustekinumab in vitro (ie, neutralizing antibodies [NAbs] to ustekinumab). 
All samples will be tested by the sponsor or sponsor's designee.
9.5.
Biomarkers 
Assessments will be performed to identify biomarkers that are relevant to ustekinumab treatment 
and/or SLE. These may include, but are not limited to, inflammatory protein markers, RNA, 
cellular markers and, for patients who complete the optional DNA informed consent, DNA 
markers.
The collection, preparation, storage, and shipment of blood and serum for biomarker analysis are 
detailed in the Laboratory Manual.
9.5.1.
Serum Analyses
Serum will be analyzed for levels of specific proteins, auto-antibodies, and other inflammation-
related molecules and/or disease-associated serologies (see Section 11.7).
9.5.2.
Whole Blood Gene Expression 
Whole blood will be collected from all subjects for RNA expression analysis. 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 SLE, and to evaluate markers that can predict 
clinical response.
9.5.3.
Peripheral Blood Mononuclear Cells (Cellular Analysis)
Whole blood will be collected and processed to peripheral blood mononuclear cells (PBMC) and 
cryopreserved for analysis. Analysis may include but is not limited to flow cytometric 


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assessment of cell populations or functional assessment of cells in response to ustekinumab 
treatment and/or SLE pathogenesis.
9.6.
Pharmacogenomic (DNA) Evaluations
Genetic (encoded DNA sequence) variation may be important contributory factors to 
interindividual differences in drug disposition, response, and clinical outcomes. Genetic (DNA) 
factors may also serve as markers for disease susceptibility and prognosis and may identify 
population subgroups that respond differently to a drug. DNA samples will be analyzed for 
identification of genetic factors to better understand the molecular effects of ustekinumab and/or 
SLE, and to evaluate markers that can predict clinical response. Genetic (DNA) research may 
consist of the analysis of 1 or more candidate genes or analysis of the entire genome (as 
appropriate) in relation to ustekinumab and/or SLE. 
Only subjects who sign the optional consent form to participate in the genetic assessment will 
have whole blood DNA samples collected and analyzed.
9.7.
Safety Evaluations
Safety evaluations will include assessment of AEs, concomitant medications, pregnancy testing
(see Section 12.3.3), administration reactions, chemistry and hematology laboratory tests, 
immunogenicity, vital signs, and general physical examinations. In addition, electrocardiogram 
(ECG), chest x-ray (consistent with local regulations), HIV, hepatitis B, hepatitis C, and TB
testing will be required at screening (Table 1 and Table 2). Refer to Section 4.1 for TB screening 
criteria. Any clinically relevant changes that occur 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 endpoint is reached. Details regarding the DMC are provided in Section 11.10.
The study will include the following evaluations of safety and tolerability according to specific 
time points provided in Table 1 and Table 2.
9.7.1.
Adverse Events
See Section 12.1 for AE definitions. Adverse events will be reported by the subject (or, when 
appropriate, by a caregiver, surrogate, or the subject's legally acceptable representative) for the 
duration of the study. Adverse events will be followed by the Investigator as specified in 
Section 12, Adverse Event Reporting.
9.7.1.1.
Infections
Subjects 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 subjects for any signs or 
symptoms of infection and ask about symptoms of infection or other AEs that may have occurred 
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Study agent should not be administered to a subject with a clinically important, active infection. 
Treatment with study agent should be withheld until serious and/or severe infections are 
completely resolved. If a subject develops a serious or severe infection, including but not limited 
to sepsis or pneumonia, discontinuation of study agent must be considered. Treatment must be 
permanently discontinued for subjects who develop a serious opportunistic infection. This should 
be discussed with the medical monitor and/or sponsor. For active varicella zoster infection or a 
significant exposure to varicella zoster infection in a subject without history of chickenpox, the 
subject should be evaluated for symptoms of infection and if the subject has received appropriate 
treatment and/or recovered or has no symptoms of infection, he/she may continue study agent
after discussion with the medical monitor and/or sponsor.
9.7.1.1.1.
Tuberculosis
Any newly identified case of active TB occurring after the first administration of study agent(s) 
in subjects participating in this clinical study must be reported by the Investigator according to 
the procedures in Section 9.1.3.2. Investigators are also advised that active TB is considered a 
reportable disease in most countries. These events are to be considered serious only if they meet 
the definition of a serious adverse event. Treatment must be permanently discontinued for 
subjects with active TB.
9.7.1.2.
Infusion or Injection-site Reactions
An infusion reaction is defined as an AE that occurs during or within 1 hour following the 
infusion of study agent, excluding laboratory abnormalities. Subjects 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 (if subject received SC injection at the study site; 
see Table 1 and Table 2). Permanent discontinuation of study agent must be considered for 
subjects who experience an adverse event of infusion reaction that is considered serious or severe 
by the Investigator.
Subjects should be instructed in the signs, symptoms, and care of injection-site reactions before 
they begin at-home administration of study agent during the extension period.
9.7.2.
Clinical Laboratory Tests
Blood samples for serum chemistry, coagulation, and hematology will be collected as shown in 
Table 1 and Table 2.
The Investigator must review the laboratory results, document this review, and record any 
clinically relevant changes occurring during the study in the adverse event 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 agent or take action to ensure subject safety.


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The following tests will be performed by the central laboratory (unless otherwise specified):

Hematology Panel
-Hemoglobin
-Hematocrit
-White blood cell (WBC) count with differential (basophils, eosinophils, 
lymphocytes, monocytes, neutrophils)
-Platelet count
-CD 19 -cell analyses by flow cytometry during screening only if needed for 
subjects previously exposed to cell depleting therapies)
-Coomb’s direct test (performed locally)

Serology Laboratory
-Ig isotype profile (IgG, IgM, IgA levels)
-C3 and C4 Complement
-ANA
-Anti-dsDNA 
-Anti-phospholipid antibodies including lupus anticoagulant, anti-cardiolipin, and 
anti-β2-glycoprotein-I antibodies
-Other autoantibodies including anti-Smith, anti-Sjögren’s-syndrome-related antigen 
A (SSA anti-Ro, and B (SSB anti-La), anti-ribonucleoprotein (anti-RNP), rheumatoid 
factor, and anti-cyclic citrullinated peptide (CCP)

Coagulation Labs
-Prothrombin Time 
-Partial Thromboplastin Time 
-International Normalized Ratio 

Serum Chemistry Panel
-Sodium
-Alkaline phosphatase
-Potassium
-Calcium
-Chloride
-Phosphorous
-Bicarbonate
-Albumin
-Blood urea nitrogen 
-Total protein
-Creatinine
-Creatinine kinase
-Nonfasting glucose 
-Aspartate aminotransferase 
-Aldolase (if creatine kinase is elevated at 
screening then perform aldolase test at 
screening, Week 0, and follow-up as 
needed)
-FSH as needed
-Alanine aminotransferase 
-total bilirubin, and if total bilirubin is 
abnormally elevated, then direct bilirubin, 
and indirect bilirubin


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
Urine Analyses – Fresh spot urine

Urinalysis using urine dipstick. Urine sample will be further analyzed.

Urinary protein/creatinine ratio10 will be analyzed using an aliquot of spot
urine collected from subjects.

Urine sediment microscopy (assessment using spot urine samples), with 
features analyzed to include: 
-Red blood cells
-WBC 
-Epithelial cells
-Crystals
-Red blood cells, WBC, or heme-granular casts
-Bacteria

Urine pregnancy testing for women of childbearing potential only (performed locally)

Serum pregnancy test (at the discretion of the Investigator)

Viral serology (HIV antibody, HBsAg, anti-HBs, anti-HBc total, and HCV antibody)

QuantiFERON® -TB test

TB skin test (where applicable; performed locally)
Dipstick and sediment analysis of the urine samples will be performed in parallel, ie, in the same 
sample at the same time. Specific gravity, pH, glucose, protein, 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, and bacteria will only be reported if they are present. Casts will be 
reported whether or not they are present.
9.7.3.
Electrocardiogram
A 12-lead ECG will be performed locally at screening. During an ECG, it is recommended that 
subjects be in a quiet setting without distractions (eg, television, cell phones), resting in a supine 
position for at least 5 minutes before ECG recording, and refraining from talking or moving arms 
or legs. If blood sample collection or vital sign measurement is scheduled for the same time point 
as ECG recording, the procedures should be performed in the following order:  ECG, vital signs, 
blood sample collection. If an abnormal result is obtained, the ECG may be repeated.
9.7.4.
Vital Signs
Weight, temperature, pulse/heart rate, respiratory rate, blood pressure will be assessed with a 
completely automated device. Manual techniques will be used only if an automated device is not
available.


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9.7.5.
Physical Examination
A full-body physical examination will be performed pretreatment and during the study as shown 
in Table 1 and Table 2. A full-body physical examination includes assessment of general 
appearance, head (including oral cavity and dentition), eyes, ears, nose, throat, neck, abdomen, 
lymph nodes, and peripheral extremities and the following systems: cardiovascular (including 
peripheral vascular), respiratory, neurologic, musculoskeletal, skin, genitourinary (if clinical 
history indicates need).
A targeted physical examination will be performed pretreatment and during the study as shown 
in Table 1 and Table 2. A targeted physical examination includes assessment of general 
appearance, head (including oral cavity and dentition), eyes, nose, throat, abdomen, lymph 
nodes, and the following systems: cardiovascular (including peripheral vascular), respiratory, 
neurologic, musculoskeletal, and skin.
9.7.6.
Pregnancy
Female subjects of childbearing potential are to be monitored for possible pregnancy using a 
urine dipstick test performed at the clinical site as shown in Table 1 and Table 2. Additional
serum hCG testing may also be performed locally or at the central lab if desired by the study 
Investigator. See Section 12.3.3 for details on reporting pregnancies that occur during the study. 
Pregnancies (of the study subject or if the subject is male, then the subject's partner) must be 
followed to determine the outcome (including spontaneous miscarriage, elective termination, 
normal birth, or congenital abnormality) and status of mother and child, even if the subject was 
discontinued from the study early. 
9.8.
Cutaneous Disease Photography Substudy
In order to correlate CLASI assessment findings with images of cutaneous lupus, a cutaneous 
disease photography substudy will be performed at selected sites on a subset of subjects with 
cutaneous lupus present at baseline. There will be no restrictions on the number of subjects with 
cutaneous disease who can enroll in the substudy. Subjects with cutaneous disease will be asked 
to provide consent for medical photographs to be collected from identified cutaneous lesions or 
areas of active disease (see Table 1).
Photography equipment and services will be provided by the photography vendor to document 
cutaneous disease. For standardization across investigative sites and visits, all study photographs 
will be captured using the equipment, supplies, and guidelines provided by the photography 
vendor. Images will be uploaded to a secure website hosted by the photography vendor and 
monitored for technical quality. Detailed instructions for all aspects of the photography 
procedures will be supplied separately in the Investigator user manuals to be provided by the 
photography vendor. Confidentiality of the subjects involved in this study will be maintained; 
specifically, photographs of subjects in this study will not be published or otherwise made public 
without blocking adequate portions of the subject’s face or body so that the individual cannot be 
identified.


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9.9.
Sample Collection and Handling
The actual dates and times of sample collection should be recorded in the eCRF or laboratory 
requisition form. Refer to Table 1 and Table 2 for the timing and frequency of all sample 
collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples 
should be under the specified, and where applicable, controlled temperature conditions as 
indicated in the laboratory manual.
10.
SUBJECT COMPLETION / DISCONTINUATION OF STUDY AGENT / 
WITHDRAWAL FROM THE STUDY
10.1.
Study Completion
A subject will be considered to have completed the double-blind phase of the study if he or she 
has completed assessments through Week 52.
A subject will be considered to have completed the extension period of the study if he or she has 
completed assessments through Week 160.
10.2.
Discontinuation of Study Agent/Withdrawal from the Study
10.2.1.
Discontinuation of Study Agent
A subject will not be automatically withdrawn from the study if he or she has to discontinue 
study agent before the end of the treatment regimen.
A subject's study agent must be discontinued if:

The Investigator, sponsor, and/or medical monitor believes that for safety reasons or 
tolerability reasons (eg, adverse event), or due to severe, unstable, or rapidly progressive 
SLE disease activity, it is in the best interest of the subject to discontinue study agent.

The subject becomes pregnant

The subject experiences an AE temporally associated with study agent infusion or injection, 
resulting in bronchospasm with wheezing and/or dyspnea requiring ventilatory support, or 
symptomatic hypotension with a greater than 40 mm Hg decrease in systolic blood pressure.

The subject develops study agent hypersensitivity (eg, anaphylaxis, angioedema) reaction 
that is reported as serious or severe.

The subject is diagnosed with a malignancy, with the exception of no more than 2 localized 
basal cell skin cancers that are treated with no evidence of recurrence or residual disease.

The subject is deemed ineligible according to the following TB criteria:

A diagnosis of active TB is made.


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
A subject has symptoms suggestive of active TB based on follow-up assessment 
questions and/or physical examination, or has had recent close contact with a person 
with active TB, and cannot or will not continue to undergo additional evaluation.

A subject undergoing evaluation has a chest radiograph with evidence of current active 
TB and/or a positive QuantiFERON®-TB test result (and/or a positive tuberculin skin 
test result in countries in which the QuantiFERON®-TB test is not approved/registered 
or the tuberculin skin test is mandated by local health authorities), unless active TB can 
be ruled out and appropriate treatment for latent TB can be initiated prior to the next 
administration of study agent and continued to completion. Indeterminate 
QuantiFERON®-TB test results should be handled as in Section 4.1.1. Subjects with 
persistently indeterminate QuantiFERON®-TB test results may continue without 
treatment for latent TB if active TB is ruled out, their chest radiograph shows no 
abnormality suggestive of TB (active or old, inactive TB) and the subject has no 
additional risk factors for TB as determined by the Investigator. This determination 
must be promptly reported to the sponsor’s medical monitor and recorded in the 
subject's source documents and initialed by the Investigator.

A subject receiving treatment for latent TB discontinues this treatment prematurely or is 
noncompliant with the therapy.

The subject develops a serious opportunistic infection.

If a new immunomodulator that is permitted per-protocol is initiated, then a subject will be
considered a treatment failure but will not need to be discontinued from the study. However, 
if a subject requires a prohibited therapy such as a non-permitted immunomodulator,
biologic, cyclophosphamide, IV glucocorticoid,
or high dose
glucocorticoid
(see 
Section 8.1.7) then the subject must be discontinued from the study. Addition of new 
therapy for SLE activity must be discussed with the medical monitor and/or sponsor to 
determine the suitability of the subject to continue participating in the study.
If a subject discontinues study agent for any reason before the end of the double-blind phase, 
end-of-treatment assessments should be obtained and scheduled assessments should be 
continued.
10.2.2.
Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent

Death

Other 
If a subject is lost to follow-up, every reasonable effort should be made by the study-site 
personnel to contact the subject and determine the reason for discontinuation/withdrawal. Due 
diligence should include repeated telephone calls, certified letters, and email requests. Measures 
taken to obtain follow-up information must be documented.


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When a subject withdraws from the study, the reason for withdrawal is to be documented in the
eCRF and in the source document. Study agent assigned to the withdrawn subject may not be 
assigned to another subject. Subjects who withdraw from this study will not be replaced. 
If the reason for withdrawal from the study is withdrawal of consent then no additional 
assessments are allowed.
10.3.
Withdrawal from the Use of Research Samples
A subject who withdraws from the study will have the following options regarding the optional
research samples:

The collected samples will be retained and used in accordance with the subject's original 
separate informed consent for optional research samples.

The subject may withdraw consent for optional research samples, in which case the samples
will be destroyed, and no further testing will take place. To initiate the sample destruction 
process, the Investigator must notify the sponsor study site contact of withdrawal of consent 
for the optional research samples and to request sample destruction. The sponsor study site 
contact will, in turn, contact the biomarker representative to execute sample destruction. If 
requested, the Investigator will receive written confirmation from the sponsor that the 
samples have been destroyed.

The subject may withdraw consent for the cutaneous lupus photography substudy, in which 
case the photographs will be destroyed. To initiate the photograph destruction process, the 
Investigator must notify the sponsor study site contact of withdrawal of consent for the 
cutaneous lupus photography substudy and to request photograph destruction. The sponsor 
study site contact will, in turn, contact the imaging vendor to execute photograph 
destruction. If requested, the Investigator will receive written confirmation from the sponsor 
that the photographs have been destroyed.
Withdrawal from the Optional Research Samples while Remaining in the Main Study
The subject may withdraw consent for optional research samples/ photographs, while remaining 
in the study. In such a case, the optional research samples/ photographs will be destroyed. The 
destruction process will proceed as described above.
Withdrawal from the Use of Samples in Future Research
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5, 
Long-Term Retention of Samples for Additional Future Research). In such a case, samples will 
be destroyed after they are no longer needed for the clinical study. Details of the sample 
retention for research are presented in the main ICF and in the separate ICF for optional research 
samples.
11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the SAP.


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Descriptive statistics (eg, mean, median, standard deviation, interquartile range, minimum, 
maximum) will be used to summarize continuous variables. Numbers and percentages will be 
used to summarize categorical variables. Median values will be reported for time to event 
variables. In addition, graphical data displays (eg, line plots) and subject listings may also be 
used to summarize/present the data.
Simple descriptive summary statistics, such as n, mean, standard deviation (SD), median, 
interquartile (IQ) range, minimum, and maximum for continuous variables, and counts and 
percentages for discrete variables will be used to summarize most data.
In general, all statistical tests will be performed at a 2-sided significance level of α=0.05.
11.1.
Subject Information
11.1.1.
Demographics and Baseline Characteristics
For all subjects who receive at least 1 dose of study agent, descriptive statistics will be provided.
Demographics and baseline disease characteristics will be summarized based on the randomized 
analysis set. Descriptive statistics (mean, standard deviation, median, and range) will be provided 
for the subjects’ age, SLEDAI-2K score, PGA score, weight, and height. Subject sex, race, 
concomitant medication use, number of BILAG A or BILAG B criteria, positivity for ANA, 
anti-dsDNA, or anti-Smith autoantibodies, number with low complement C3 or C4 levels will be 
summarized as frequency distributions by treatment group. Prior and concomitant medications 
used at baseline will be listed.
11.1.2.
Disposition Information
Disposition information will be summarized by treatment group by numbers of subjects 
randomized, treated, and completing scheduled visits. Disposition information will be based on 
the randomized analysis set. Additionally, the number of subjects who discontinued study agent
and the reason for discontinuation as well as those who terminated the study and reason for 
termination will be summarized.
11.1.3.
Treatment Compliance
Study agent will be administered as an IV (initial dose) and SC injection by an authorized and 
qualified staff member and the details of each administration will be recorded in the eCRF 
including date, start and stop times for infusion and start time for injection. Compliance with the 
treatment assignments will be controlled by the study site personnel. Subjects will be required to 
record in their subject diaries, all doses of study agent that are administered at home. 
11.1.4.
Extent of Exposure
The number of subjects exposed to study agent, the number of administrations of study agent by 
type of administration (IV and SC), and cumulative dose (IV and SC) of study agent will be 
summarized by randomized treatment group.


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11.1.5.
Protocol Deviations
Major protocol deviations will be tabulated by treatment group in the following categories:
Subjects who “entered but did not satisfy entry criteria” or “received wrong treatment or 
incorrect dose” or “developed withdrawal criteria but not withdrawn” or “received a disallowed 
concomitant medication” and “other study procedures.”
11.1.6.
Prior and Concomitant Medications
Background medication use for active SLE will be summarized by treatment group. Subjects 
initiating new medications or changes in dose (increasing or decreasing) of medication for active 
SLE during the study will be summarized over time. Subjects with increases in medication will 
be listed. Subject diary cards will be used to capture changes in subject-administered medications 
that occur in between study visits, and these changes should also be recorded in the concomitant 
therapy section of the eCRF.
Prior and concomitant medications will be coded according to the World Health Organization 
(WHO) encoding dictionary, and the number and percent of subjects receiving each medication 
in each treatment group will be summarized by Level 3 Anatomical Therapeutic Chemical 
Classification (ATC) code (first four numbers in the code).
11.2.
Sample Size Determination
The sample size calculation is based upon the primary endpoint, the proportion of SRI-4 
composite responders at Week 52. A sample size of 300 subjects treated with ustekinumab and 
200 subjects with placebo is projected to give approximately 98% power to detect a significant 
difference in response rate compared with placebo (assuming 35% and 53% response rates in 
placebo and ustekinumab, respectively, which translates to 18% absolute increase over placebo 
or an odds ratio of 2.09) with an alpha (α) level of 0.05. The assumption of a 35% responder rate 
for placebo is based upon a previous study in which a similar SLE population was treated53,54 and
is consistent with the results observed in CNTO1275SLE2001.
The power to detect a significant treatment difference at α=0.05 (2-sided) is calculated under 
various assumptions (Table 7).


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Table 7:
Power to Detect a Significant Treatment Difference in the Proportion of Subjects with SRI-4 
Response at Week 52
Proportion of Placebo 
Group with Response (%)
Absolute Increase in 
Response (%)
Proportion of 
Ustekinumab Group with 
Response (%)
Odds Ratio
Power
20
15
35
2.15
96%
20
40
2.67
99%
25
45
3.27
99%
25
15
40
2.00
94%
20
45
2.45
99%
25
50
3.00
99%
30
15
45
1.91
93%
20
50
2.33
99%
25
55
2.85
99%
35
15
50
1.86
91%
18
53
2.09
98%
20
55
2.27
99%
40
25
60
2.79
99%
15
55
1.83
91%
20
60
2.25
99%
45
25
65
2.79
99%
20
65
2.27
99%
25
70
2.85
99%
*Note: SRI-4 composite response is defined as a ≥4-point reduction in SLEDAI-2K score, no new BILAG A and no more than 
1 new BILAG B domain score, and no worsening (10% increase) from baseline in the PGA.12,34
This sample size of 500 is based on (1) the sample size needed to power the study appropriately, 
(2) increasing the ability to have adequate numbers of subjects for subgroup analyses and, (3) 
maintaining appropriate safety exposure in accordance with International Conference on 
Harmonisation (ICH) guidelines. Differences in racial/ethnic background have been noted in 
biomarkers, such as the Type I IFN signature response and in response rates to SLE treatment. 
Sizing will accommodate investigation of biomarkers in these subgroups, to better characterize 
impact on disease signaling in diverse patient populations, and its relationship to clinical 
response to study agent.
If the primary endpoint analysis is significant, subsequent analyses will hold to the standard α
level control of a pivotal study (ie, 2-sided α level of 0.05 for major secondary endpoints). The 
major secondary endpoints will be tested sequentially according to the order specified in the 
protocol. If the previous endpoint is not statistically significant, subsequent endpoint(s) will not 
be tested and nominal p-values will be provided.
11.3.
Analysis Sets
The primary efficacy analysis set will be based upon the Full Analysis Set (FAS), defined as 
randomized subjects who receive at least 1 dose (partial or complete, IV or SC) of ustekinumab 
or placebo and will be analyzed based on randomized treatment groups, regardless of the 
treatment received.


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The safety analysis set will include all randomized subjects who receive at least 1 dose (partial or 
complete, IV or SC) of ustekinumab or placebo and subjects will be analyzed based on the 
treatment they received, regardless of the treatment groups to which they were assigned. 
The PK analysis set will include all subjects who receive at least 1 complete dose of ustekinumab 
and have at least one post initial dose sample collection.
The immunogenicity analysis set is defined as all subjects who received at least 1 dose (partial or 
complete) of ustekinumab and have at least one post initial dose sample collection.  Subjects will 
be analyzed according to the actual treatment received.
The PD analysis set is defined as all subjects who received at least one dose (complete or partial, 
IV or SC) of study agent.  Subjects will be analyzed according to the actual treatment received.
11.4.
Efficacy Analyses 
In general, for treatment response efficacy endpoints, treatment comparisons will be performed 
using a logistic regression model, adjusting for baseline stratification factors, baseline 
SLEDAI-2K score, and region. In general, for continuous efficacy endpoints, treatment 
comparisons will be performed using either an MMRM model or an analysis of covariance 
model. All the models will include treatment group, adjustments for baseline stratification 
factors, baseline SLEDAI-2K score, and region as appropriate, and may include baseline values
of the dependent variable as explanatory factors.
11.4.1.
Primary Endpoint Analysis
Analyses of the primary efficacy endpoint (SRI-4 composite response at Week 52) will include 
data from all randomized subjects who received at least 1 dose of study agent based on their 
assigned treatment group regardless of the actual treatment received. The primary analysis will 
be based upon the composite estimand where subjects meeting treatment failure criteria are 
assumed nonresponders from the point of treatment failure forward, and missing data are 
assumed as nonresponse.
The SRI-4 composite response is defined as ≥ 4-point reduction from baseline in SLEDAI-2K 
score, no new BILAG A and no more than 1 new BILAG B domain score, and no worsening 
from baseline in the PGA.12,34 Subjects who meet 1 or more treatment failure criteria prior to 
Week 52 will be considered SRI-4 nonresponders at Week 52 regardless of the observed SRI-4 
response status.
Logistic regression, adjusting for baseline stratification
factors, region,
and baseline 
SLEDAI-2K, will be used to analyze the primary endpoint. The logistic regression model will 
include treatment group and stratification factors. The baseline SLEDAI-2K value will be
defined as the closest nonmissing measurement taken prior to the Week 0 infusion. See the SAP 
for further details about the analysis of the primary endpoint, including sensitivity analyses. 


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11.4.1.1.
Subgroup Analyses
Subgroup analysis of the primary endpoint based on region may be performed. This is due to 
potential regional differences in evaluating efficacy, and high placebo response rates in certain 
regions. Subgroup analysis of the primary endpoint by other selected baseline characteristics 
may be presented:

Age

Race 

Baseline SLE Medications and SLEDAI-2K (combined) Score

Baseline lupus nephritis

Weight

Body mass index
For subgroup analyses, odds ratios and corresponding 95% confidence intervals will be 
presented graphically. Additionally, p-values for the comparison across treatment groups for the 
subgroups as well as for the interaction between treatment groups will be presented.
11.4.2.
Major Secondary Analyses
With the order specified in Section 2.2.2, each of the secondary endpoints will be tested at a 
2-sided α level of 0.05 if significance is achieved for the preceding hypothesis. If a given 
comparison is not significant at the 2-sided α level of 0.05, the remaining treatment group 
comparisons will be considered supportive analysis.
11.4.3.
Other Planned Efficacy Analyses
Other endpoints (see Section 2.2.3) will be summarized over time by treatment group. Treatment 
comparisons will be performed at Week 24 and Week 52. The methods of analysis and the data-
handling rules will be provided in the SAP. 
11.4.4.
Handling Missing Data
For the primary endpoint, subjects with missing data or meeting treatment failure criteria will be 
imputed as nonresponders. Sensitivity analyses will be performed and include (1) considering 
primary endpoint data for subjects meeting treatment failure criteria as missing and (2) using 
observed data regardless of whether the subject met treatment failure criteria. In both sensitivity 
analyses, missing response will be imputed by multiple imputation methods (eg, serial logistic 
regression) under the assumption of missing at random.  
For binary major secondary endpoints, analyses will be similar to the analysis of the primary 
endpoint:  subjects with missing data or meeting treatment failure criteria will be imputed as 
nonresponders. For other secondary endpoints, observations after meeting treatment failure 
criteria will be set to missing for subjects who met the criteria. No imputation will be performed 
for missing postbaseline continuous values; the statistical model (ie, MMRM) will adjust for 
missing data.


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For all other endpoints, observations after meeting treatment failure criteria will be set to missing 
for subjects who met the criteria. For binary endpoints, missing data will be imputed using 
multiple imputation methods (eg, serial logistic regression) under the assumption of missing at 
random. For continuous endpoints, the statistical model (ie, MMRM) will adjust for missing 
data.  
11.4.5.
Treatment Failure Criteria
Subjects who meet 1 or more of the following criteria (due to increased SLE disease activity) 
will be defined as treatment failures from the time the treatment failure occurs onward:

Exceed 
the 
baseline 
dose 
of 
permitted 
SLE 
medications 
(eg,
antimalarials, 
immunosuppressants, glucocorticoids) between the Week 12 and the Week 52 visits

Initiate
a new permitted SLE medication (eg, antimalarials, immunosuppressants, 
glucocorticoids) between the Week 12 and Week 52 visits. A “new” SLE medication is one 
that was not present at randomization or is not a replacement for (in the same class as) a 
medication present at randomization at an equivalent or lower dose (see note below)

Initiate a new protocol-prohibited medication (eg, intravenous glucocorticoid exceeding 
625 mg prednisone equivalent/day for 2 or more days, disallowed route of systemic 
glucocorticoid administration, systemic immunomodulators, cytotoxic agent, biologic agent) 
at any time between randomization and the Week 52 visit

Discontinue study agent for any reason prior to Week 52
Note: Substitution of an agent with a similar mechanism of action at an equivalent or lower dose 
will not be considered a treatment failure (eg, MMF substitution for MPA or vice versa, AZA 
substitution for 6-MP or vice versa, glucocorticoid substitutions for other glucocorticoids). In 
addition, MTX oral can replace MTX subcutaneous (or intramuscular) or MTX subcutaneous (or 
intramuscular) can replace MTX oral).
Further details of data handling rules, including treatment failure criteria, will be presented in the 
SAP.
11.5.
Pharmacokinetic Analyses
Serum ustekinumab concentrations will be summarized over time. Descriptive statistics, 
including arithmetic mean, standard deviation, median, interquartile range, minimum, and
maximum will be calculated at each sampling time point. All concentrations below the lowest 
quantifiable sample concentration of the assay (BQL) or missing data will be labeled as such in 
the concentration data listing or statistical analysis system (SAS) dataset. The BQL 
concentrations will be treated as zero in the summary statistics.
If feasible, population PK analysis of ustekinumab may be performed using nonlinear 
mixed-effects modeling. Data may be combined with those of other selected studies to support a 
relevant structural model. Available baseline subject characteristics (demographics, laboratory 
variables, disease characteristics, etc) will be tested as potential covariates affecting PK 


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parameters. Details will be given in a population PK analysis plan and the results of the 
population PK analysis will be presented in a separate report.
11.6.
Immunogenicity Analyses 
The incidence and titers of anti-ustekinumab antibodies will be summarized for all subjects who 
receive at least 1 dose of ustekinumab and have appropriate samples for detection of antibodies 
to ustekinumab (ie, subjects with at least 1 sample obtained after their first dose of ustekinumab).
A listing of subjects who are positive for antibodies to ustekinumab will be provided. The 
maximum titers of antibodies to ustekinumab will be summarized for subjects who are positive 
for antibodies to ustekinumab.
The incidence of NAbs to ustekinumab will be summarized for subjects who are positive for 
antibodies to ustekinumab and have samples evaluable for NAbs to ustekinumab.
Other immunogenicity analyses may be performed to further characterize the immune responses 
that are generated.
11.7.
Pharmacodynamic and Biomarker Analyses
Biomarker analyses may be performed, including serum analysis for levels of IFN as well as 
molecular pathway profiling for evidence of IL-12 and IL-23 pathway modulation. The 
biomarkers analyzed may include inflammatory markers, RNA, auto-antibodies, T, B, and NK 
cell immunophenotyping, and other categories of biomarkers potentially involved in the 
development and the progression of SLE.
Analytes may include (but are not limited to):

Type I, II, and III IFNs

IL-6

C-X-C motif chemokine 10 (CXCL10)

Antibodies associated with coagulopathy

Immunoglobulin characterization

BAFF, also known as BLyS

Other inflammation-related molecules

Other known SLE auto-antibodies (ANA, anti-Smith antibody, anti-SSA [anti-Ro], and 
anti-SSB [anti-La])

Subject whole blood IFN signature response
Biomarker results will be summarized in a separate technical report. Planned biomarker analyses 
may be deferred if emerging study data show no likelihood of providing useful scientific 
information. Any PD samples received by the contract vendor or sponsor after the cutoff date 
will not be analyzed, and therefore, excluded from the PD analysis.


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Genetic (DNA) analyses will be conducted only in subjects who sign the optional DNA consent 
form. These analyses will be summarized in a separate technical report.
11.8.
Pharmacokinetic and Pharmacodynamic Analyses 
11.8.1.
Pharmacokinetic/Pharmacodynamic Evaluations
If data permit, the relationship between serum ustekinumab concentration and efficacy or PD
measures may be analyzed graphically. In addition, population PK/PD modeling may be 
performed to characterize the relationship between serum ustekinumab exposure and efficacy 
measures. Further details will be provided in a population PK/PD analysis plan and the results 
will be summarized in a separate report.
11.9.
Safety Analyses
Safety analyses will include summaries of discontinuations, deaths, AEs, SAEs, and clinical 
laboratory tests. Targeted safety events in SLE, based on mechanistic plausibility (eg, serious 
infections, opportunistic infections, TB, hypersensitivity reactions) or potential population risks 
(eg, worsening of renal or CNS disease) will also be summarized.
11.9.1.
Adverse Events
The verbatim terms used in the eCRF by Investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent adverse 
events are adverse events with onset during the treatment phase or that are a consequence of a 
pre-existing condition that has worsened since baseline. All reported adverse events will be 
included in the analysis. For each adverse event, the percentage of subjects who experience at 
least 1 occurrence of the given event will be summarized by treatment group. In addition, 
comparisons between treatment groups will be provided if appropriate. The incidence, severity,
and types of infections, infusion reactions, and injection-site reactions will be analyzed for this 
study.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue treatment due to an adverse event, or who experience a severe 
or a serious adverse event.
11.9.2.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the Statistical Analysis Plan) 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 Changes from baseline results will be presented in 
pre- versus posttreatment cross-tabulations (with classes for below, within, and above normal 
ranges). Frequency tabulations of the abnormalities will be made. A listing of subjects with any 
laboratory results outside the reference ranges will be provided. A listing of subjects with any 
markedly abnormal laboratory results will also be provided.


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11.10. Interim Analysis
A futility analysis will be carried out 24 weeks after approximately 50% of the planned subjects 
have been randomized. The analysis will be performed in an unblinded fashion by the 
independent DMC based primarily on Week 24 efficacy data. Additional data available at the 
time of the futility analysis (eg, other endpoints, other time points) may also be considered. The 
details of the futility analysis will be included in the SAP. As this is a futility analysis and the 
study will not be stopped early to claim success, no alpha adjustment will be implemented due to 
the futility analysis.
11.11. Data Monitoring Committee 
An independent DMC will be established to monitor data on an ongoing basis to ensure the 
continuing safety of the subjects enrolled in this study. The committee will meet periodically to 
review interim data. After the review, the DMC will make recommendations regarding the 
continuation of the study. The details will be provided in a separate DMC charter.
In addition to regular safety reviews, the DMC will perform a futility analysis 24 weeks after 
approximately 50% of the planned subjects have been randomized. After reviewing the data, the 
DMC will make a recommendation to the Sponsor Committee, which is independent of the study 
team, based on the predefined futility rules (details are included in the SAP and the DMC 
Charter). The possible recommendations are (1) to stop the study for futility or (2) continue the 
study without modification. The Sponsor Committee will then communicate the final decision to 
the study team.
The DMC will consist of at least one medical expert in the relevant therapeutic area and at least 
one statistician. The DMC responsibilities, authorities, and procedures will be documented in its 
charter.
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, Investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting adverse events or serious adverse events. 
Open-ended and nonleading verbal questioning of the subject is the preferred method to inquire 
about adverse event occurrence.
Solicited Adverse Events
Solicited adverse events are predefined local and systemic events for which the subject is 
questioned specifically (see Section 9.1.1, Overview).


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Unsolicited Adverse Events
Unsolicited adverse events are all adverse events for which the subject is not questioned 
specifically.
12.1.
Definitions
For a definition of medical device incidents and procedures for documenting them, see 
Attachment 5.
12.1.1.
Adverse Event Definitions and Classifications
Adverse Events
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated
with the use of a medicinal (investigational or non-investigational) product, whether or not 
related to that medicinal (investigational or non-investigational) product. (Definition per ICH)
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Results in serious injury/death possibly caused by device malfunction

Results in medical or surgical intervention to prevent permanent impairment or damage 
caused by device malfunction.

Is Medically Important*


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*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study agent 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 adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For ustekinumab, the expectedness of an 
adverse event will be determined by whether or not it is listed in the Investigator's Brochure. For 
standard-of-care background therapies with a marketing authorization, the expectedness of an 
adverse event will be determined by whether or not it is listed in the package insert/summary of 
product characteristics.
Adverse Event Associated with the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2.
12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).


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Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria 
An assessment of severity grade will be made using the following general categorical 
descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The Investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study agent that may require expedited reporting or safety 
evaluation include, but are not limited to:

Overdose of a sponsor study agent

Suspected abuse/misuse of a sponsor study agent

Accidental or occupational exposure to a sponsor study agent

Unexpected therapeutic or clinical benefit from use of a sponsor medicinal product

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study agent, eg, name confusion)

Exposure to a sponsor study agent from breastfeeding
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the eCRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be 
reported from the time a signed and dated ICF is obtained until completion of the subject's last 
study-related procedure, which may include contact for follow-up of safety. Serious adverse 
events, including those spontaneously reported to the Investigator within 16 weeks after the last 


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dose of study agent, must be reported using the Serious Adverse Event Form. The sponsor will 
evaluate any safety information that is spontaneously reported by an Investigator beyond the 
time frame specified in the protocol.
All events that meet the definition of a serious adverse event will be reported as serious adverse 
events, regardless of whether they are protocol-specific assessments. Anticipated events will be 
recorded and reported as described in Attachment 3 (and consistent with local guidelines).
All adverse events, regardless of seriousness, severity, or presumed relationship to study agent, 
must be recorded using medical terminology in the source document and the 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 adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the Investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). For 
anticipated events reported as individual serious adverse events the sponsor will make a 
determination of relatedness in addition to and independent of the Investigator’s assessment. The 
sponsor will periodically evaluate the accumulating data and, when there is sufficient evidence 
and the sponsor has determined there is a reasonable possibility that the drug caused a serious 
anticipated event, they will submit a safety report in narrative format to the Investigators (and the 
head of the investigational institute where required). 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.
For all studies with an outpatient phase, including open-label studies, the subject must be 
provided with a "wallet (study) card" and instructed to carry this card with them for the duration 
of the study indicating the following:

Study number

Statement, in the local language(s), that the subject is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical staff only)

Site number

Subject number

Any other information that is required to do an emergency breaking of the blind


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12.3.2.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form and Safety Report Form of the eCRF, which must be completed and 
reviewed by a physician from the study site, and transmitted to the sponsor within 24 hours. The 
initial and follow-up reports of a serious adverse event should be transmitted electronically or by 
facsimile (fax).
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study agent or to factors unrelated to 
study conduct

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a 
serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization) 
that occurs during a subject's participation in a study must be reported as a serious adverse event, 
except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons 
such as pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the 
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 serious adverse events. Any adverse event that results in a prolongation of 
the originally planned hospitalization is to be reported as a new serious adverse event.

For convenience, the Investigator may choose to hospitalize the subject for the duration of 
the treatment period.
The cause of death of a subject in a study within 16 weeks of the last dose of study agent, 
whether or not the event is expected or associated with the study agent, is considered a serious 
adverse event.


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Disease progression should not be recorded as an adverse event or serious adverse event term; 
instead, signs and symptoms of clinical sequelae resulting from disease progression/lack of 
efficacy will be reported if they fulfill the serious adverse event definition (refer to
Section 12.1.1, Adverse Event Definitions and Classifications).
12.3.3.
Pregnancy 
All initial reports of pregnancy in female subjects or partners of male subjects 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 serious 
adverse events and must be reported using the Serious Adverse Event Form. Any subject who 
becomes pregnant during the study must be promptly withdrawn from the study and discontinue 
further study agent.
Because the effect of the study agent on sperm is unknown, pregnancies in partners of male 
subjects included in the study will be reported as noted above. Follow-up information regarding 
the outcome of the pregnancy and any postnatal sequelae in the infant will be required.
12.3.4.
Events of Special Interest
Adverse events of special interest: infusion or hypersensitivity reactions, serious infections, 
opportunistic infection (ie, infection by an organism that normally is not pathogenic or does not 
cause invasive infection in immunocompetent hosts), or case of active TB occurring after the 
first administration of study agent in subjects participating in this clinical study must be reported 
by the Investigator following procedures. Investigators are also advised that active TB is 
considered a reportable disease in most countries. These events are to be considered serious only 
if they meet the definition of an SAE as shown in Section 12.1.1.
12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and
analysis of PQC information from studies are crucial for the protection of subjects, Investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.


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13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be 
maintained for further investigation if requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY AGENT INFORMATION
14.1.
Physical Description of Study Agent(s)
14.1.1.
Intravenous Administration
The ustekinumab supplied for this study is a single-use, sterile solution in 30 mL vials with 
1 dose strength (ie, 130 mg in 26 mL nominal volume). In addition to ustekinumab, the solution 
contains 10 mM L-histidine, L-histidine monohydrochloride monohydrate, 8.5% (w/v) sucrose, 
0.04% (w/v) polysorbate 80, 0.4 mg/mL L-methionine, and 20 µg/mL ethylenediaminetetraacetic 
acid (EDTA) disodium salt dihydrate at pH 6.0. No preservatives are present. It will be 
manufactured and provided under the responsibility of the sponsor.
Placebo administrations will have the same appearance as the respective ustekinumab 
administrations. Matching placebo for final vialed product (IV) is supplied as single-use, sterile 
solution in 30 mL vials with a 26 mL nominal volume. The composition of the placebo is 10 mM 
L-histidine, L-histidine monohydrochloride monohydrate, 8.5% (w/v) sucrose, 0.04% (w/v) 
polysorbate 80, 0.4 mg/mL L-methionine, and 20 µg/mL EDTA disodium salt dihydrate at pH
6.0. No preservatives are present. 
Body weight-range based dosing will allow administration of complete vials to subjects to
simplify dose calculation and reduce the potential for errors in dosing. This body weight-range 
based IV dosing is intended to achieve drug exposure similar to that observed with weight-range 
based dosing at ~6 mg/kg. Comparable numbers of vials will be administered to subjects 
receiving placebo based on their body weight. 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)

Body weight ˃85 kg: 520 mg ustekinumab (4 vials)


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14.1.2.
Subcutaneous Administration
Ustekinumab will also be supplied as a single-use prefilled syringe (PFS) in a strength of 90 mg
in 1 mL nominal volume for SC administration. Each 1 mL of ustekinumab solution in the PFS 
contains 90 mg ustekinumab with nominal excipient concentrations of 6.7 mM L-histidine, 7.6% 
(w/v) sucrose, 0.004% (w/v) polysorbate 80, at pH 6.0. No preservatives are present. The needle 
cover on the PFS contains dry natural rubber (a derivative of latex), which may cause allergic 
reactions in individuals sensitive to latex.
Placebo administrations will have the same appearance as the respective ustekinumab 
administrations. Liquid placebo will also be supplied in a 1 mL PFS, and have a composition 
10 mM L-histidine, 8.5% (w/v) sucrose, 0.004% (w/v) polysorbate 80, at pH 6.0. No 
preservatives are present. The needle cover on the PFS contains dry natural rubber (a derivative 
of latex), which may cause allergic reactions in individuals sensitive to latex. 
14.2.
Packaging
The investigational supplies will be uniquely packaged to assure that they are appropriately 
managed throughout the supply chain process. The study agent will be packaged in individual 
subject kits. Each kit will consist of a single vial or PFS packaged inside a protective outer 
carton.
Study agent will not be dispensed in child-resistant packaging.
14.3.
Labeling
Study agent labels will contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage 
All study agent must be stored at controlled temperatures ranging from 2°C to 8°C (36°F to 
46°F), not frozen, and protected from light. Allowable temperature excursions are described in 
the Temperature out of Range (TOR) document. Vigorous shaking of the product should be 
avoided. Prior to administration, the product should be inspected visually for particulate matter 
and discoloration. If discoloration (other than a slight yellow color), visible opaque particles, or 
other foreign particles are observed in the solution, the product should not be used.
Study agent in glass vials or PFS will be ready to use. The infusions will be prepared according
to the subject’s treatment assignment and weight (for weight-range based infusions). The 
pharmacist (or designated personnel) will prepare the required volume of study agent to be 
infused using the appropriate number of vials.
Aseptic procedures must be used during the preparation and administration of the study material. 
Exposure to direct sunlight should be avoided during preparation and administration. 
Refer to the pharmacy manual/study site IP and procedures manual for additional guidance on 
study agent preparation, handling, and storage.


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14.5.
Drug Accountability
The Investigator is responsible for ensuring that all study agent received at the site is inventoried 
and accounted for throughout the study. The study agent administered to the subject must be 
documented on the drug accountability form or in the drug accountability system as applicable. 
All study agent will be stored and disposed of according to the sponsor's instructions. Study-site 
personnel must not combine contents of the study agent containers.
Study agent must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study agent, and study agent returned by the subject, must be 
available for verification by the sponsor's study site monitor during on-site monitoring visits. The 
return to the sponsor of unused study agent, or used returned study agent for destruction, will be 
documented on the drug return form. When the study site is an authorized destruction unit and 
study agent supplies are destroyed on-site, this must also be documented on the drug return form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes. 
Study agent should be dispensed under the supervision of the Investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study agent will be supplied only 
to subjects participating in the study. Returned study agent must not be dispensed again, even to 
the same subject. Study agent may not be relabeled or reassigned for use by other subjects. The 
Investigator agrees neither to dispense the study agent from, nor store it at, any site other than the 
study sites agreed upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The Investigator will be provided with the following supplies:

Investigator's Brochure 

Study site IP and procedures manual

Laboratory manual(s) and laboratory supplies

Medical Photography manual

Certain Clinical Outcome Assessments (COAs; includes both PROs and ClinROs) will be 
collected using an electronic device while others will be collected on paper worksheets. 
Therefore, the following materials will be provided:

COA questionnaires and completion instructions. The following ClinROs and PROs 
will be collected on the paper worksheets provided:
o
ClinROs:

SLEDAI-2K RI-50

BILAG


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
mSFI

CLASI

LFA REAL – ClinRO portion

SLICC/ACR Damage Index
o
PROs:

LFA REAL – PRO portion. Collection only in US for native English speakers.

Electronic COA device and user manual. The following ClinROs and PROs will be 
collected using an electronic device:
o
ClinROs:

PGA VAS

Joint count assessment (used to obtain number of active joints for entry into 
SLEDAI-2K-RI50)
o
PROs:

Patient Assessment of Pain Intensity VAS

FACIT-Fatigue 

SF-36 v2

EQ-5D-5L Descriptive System

LupusQoL

WPAI-Lupus

IWRS user guide and worksheets

eCRF completion guidelines

Sample ICFs

Subject diary card

Any other manual or guideline that is deemed necessary for good execution of the study
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
Potential subjects will be fully informed of the risks and requirements of the study and, during the
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential adverse events of the study, and provide their consent voluntarily will be enrolled.


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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 subject, 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 subjects 
7 years of age and older, depending on the institutional policies. For the purposes of this study, all 
references to subjects who have provided consent (and assent as applicable) refers to the subjects 
and his or her parent(s) or the subject's legal guardian(s) or legally acceptable representative(s) 
who have provided consent according to this process. Minors who assent to a study and later 
withdraw that assent should not be maintained in the study against their will, even if their parents 
still want them to participate.
The total blood volume to be collected is considered an acceptable amount of blood to be 
collected over this period from the population. The total blood volume to be collected from each 
subject over the course of the double-blind period of the study through Week 64 follow-up will 
be approximately 730 mL over 1 year, which is less than 2 typical blood donations of 500 mL 
each. The total blood volume to be collected in the study extension between Weeks 56 and 176 
will be approximately 140 mL.
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The Investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the Investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials


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
Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct, unless required locally), the ICF, applicable 
recruiting materials, and subject compensation programs, and the sponsor has received a copy of 
this approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
Approval for the collection of optional pharmacogenetics and/or cutaneous skin biopsies for 
research and for the corresponding ICF must be obtained from the IEC/IRB. Approval for the 
protocol can be obtained independent of this optional research component. 
During the study, the Investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the 
study agent

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the Investigator's care

Notification if a new Investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB


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For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where 
required.
At the end of the study, the Investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion.
16.2.3.
Informed Consent and Assent Form
Each subject (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) and assent form that are used must 
be approved by both the sponsor and by the reviewing IEC/IRB and be in a language that the 
subject can read and understand. The informed consent should be in accordance with principles 
that originated in the Declaration of Helsinki, current ICH and GCP guidelines, applicable 
regulatory requirements, and sponsor policy.
Before enrollment in the study, the Investigator or an authorized member of the study-site 
personnel must explain to potential subjects (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. Subjects will be informed that their participation is 
voluntary and that they may withdraw consent to participate at any time. They will be informed 
that choosing not to participate will not affect the care the subject will receive for the treatment 
of his or her disease. Subjects will be told that alternative treatments are available if they refuse 
to take part and that such refusal will not prejudice future treatment. Finally, they will be told 
that the Investigator will maintain a subject identification register for the purposes of long-term 
follow up if needed and that their records may be accessed by health authorities and authorized 
sponsor personnel without violating the confidentiality of the subject, to the extent permitted by 
the applicable law(s) or regulations. By signing the ICF
the subject or legally 
acceptable representative is authorizing such access, which includes permission to obtain 
information about his or her survival status. It also denotes that the subject agrees to allow his or 
her study physician to recontact the subject for the purpose of obtaining consent for additional 
safety evaluations, and subsequent disease-related treatments, if needed.
The subject 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 subject'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 subject.


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Assent must be obtained from children (minors) capable of understanding the nature of the study, 
depending on the institutional policies. A separate assent form written in language the subject can 
understand should be developed for subjects who are not considered to be adults legally (per 
local requirements). After having obtained the assent, a copy of the assent form must be given to 
the subject, and to the subject's parent or, if applicable, legally acceptable representative.
Subjects must be able to read and write and give informed consent/assent without assistance. A 
subject who is unable to read or write or to give informed consent/assent is not eligible to 
participate in the study.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alternative must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential.
The informed consent obtained from the subject (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 subject has the right to request through the Investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
DNA, PD biomarker, PK, and immunogenicity research in this study is not conducted under 
standards appropriate for the return of data to subjects. In addition, the sponsor cannot make 
decisions as to the significance of any findings resulting from this research. Therefore, these 
research data will not be returned to subjects or Investigators, unless required by law or local 
regulations. Privacy and confidentiality of data generated in the future on stored samples will be 
protected by the same standards applicable to all other clinical data.
16.2.5.
Long-term Retention of Samples for Additional Future Research 
Samples collected in this study for PK, immunogenicity, and biomarker analyses 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 lupus, to understand differential drug 
responders, and to develop tests/assays related to ustekinumab and lupus. The research may 
begin at any time during the study or the post-study storage period. 


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Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 10.3, Withdrawal From the Use of Samples in Future 
Research.
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product if the need for the product persists, unless explicitly 
addressed as a specific ethical consideration in Section
16.1, Study-Specific Design 
Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the Investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the Investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the Investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IEC/IRB (where required) only needs to be notified.
During 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 Contact 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.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study agent to the 
study site:


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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, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an Investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of Investigator (eg, Form FDA 1572), if applicable

Documentation of Investigator qualifications (eg, curriculum vitae)

Completed Investigator financial disclosure form from the principal Investigator, where 
required

Signed and dated clinical study agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed Investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
17.3.
Subject Identification, Enrollment, and Screening Logs
The Investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the Investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification
and date of birth (as allowed by local regulations). In cases where the subject is not randomized 
into the study, the date seen and date of birth will be used.


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The Investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source 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: 
subject identification, eligibility, and study identification; study discussion and date of signed 
informed consent; dates of visits; results of safety and efficacy parameters as required by the 
protocol; record of all adverse events and follow-up of adverse events; concomitant medication; 
drug receipt/dispensing/return records; study agent administration information; and date of study 
completion and reason for early discontinuation of study agent or withdrawal from the study, if 
applicable. 
The author of an entry in the source documents should be identifiable.
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).
Information collected at unscheduled visits should be documented as described for scheduled 
visits.
The minimum source documentation requirements for Section 4.1.1, Inclusion Criteria and 
Section 4.1.2, Exclusion Criteria that specify a need for documented medical history are as 
follows:

Referral letter from treating physician or

Complete history of medical notes at the site

Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents.
An electronic source 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 the electronic source system is utilized, references made to 
the eCRF in the protocol include the electronic source system but information collected through 
the electronic source system may not be limited to that found in the eCRF. Data in this system 
may be considered source documentation.
17.5.
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each subject in electronic format.
All eCRF entries, corrections, and alternatives must be made by the Investigator or authorized 


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study-site personnel. The Investigator must verify that all data entries in the eCRF are accurate 
and correct.
The study data will be transcribed by study-site personnel from the source documents onto an 
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 subject's source documents. Data must be entered into 
eCRF in English. The eCRF must be completed as soon as possible after a subject visit and the 
forms should be available for review at the next scheduled monitoring visit.
All subjective measurements (eg, pain scale information or other questionnaires) will be 
completed by the same individual who made the initial baseline determinations whenever 
possible.
If necessary, queries will be generated in the eDC tool. If corrections to a 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.
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
Investigators and appropriate study sites, review of protocol procedures with the Investigator and 
study-site personnel before the study, periodic monitoring visits by the sponsor, 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. 
17.7.
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 subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The Investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.


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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 IP. These documents will be retained for a longer 
period if required by the applicable regulatory requirements or by an agreement with the sponsor. 
It is the responsibility of the sponsor to inform the Investigator/institution as to when these 
documents no longer need to be retained.
If the responsible Investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the Investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the Investigator/institution must permit access to such 
reports.
17.8.
Monitoring
The sponsor will 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). 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.
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.


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17.9.
Study Completion/Termination
17.9.1.
Study Completion/End of Study
The study is considered completed with the last follow-up assessment at Week 176 for the last 
subject participating in the study. The final data from the study site will be sent to the sponsor (or 
designee) after completion of the final subject visit at that study site, in the time frame specified 
in the Clinical Trial Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or Investigator may include but are 
not limited to:

Failure of the Investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the Investigator

Discontinuation of further study agent development
17.10. On-site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. Subject privacy must, however, be 
respected. The Investigator and study-site personnel are responsible for being present and 
available for consultation during routinely scheduled study-site audit visits conducted by the 
sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The Investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding ustekinumab or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the Investigator and not 
previously published, and any data, including biomarker research data, generated as a result of 


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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 biomarker 
analyses performed after the Clinical Study Report has been issued will be summarized in a 
separate report and will not require a revision of the Clinical Study Report. Study subject 
identifiers will not be used in publication of results. Any work created in connection with 
performance of the study and contained in the data that can benefit from copyright protection 
(except any publication by the Investigator as provided for below) shall be the property of the 
sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data
and information without approval from the Investigator. The Investigator has the right to publish 
study site-specific data after the primary data are published. If an Investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the Investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the Investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
Investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study
have been submitted for publication, within 12 months of the availability of the final data (tables, 
listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.


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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.


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lupus erythematosus patients. Lupus. 2013; 22(10):1011-1016.


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43.
Samsa G, Edelman D, Rothman ML, et al. Determining clinically important differences in health status 
measures: a general approach with illustration to the Health Utilities Index Mark II. Pharmacoeconomics. 
1999; 15(2):141-155.
44.
Sánchez E, Rueda B, Callejas JL, et al. Analysis of interleukin-23 receptor (IL23R) gene polymorphisms in 
systemic lupus erythematosus. Tissue Antigens. 2007; 70:233–237.
45.
Sanchez R, Comeau ME, Freedman BI, et al. Identification of novel genetic susceptibility loci in African-
American lupus patients using a candidate gene association study. Arthritis Rheum. 2011; 63(11): 3493–3501.
46.
Sestak AL, Fürnrohr BG, Harley JB, Merrill JT, Namjou B. The genetics of systemic lupus erythematosus and 
implications for targeted therapy. Ann Rheum Dis. 2011; 70(S1): i37–i43.
47.
Shah K, Lee WW, Lee SH, et al. Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus. 
Arthritis Res Ther. 2010; 12:R53.
48.
Tektonidou MG, Wang Z, Dasgupta A, Ward MM. Burden of serious infections in adults with systemic lupus 
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67(8):1078–1085.
49.
Touma Z, Gladman DD, Ibanez D, Urowitz MB. Development and initial validation of the Systemic Lupus 
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Touma Z, Gladman DD, Urowitz MB. SLEDAI-2K for a 30-day window. Lupus. 2010;19(1):49-51.
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Touma Z, Urowitz M, Ibañez D, Gladman D. SLEDAI-2K 10 days versus SLEDAI-2K 30 days in a 
longitudinal evaluation. Lupus. 2011; 20(1):67-70.  
52.
Touma Z, Urowitz MB, Fortin PR, et al. Systemic Lupus Erythematosus Disease Activity Index 2000 
Responder Index-50: a reliable index for measuring improvement in disease activity. J Rheumatol. 2011; 
38(5):868-873. 
53.
van Vollenhoven R, Hahn BH, Tsokos GC, et al. Efficacy and safety of ustekinumab, an interleukin 12/23 
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Van Vollenhoven R, Voskuyl A, Bertsias G, et al. A framework for remission in SLE: consensus findings from 
a large international task force on definitions of remission in SLE (DORIS). Ann Rheum Dis. 2017; 76(3):554-
561.
56.
Wallace DJ. Lupus: The Essential Clinician’s Guide, 2nd edition. New York, NY: Oxford University Press, Inc; 
2014.
57.
Ware JE Jr, Sherbourne CD. The MOS 36 item Short-Form Health Survey (SF 36), I: conceptual framework 
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58.
Ware JE, Kosinski M, Keller SK. SF-36 Physical and Mental Health Summary Scales: A User’s Manual. 
Boston, MA: The Health Institute, 1994.
59.
Ware JE. SF-36 Health Survey Update. Spine. 2000; 25(24):3130-3139.
60.
Wilhelm TR, Magder LS, Petri M. Remission in systemic lupus erythematosus: durable remission is rare. Ann 
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61.
Wong CK, Lit LCW, Tam LS, et al. Hyperproduction of IL-23 and IL-17 in patients with systemic lupus 
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127:385–393.


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ATTACHMENTS
Attachment 1: SLICC Classification Criteria ............................................................................................. 140
Attachment 2: Tuberculin Skin Testing ..................................................................................................... 142
Attachment 3: Anticipated Events ............................................................................................................. 143
Attachment 4: Hepatitis B Virus (HBV) Screening with HBV DNA Testing............................................... 144
Attachment 5: Medical Device Incidents: Definition and Procedures for Recording................................. 145


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Attachment 1: SLICC Classification Criteria
Clinical and Immunological Criteria Used in the SLICC Classification Criteria*+ 
Clinical Criteria
Specific Criteria
1.
Acute Cutaneous Lupus including 
lupus malar rash (do not count if malar 
discoid)

Bullous lupus

Toxic epidermal necrolysis variant of SLE

Maculopapular lupus rash

Photosensitive 
lupus 
rash 
(in 
absence 
of 
dermatomyositis)

Subacute cutaneous lupus (nonindurated psoriaform 
and/or annular polycyclic lesions that resolve 
without scarring, although occasionally 
with 
postinflammatory 
dyspigmentation 
or 
telangiectasias)
2.
Chronic cutaneous lupus including 
classical discoid rash

Localized (above the neck)

Generalized (above and below the neck)

Hypertrophic (verrucous) lupus

Lupus panniculitis (profundus)

Mucosal lupus

Lupus erythematosus tumidus

Chilblains lupus

Discoid lupus / lichen planus overlap
3.
Oral ulcers: palate

Buccal

Tongue

Nasal
In the absence of other causes such as vasculitis, 
Behcets, infection (herpes), inflammatory bowel disease, 
reactive arthritis, and acidic foods
4.
Non-scarring alopecia (diffuse thinning 
or hair fragility with visible broken 
hairs)
In the absence of other causes such as alopecia areata, 
drugs, iron deficiency and androgenic alopecia
5.
Synovitis involving two or more joints
Characterized by swelling or effusion OR tenderness in 
2 or more joints and thirty minutes or more of morning 
stiffness
6.
Serositis

Typical pleurisy for more than 1 day
o
Or pleural effusions
o
Or pleural rub

Typical pericardial pain (pain with recumbency 
improved by sitting forward) for more than 1 day
o
Or pericardial effusion
o
Or pericardial rub
o
Or pericarditis by ECG
In the absence of other causes such as infection, uremia 
and Dressler’s pericarditis
7.
Renal

Urine protein/creatinine (or 24-hour urine protein) 
representing 500 mg of protein/24 hour, or

Red blood cell casts


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Clinical and Immunological Criteria Used in the SLICC Classification Criteria*+ 
8.
Neurologic

Seizures

Psychosis

Mononeuritis multiplex (in the absence of other 
known causes such as primary vasculitis)

Myelitis

Peripheral or cranial neuropathy (in the absence of 
other known causes such as primary vasculitis, 
infection and diabetes mellitus)

Acute confusional state (in the absence of other 
causes including toxic-metabolic, uremia, drugs)
9.
Hemolytic anemia

Presence
10a. Leukopenia (<4000/mm3
at least 
once), or
10b. Lymphopenia (<1000/mm3 at least 
once)
In the absence of other known causes such as Felty’s, 
drugs, and portal hypertension
In the absence of other known causes such as 
glucocorticoids, drugs, and infection
11. Thrombocytopenia (<100,000/mm3 at 
least once)
In the absence of other known causes such as drugs, 
portal hypertension, and TTP
Immunological Criteria
Specific Criteria 
1.
ANA 
above laboratory reference range
2.
Anti-dsDNA
above laboratory reference range, except ELISA; twice 
above laboratory reference range
3.
Anti-Smith

Presence
4.
Anti-phospholipid
antibody 
(any 
shown to right)

Lupus anticoagulant

False-positive RPR

Medium or high titer anticardiolipin (IgA, IgG or 
IgM)

Anti-β2 glycoprotein 1 (IgA, IgG or IgM)
5.
Low Complement

Low C3

Low C4

Low CH50
6.
Direct Coombs test
In the absence of hemolytic anemia
*
Criteria are cumulative and do not need to be present concurrently
+
Petri M, Orbai AM, Alarcón GS, et al. Derivation and validation of the Systemic Lupus International 
Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 
2012;64(8):2677-2686.


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Attachment 2: Tuberculin Skin Testing
Administering the Mantoux Tuberculin Skin Test
The Mantoux tuberculin skin test (CDC, 2000) is the standard method of identifying persons infected 
with Mycobacterium tuberculosis. Multiple puncture tests (Tine and Heaf) should not be used to 
determine whether a person is infected because the amount of tuberculin injected intradermally cannot be 
precisely controlled. Tuberculin skin testing is both safe and reliable throughout the course of pregnancy.
The Mantoux tuberculin test is performed by placing an intradermal injection of 0.1 mL of tuberculin into 
the inner surface of the forearm. The test must be performed with tuberculin that has at least the same 
strength as either 5 tuberculin units (TU) of standard purified protein derivative (PPD) S or 2 TU of PPD 
RT 23, Statens Seruminstitut, as recommended by the World Health Organization. PPD strengths of 1 TU 
or 250 TU are not acceptable (Menzies, 2000). Using a disposable tuberculin syringe with the needle 
bevel facing upward, the injection should be made just beneath the surface of the skin. This should 
produce a discrete, pale elevation of the skin (a wheal) 6 mm to 10 mm in diameter. To prevent 
needle-stick injuries, needles should not be recapped, purposely bent or broken, removed from disposable 
syringes, or otherwise manipulated by hand. After they are used, disposable needles and syringes should 
be placed in puncture-resistant containers for disposal. Institutional guidelines regarding universal 
precautions for infection control (eg, the use of gloves) should be followed. A trained health care worker, 
preferably the Investigator, should read the reaction to the Mantoux test 48 to 72 hours after the injection.
Subjects should never be allowed to read their own tuberculin skin test results. If a subject fails to show 
up for the scheduled reading, a positive reaction may still be measurable up to 1 Week after testing.
However, if a subject who fails to return within 72 hours has a negative test, tuberculin testing should be 
repeated. The area of induration (palpable raised hardened area) around the site of injection is the reaction 
to tuberculin. For standardization, the diameter of the induration should be measured transversely 
(perpendicular) to the long axis of the forearm. Erythema (redness) should not be measured. All reactions 
should be recorded in millimeters, even those classified as negative.
Interpreting the Tuberculin Skin Test Results
In the US and many other countries, the most conservative definition of positivity for the tuberculin skin 
test is reserved for immunocompromised patients, and this definition is to be applied in this study to 
maximize the likelihood of detecting latent TB, even though the subjects may not be 
immunocompromised at baseline.
In the US and Canada, an induration of 5 mm or greater in response to the intradermal tuberculin skin test 
is considered to be a positive result and evidence for either latent or active TB.
In countries outside the US and Canada, country-specific guidelines for immunocompromised patients 
should be consulted for the interpretation of tuberculin skin test results. If no local country guidelines for 
immunocompromised patients exist, US guidelines must be followed.
Treatment of Latent Tuberculosis
Local country guidelines for immunocompromised patients should be consulted for acceptable anti-
tuberculous treatment regimens for latent TB. If no local country guidelines for immunocompromised 
patients exist, US guidelines must be followed.
References
Centers for Disease Control and Prevention. Core curriculum on tuberculosis: What the clinician should know 
(Fourth Edition). Atlanta, GA: Department of Health and Human Services; Centers for Disease Control and 
Prevention; National Center for HIV, STD, and TB Prevention; Division of Tuberculosis Elimination; 2000:25-86.
Menzies RI. Tuberculin skin testing. In: Reichman LB, Hershfield ES (eds). Tuberculosis, a comprehensive 
international approach. 2nd ed. New York, NY: Marcel Dekker, Inc; 2000:279-322. 


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Attachment 3: Anticipated Events
Anticipated Event
An anticipated event is an adverse event (serious or non-serious) that commonly occurs as a 
consequence of the underlying disease or condition under investigation (disease related) or 
background regimen.
For the purposes of this study the following events will be considered anticipated events:

Systemic lupus erythematosus worsening disease activity

Selected hematologic abnormal laboratory values (CTCAE grade 1 or 2 leukopenia, 
lymphopenia, neutropenia, anemia, and thrombocytopenia)
Reporting of Anticipated Events
All adverse events will be recorded in the eCRF regardless of whether considered to be 
anticipated events and will be reported to the sponsor as described under All Adverse Events in 
Section 12, Adverse Event Reporting. Any anticipated event that meets serious adverse event 
criteria will be reported to the sponsor as described under Serious Adverse Events in Section 12. 
These anticipated events are exempt from expedited reporting as individual single cases to 
Health Authorities. However, if based on an aggregate review it is determined that an anticipated 
event is possibly related to study agent, the sponsor will report these events in an expedited 
manner.
Anticipated Event Analysis Committee) 
An Anticipated Event Analysis Committee (AAC) will be established to perform reviews of 
prespecified anticipated events at an aggregate level. The AAC is a safety committee within the 
sponsor’s organization that is independent of the sponsor’s study team. The AAC will meet to 
aid in the recommendation to the sponsor’s study team as to whether there is a reasonable 
possibility that an anticipated event is related to the study agent.
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and 
threshold to trigger an aggregate analysis of anticipated events will be provided in a separate 
Anticipated Events Safety Monitoring Plan (ASMP).


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Attachment 4: Hepatitis B Virus (HBV) Screening with HBV DNA Testing
Subjects must undergo screening for hepatitis B virus (HBV). At a minimum, this includes 
testing for HBsAg (HBV surface antigen), anti-HBs (HBV surface antibody), and anti-HBc total 
(HBV core antibody total): 

Subjects who test negative for all HBV screening tests (ie, HBsAg-, anti-HBc-, and 
anti-HBs-) are eligible for this study.

Subjects who test negative for surface antigen (HBsAg-) and test positive for core 
antibody (anti-HBc+) and surface antibody (anti-HBs+) are eligible for this study.

Subjects who test positive only for surface antibody (anti-HBs+) are eligible for this 
study.

Subjects who test positive for surface antigen (HBsAg+) are NOT eligible for this study, 
regardless of the results of other hepatitis B tests.

Subjects who test positive only for core antibody (anti-HBc+) must undergo further 
testing for the presence of hepatitis B virus deoxyribonucleic acid (HBV DNA test). If 
the HBV DNA test is positive, the subject is NOT eligible for this study. If the HBV 
DNA test is negative, the subject is eligible for this study. In the event the HBV DNA 
test cannot be performed, the subject is NOT eligible for this study. 
For subjects who are not eligible for this study due to HBV test results, consultation with a 
physician with expertise in the treatment of hepatitis B virus infection is recommended.  
Eligibility based on hepatitis B virus test results
Hepatitis B test result
Action
Hepatitis B 
surface antigen
(HBsAg)
Hepatitis B 
surface antibody
(anti-HBs)
Hepatitis B core 
antibody
(anti-HBc total)
Include
—
—
—
—
+
—
—
+
+
Exclude
+
— or +
— or +
Require testing for presence 
HBV DNA*
—
—
+
* If HBV DNA is detectable, exclude from the clinical study. If HBV DNA testing cannot be 
performed, or there is evidence of chronic liver disease, exclude from the clinical study.  


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Attachment 5: Medical Device Incidents: Definition and Procedures for Recording
The detection and documentation procedures described in this protocol apply to all sponsor 
medical devices provided for use in the study (see Section 14.1.2).
Medical Device Incident Definition

A medical device incident is any malfunction or deterioration in the characteristics or 
performance of a device as well as any inadequacy in the labeling or the instructions for use 
which, directly or indirectly, might lead to or might have led to the death of a 
subject/user/other person or to a serious deterioration in his/her state of health.

Not all incidents lead to death or serious deterioration in health. The nonoccurrence of such 
a result might have been due to other fortunate circumstances or to the intervention of health 
care personnel.
It is sufficient that:

An incident associated with a device happened.
AND

The incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.
A serious deterioration in state of health can include any of the following:

Life-threatening illness

Permanent impairment of body function or permanent damage to body structure

Condition necessitating medical or surgical intervention to prevent one of the above

Fetal distress, fetal death, or any congenital abnormality or birth defects
Examples of Incidents

A subject, user, caregiver, or healthcare professional is injured as a result of a medical 
device failure or its misuse.

A subject’s study agent administration is interrupted or compromised by a medical device 
failure.

A misdiagnosis due to medical device failure leads to inappropriate treatment.

A subject’s health deteriorates due to medical device failure.
Documenting Medical Device Incidents

Any medical device incident occurring during the study will be documented in the subject’s
medical records, in accordance with the Investigator’s normal clinical practice, and on the 
appropriate form of the eCRF.

For incidents fulfilling the definition of an adverse event or a serious adverse event, the
appropriate Adverse Event/Serious Adverse Event eCRF page will be completed.


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
The eCRF will be completed as thoroughly as possible and signed by the Investigator before 
transmittal to the sponsor or designee.

It is very important that the Investigator provides his/her assessment of causality 
(relationship to the medical device provided by the sponsor) at the time of the initial adverse 
event or serious adverse event report and describes any corrective or remedial actions taken 
to prevent recurrence of the incident.

A remedial action is any action other than routine maintenance or servicing of a medical 
device where such action is necessary to prevent recurrence of an incident. This includes any 
amendment to the device design to prevent recurrence.


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INVESTIGATOR AGREEMENT
PPD


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 23 April 2020
Janssen Research & Development *
Clinical Protocol
COVID-19 Appendix
Protocol Title
A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Study of 
Ustekinumab in Subjects with Active Systemic Lupus Erythematosus
Protocol CNTO1275SLE3001; Phase 3
STELARA® (ustekinumab)
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen Biologics, 
BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen Sciences Ireland
UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term “sponsor” is used 
throughout the protocol to represent these various legal entities; the sponsor is identified on the Contact 
Information page that accompanies the protocol.
United States (US) sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).]
Status:
Approved
Date:
23 April 2020
Prepared by:
Janssen Research & Development, LLC  
EDMS number:
EDMS-RIM-37731, 1.0
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF
PROTOCOL CNTO1275SLE3001
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.
NCT03517722


COVID-19 Appendix
STELARA® (ustekinumab)
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Status: Approved,  Date: 23 April 2020
COVID-19 APPENDIX
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, self-isolation/quarantine by subjects 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 subject 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 subjects and site staff. If, at 
any time, a subject’s safety is considered to be at unacceptable risk, study agent 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, subjects will be interviewed to collect safety data. Key efficacy endpoint assessments 
should be performed if required and as feasible. Subjects 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 subjects on study 
agent, including follow up. Modifications to protocol-required assessments may be permitted via 
COVID-19 Appendix after consultation between the subject 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 subject has tested positive for COVID-19, the investigator should contact the sponsor’s 
responsible medical officer to discuss plans for study agent and follow-up. Modifications made to 
the study conduct as a result of the COVID-19 pandemic should be summarized in the clinical 
study report.


COVID-19 Appendix
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Status: Approved,  Date: 23 April 2020
ADDITIONAL ELEMENTS, WHERE APPLICABLE:

Certain protocol-mandated visits to the study site may not be possible during the COVID-19 
outbreak. Therefore, temporary measures may be implemented if considered appropriate by 
the sponsor and investigator to maintain continuity of subject care and study integrity. Certain 
measures, such as those listed below, may be necessary and should be instituted in accordance 
with applicable (including local) laws, regulations, guidelines, and procedures:
o
remote (eg, by phone / telemedicine) or in-person, off-site (eg, in-home) interactions 
between site staff (or designees) and subjects for study procedures e.g. those related to 
safety monitoring / efficacy evaluation / study agent storage and administration (including 
training where pertinent)
o
procurement of study agent by subjects (or designee) or shipment of study agent from the 
study site directly to subjects for at home administration (including the potential for self-
administration of study agent)
o
laboratory assessments using a suitably accredited local laboratory; for selected measures 
(eg, urine pregnancy), home testing may be employed
o
other procedures, eg, imaging, may be conducted at an appropriate facility

Missed assessments/visits will be captured in the clinical trial management system for 
protocol deviations. Discontinuations of study agent and withdrawal from the study should be 
documented with the prefix “COVID-19-related” in the case report form (CRF).  
o
other relevant study data elements impacted by the pandemic should also be documented 
/ labeled as “COVID-19-related” in CRFs and / or other study systems, as directed by 
detailed sponsor guidance. These may include missed / delayed / modified study visits / 
assessments / dosing, and instances where temporary measures such as those above are 
implemented.  

The sponsor will evaluate the totality of impact of COVID-19 on collection of key study data 
and additional data analyses will be outlined in study SAP(s). 

Exclusion: a potential subject with the following features will be excluded from participating 
in the study protocol:
o
During the 6 weeks prior to baseline, have had ANY of (a) confirmed SARS-CoV-2 
(COVID-19) infection (test positive), OR (b) suspected SARS-CoV-2 infection (clinical 
features without documented test results), OR (c) close contact with a person with known 
or suspected SARS-CoV-2 infection 


COVID-19 Appendix
STELARA® (ustekinumab)
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Status: Approved,  Date: 23 April 2020

Exception: may be included with a documented negative result for a validated 
SARS-CoV-2 test
(i) obtained at least 2 weeks after conditions (a), (b), (c) above (timed from 
resolution of key clinical features if present, e.g. fever, cough, dyspnea)
AND
(ii) with absence of ALL conditions (a), (b), (c) above during the period 
between the negative test result and the baseline study visit 

NOTES on COVID-related exclusion:
1.
If a subject 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 subject’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 / standards of care. 

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. 


COVID-19 Appendix
STELARA® (ustekinumab)
Clinical Protocol CNTO1275SLE3001
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Status: Approved,  Date: 23 April 2020
INVESTIGATOR AGREEMENT

SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 23 September 2020
Janssen Research & Development*
Statistical Analysis Plan
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group 
Study of Ustekinumab in Subjects with Active Systemic Lupus Erythematosus
Protocol CNTO1275SLE3001; Phase 3
AMENDMENT 2
STELARA®  (ustekinumab)
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen 
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Infectious Diseases BVBA; Janssen 
R&D Ireland; or Janssen Research & Development, LLC. The term “sponsor” is used throughout the 
protocol to represent these various legal entities; the sponsor is identified on the Contact Information page 
that accompanies the protocol.
Status:
Approved
Date:
23 September 2020
Prepared by:
Janssen Research & Development
Document No.: EDMS-ERI-161845442
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.
NCT03517722


STELARA®  (ustekinumab)
Statistical Analysis Plan CNTO1275SLE3001 Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved, Date: 23 September 2020
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
AMENDMENT HISTORY.............................................................................................................................. 4
ABBREVIATIONS ........................................................................................................................................ 5
1.
INTRODUCTION.................................................................................................................................. 7
1.1.
Trial Objectives ................................................................................................................................ 7
1.2.
Trial Design ...................................................................................................................................... 8
1.3.
Statistical Hypotheses for Trial Objectives..................................................................................... 11
1.4.
Sample Size Justification ............................................................................................................... 11
1.5.
Randomization and Blinding .......................................................................................................... 12
1.6.
Coronavirus 2019 (COVID-19)....................................................................................................... 13
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 14
2.1.
Visit Windows................................................................................................................................. 14
2.2.
Pooling Algorithm for Analysis Centers.......................................................................................... 14
2.3.
Analysis Sets.................................................................................................................................. 14
2.3.1.
Randomized Analysis Set........................................................................................................... 14
2.3.2.
Efficacy Analysis Set(s) .............................................................................................................. 14
2.3.2.1.
Full Analysis Set ...................................................................................................................... 14
2.3.3.
Safety Analysis Set..................................................................................................................... 15
2.3.4.
Pharmacokinetics Analysis Set .................................................................................................. 15
2.3.5.
Immunogenicity Analysis Set...................................................................................................... 16
2.3.6.
Pharmacodynamics Analysis Set ............................................................................................... 16
2.4.
Definition of Subgroups.................................................................................................................. 16
2.5.
Study Day and Relative Day .......................................................................................................... 17
2.6.
Baseline ......................................................................................................................................... 17
2.7.
Imputation Rules for Missing AE Date/Time of Onset/Resolution ................................................. 18
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 19
3.1.
Interim Analysis.............................................................................................................................. 19
3.2.
Data Monitoring Committee ........................................................................................................... 20
4.
SUBJECT INFORMATION................................................................................................................ 21
4.1.
Demographics and Baseline Characteristics ................................................................................. 21
4.2.
Disposition Information................................................................................................................... 22
4.3.
Treatment Compliance................................................................................................................... 23
4.4.
Extent of Exposure......................................................................................................................... 23
4.5.
Protocol Deviations ........................................................................................................................ 23
4.6.
Prior and Concomitant Medications ............................................................................................... 23
4.7.
COVID-19 Related Summaries...................................................................................................... 24
5.
EFFICACY ......................................................................................................................................... 24
5.1.
Analysis Specifications................................................................................................................... 24
5.1.1.
Level of Significance................................................................................................................... 24
5.1.2.
Multiplicity Adjustment for Testing Procedures .......................................................................... 24
5.1.3.
Data Handling Rules................................................................................................................... 27
5.1.3.1.
Treatment Failure .................................................................................................................... 27
5.2.
Primary Efficacy Endpoint(s).......................................................................................................... 29
5.2.1.
Definition..................................................................................................................................... 30
5.2.2.
Estimands ................................................................................................................................... 30
5.2.3.
Analysis Methods:  Primary Endpoint......................................................................................... 30
5.2.3.1.
Subgroup Analyses ................................................................................................................. 31
5.2.3.2.
Sensitivity Analyses................................................................................................................. 32


STELARA®  (ustekinumab)
Statistical Analysis Plan CNTO1275SLE3001 Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Approved, Date: 23 September 2020
5.2.4.
Analysis Methods:  Sensitivity Analyses..................................................................................... 33
5.2.4.1.
Component Analysis (Sensitivity Analysis 1) .......................................................................... 33
5.2.4.2.
Primary Endpoint using the Full Analysis Set (Sensitivity Analysis 2) .................................... 33
5.2.4.3.
Stratification Analysis (Sensitivity Analysis 3) ......................................................................... 34
5.3.
Major Secondary Endpoints........................................................................................................... 34
5.3.1.
Definition..................................................................................................................................... 34
5.3.1.1.
British Isles Lupus Assessment Group (BILAG)...................................................................... 34
5.3.1.2.
SRI-4 Composite Response.................................................................................................... 36
5.3.1.3.
Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K)........................... 36
5.3.1.4.
Physicians Global Assessment (PGA) of Disease Activity...................................................... 36
5.3.1.5.
Joints with Pain and Signs of Inflammation............................................................................. 37
5.3.1.6.
Glucocorticoid Reduction......................................................................................................... 37
5.3.1.7.
Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI)........................ 39
5.3.2.
Analysis Methods:  Secondary Endpoints .................................................................................. 39
5.4.
Additional Efficacy Endpoints......................................................................................................... 40
5.4.1.
Definition..................................................................................................................................... 41
5.4.1.1.
Measures of Improvement in Global Disease Activity............................................................. 41
5.4.2.
Analysis Methods........................................................................................................................ 42
5.5.
SLEDAI-2K Supportive Analyses................................................................................................... 44
5.5.1.
Definition..................................................................................................................................... 45
5.5.1.1.
SLEDAI-2K v10Oct2015 (modified SLEDAI-2K/S2K- RI-50) .................................................. 45
5.5.1.2.
SLEDAI-2K Pre-v2015 (Traditional SLEDAI-2K)..................................................................... 45
5.5.1.3.
SLEDAI-2K Recode................................................................................................................. 45
5.5.2.
Analysis Specifications ............................................................................................................... 46
5.5.2.1.
SLEDAI-2K v10Oct2015 (modified SLEDAI-2K) ..................................................................... 46
5.5.2.2.
SLEDAI-2K Re-Code............................................................................................................... 47
5.5.3.
Analysis Methods........................................................................................................................ 47
6.
SAFETY............................................................................................................................................. 47
6.1.
Adverse Events .............................................................................................................................. 47
6.2.
Clinical Laboratory Tests................................................................................................................ 49
6.3.
Vital Signs and Physical Examination Findings ............................................................................. 50
6.4.
Electrocardiogram.......................................................................................................................... 51
6.5.
Other Safety Parameters ............................................................................................................... 51
6.6.
COVID-19 Summaries ................................................................................................................... 51
7.
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................... 51
7.1.
Pharmacokinetics........................................................................................................................... 51
7.2.
Immune Response......................................................................................................................... 52
7.3.
Pharmacodynamics........................................................................................................................ 53
7.4.
Pharmacokinetic/Pharmacodynamic Relationships....................................................................... 53
8.
LONG TERM EXTENSION (THROUGH WEEK 176) SUMMARIES................................................ 53
8.1.
Demographics ................................................................................................................................ 53
8.2.
Disposition...................................................................................................................................... 53
8.3.
Protocol Deviations ........................................................................................................................ 54
8.4.
Concomitant Medications............................................................................................................... 54
8.5.
Efficacy........................................................................................................................................... 54
8.6.
Adverse Events .............................................................................................................................. 54
8.7.
Clinical Laboratory Tests................................................................................................................ 54
8.8.
Vital Signs and Physical Examination Findings ............................................................................. 54
8.9.
Pharmacokinetics/Immunogenicity/Pharmacodynamics................................................................ 54
REFERENCES............................................................................................................................................ 55


STELARA®  (ustekinumab)
Statistical Analysis Plan CNTO1275SLE3001 Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 23 September 2020
AMENDMENT HISTORY
DATE
AMENDMENT
23 April 2018
Original STABLE DRAFT Version
31 January 2019
Approved Version 1:  Updates to address 
regulatory response, clarification to endpoints, 
sensitivity analyses and other analyses
8 January 2020
Amendment 1:  Updates to imputation rules for 
missing AE time to onset.  Update to prohibited 
medication rules.  Update to treatment failure rules 
with inclusion of periodic review text.  Updates to 
address regulatory response, clarifications to 
endpoints, sensitivity analyses (including tipping 
point analyses) and supportive analyses, and 
inclusion of sample SAS® code.  Addition of a 
linear regression supportive analysis.  Detailed 
explanation of glucocorticoid reduction rules.  
Addition of text addressing handling of data from 
any site closures.
22 Sep 2020
Amendment 2:  Added SLEDAI-2K supportive 
analyses.  Updated for COVID-19 including adding 
impact assessments, adjustment of analyses and 
estimands.  Due to the planned futility analysis 
meeting criteria and the trial termination on 26 June 
2020, the SAP has reduced efficacy analyses.


STELARA®  (ustekinumab)
Statistical Analysis Plan CNTO1275SLE3001 Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
5
Status: Approved, Date: 23 September 2020
ABBREVIATIONS
ACE
angiotensin-converting enzyme
ADA
anti-drug antibody
AE
adverse event
ALT/SGPT
alanine aminotransferase
ANCOVA
analysis of covariance
APAC
Asia Pacific
ARB
angiotensin II receptor blocker
AST/SGOT
aspartate aminotransferase
ATC
anatomic and therapeutic Class
AUC
area under the curve
AZA/6 MP
Azathioprine / 6-mercaptopurine
BILAG
The British Isles Lupus Assessment Group
BMI
body mass index
BSA
body surface area
CI
confidence interval
CLASI
Cutaneous Lupus Erythematosus Disease Activity Index
Cmax
maximum concentration
COVID-19
Coronavirus Disease 2019
CRF
case report form
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
DMC
Data Monitoring Committee
DPS
Data Presentation Specifications
ECG
Electrocardiogram
eCRF
electronic case report form
EEU
Eastern European Union
EMEA
Europe, Middle East and Africa
F (%)
absolute SC bioavailability
FAS
full analysis set
FDA
Food and Drug Administration
HLGT
higher level group term
ICH
International Conference on Harmonization
IN
interim analysis
IQ
Interquartile
IV
Intravenous
IWRS
interactive web response system
LA
Latin America
LLOQ
lower limit of quantification
LOCF
last observation carried forward
MACE
major adverse cardiovascular event
MedDRA
Medical Dictionary for Regulatory Activities
mFAS
modified full analysis set
MMF
mycophenolate mofetil
MPA
mycophenolate acid
MTX
Methotrexate
NA
North America
NAb
neutralizing antibodies
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NSAIDS
nonsteroidal anti-inflammatory drugs
P/C
protein/creatinine ratio
PD
pharmacodynamic
PI
principal investigator
PK
pharmacokinetic(s)
S2K RI-50
SLEDAI-2K Responder Index


STELARA®  (ustekinumab)
Statistical Analysis Plan CNTO1275SLE3001 Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
6
Status: Approved, Date: 23 September 2020
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SMQs
standardized MedDRA queries
SLE
systemic lupus erythematosus
SLEDAI-2K
Systemic Lupus Erythematosus Disease Activity Index 2000
SLICC
Systemic Lupus International Collaborating Clinics
SRI
Systemic Lupus Erythematosus Responder Index
TEAE
treatment-emergent adverse event
Tmax
time to maximum concentration
US
United States
V
volume distribution
VAS
visual analogue scale
Vz
volume of distribution based on terminal phase
Vz/F
apparent volume of distribution based on terminal phase after extravascular administration
WEU
Western European Union
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary


STELARA®  (ustekinumab)
Statistical Analysis Plan CNTO1275SLE3001 Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
7
Status: Approved, Date: 23 September 2020
1.
INTRODUCTION
This Statistical Analysis Plan (SAP) contains definitions of analysis sets, derived variables, and 
statistical methods for all planned analyses of efficacy, safety, tolerability, pharmacokinetics 
(PK), pharmacodynamics (PD) and immunogenicity of ustekinumab.  
The trial was terminated for futility on June 26th 2020, therefore this SAP covers all analyses for 
the study including analyses for the primary Week 52 DBL as well as those planned for the long 
term extension (through final Week 176 visit) of the study.  As the trial was terminated for 
meeting futility criteria (see Section 3) efficacy analyses have been reduced to mainly the 
primary and major secondary endpoints and minimal additional analyses.  See SAP Amendment 
#1, dated January 8th, 2020 for the originally planned analyses, sensitivity analyses and 
exploratory work.  
1.1.
Trial Objectives
Primary Objectives
The primary objectives are:
The primary objective is to evaluate the efficacy of ustekinumab in subjects with active Systemic 
Lupus Erythematosus (SLE) who have not adequately responded to one or more standard of care 
treatments.
Secondary Objectives
The secondary objectives are to evaluate the following in subjects with active SLE who have not 
adequately responded to one or more standard-of-care treatments:

Reduction in SLE flares

Improvement in global and organ-specific (mucocutaneous, musculoskeletal, etc.) measures of 
SLE disease activity

Glucocorticoid sparing
Additional Objectives
The additional objectives are to evaluate: 

Safety and tolerability

Pharmacokinetics and immunogenicity

Pharmacodynamic biomarkers and predictive biomarkers to identify subjects most 
likely to benefit from treatment with ustekinumab

Measures of low disease activity state, remission, and organ damage

Effect on health-related quality of life, physical function, and work productivity


STELARA®  (ustekinumab)
Statistical Analysis Plan CNTO1275SLE3001 Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
8
Status: Approved, Date: 23 September 2020
1.2.
Trial Design
CNTO1275SLE3001 is a multicenter, randomized, double-blind, placebo-controlled, parallel 
group, study to evaluate the efficacy, safety, and tolerability of ustekinumab in addition to 
standard-of-care background therapy in subjects between 16 (unless restricted by local 
requirements) and 75 years of age, inclusive, with active, autoantibody-positive SLE who have 
not adequately responded to one or more standard-of-care treatments.
The total duration of the study is up to 182 weeks, consisting of 3 study periods:  a ≤6-week 
screening period (re-screening is permitted once per subject), a 52-week double blind period, and 
a 124-week extension period.
Approximately 500 subjects will be randomly assigned in a 3:2 ratio to receive either 
ustekinumab or placebo with the following treatment administrations:

Week 0: Body weight-range based IV administration of ustekinumab (~6 mg/kg) or 
placebo

Week 8 and every 8 weeks (q8w) thereafter through Week 48: SC administration of 
90 mg ustekinumab or placebo 

Subjects entering the extension period:  SC administration of 90 mg ustekinumab q8w 
through Week 160
A placebo comparator (in addition to standard of care background therapy) will be used in this 
study through Week 52 to allow for blinded, placebo-controlled evaluation of the long-term 
efficacy and safety of ustekinumab in subjects with SLE. 
Subjects will be stratified by race, presence of lupus nephritis, and a combined factor (baseline 
SLE medications and clinical SLEDAI-2K score), using permuted block central randomization. 
Note that the clinical SLEDAI score stratification factor utilized in the randomization procedure 
is collected at baseline and therefore baseline laboratory results (part of the total SLEDAI score) 
are not available.  The clinical SELDAI score as defined in the protocol does not include 
laboratory results or lupus headache. All demographics, efficacy and subgroup analyses will 
utilize the total SLEDAI score.
The primary efficacy analysis will be performed after all subjects have completed Week 52 
efficacy assessments (or discontinued) with additional secondary endpoints to be analyzed at 
Week 24 and Week 52. After Week 52, eligible subjects may enter the extension period.
Every reasonable effort should be made to keep concomitant medications stable as defined in the 
protocol, with the exception that glucocorticoid tapering will be instituted between Week 24 and 
Week 40. Beginning at the screening visit, all concomitant therapies and all changes in 
concomitant therapies should be recorded throughout the study.
Subjects with cutaneous disease who provide consent will participate in medical photography to 
evaluate skin photographs at participating study sites. 


STELARA®  (ustekinumab)
Statistical Analysis Plan CNTO1275SLE3001 Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 23 September 2020
Database locks are planned at Week 52, Week 112, and at Week 176. The end of the study is
defined as the last follow-up assessment (16 weeks after the last dose of study agent is 
administered at Week 160) for the last subject. 
An independent Data Monitoring Committee (DMC) will be commissioned for this study.
A futility analysis will be conducted 24 weeks after 50% of the planned subjects have been
randomized. The analysis will be performed in an unblinded fashion by the independent DMC 
based primarily on Week 24 efficacy data. Additional data available at the time of the futility 
analysis (e.g., other endpoints, other time points) may also be considered. 
A diagram of the study design is provided in Figure 1.


STELARA®  (ustekinumab)
Statistical Analysis Plan CNTO1275SLE3001 Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
10
Status: Approved, Date: 23 September 2020
Figure 1:
Schematic Overview of the Study


STELARA®  (ustekinumab)
Statistical Analysis Plan CNTO1275SLE3001 Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
11
Status: Approved, Date: 23 September 2020
1.3.
Statistical Hypotheses for Trial Objectives
The primary endpoint of the study is the proportion of subjects achieving a SRI-4 composite
response at Week 52.  
The statistical hypothesis for the study is that treatment with ustekinumab is superior to placebo 
in subjects with active SLE who have not adequately responded to one or more standard-of-care 
treatments as measured by the proportion of subjects achieving a SRI-4 composite response at 
Week 52.
1.4.
Sample Size Justification
The sample size calculation is based upon the primary endpoint, the proportion of SRI-4 
composite responders at Week 52. A sample size of 300 subjects treated with ustekinumab and 
200 subjects with placebo is projected to give approximately 98% power to detect a significant 
difference in response rate compared with placebo (assuming 35% and 53% response rates in 
placebo and ustekinumab, respectively, which translates to 18% absolute increase over placebo 
or an odds ratio of 2.09) with an alpha (α) level of 0.05. The assumption of a 35% responder rate 
for placebo is based upon a previous study in which a similar SLE population was treated and is 
consistent with the results observed in the recent ustekinumab SLE study, CNTO1275SLE2001.9
The power to detect a significant treatment difference at α = 0.05 (2-sided) is calculated under 
various assumptions (Table 1).
Table 1:
Power to Detect a Significant Treatment Difference in the Proportion of Subjects with SRI-4 
Response at Week 52
Proportion of Placebo 
Group with Response (%)
Absolute Increase in 
Response (%)
Proportion of 
Ustekinumab Group with 
Response (%)
Odds Ratio
Power
20
15
35
2.15
96%
20
40
2.67
99%
25
45
3.27
99%
25
15
40
2.00
94%
20
45
2.45
99%
25
50
3.00
99%
30
15
45
1.91
93%
20
50
2.33
99%
25
55
2.85
99%
35
15
50
1.86
91%
18
53
2.09
98%
20
55
2.27
99%
40
25
60
2.79
99%
15
55
1.83
91%
20
60
2.25
99%
45
25
65
2.79
99%
20
65
2.27
99%
25
70
2.85
99%
*Note: SRI-4 composite response is defined as a ≥ 4-point reduction in SLEDAI-2K score, no new BILAG A and no more 
than 1 new BILAG B domain score, and no worsening (<10% increase) from baseline in the PGA.4


STELARA®  (ustekinumab)
Statistical Analysis Plan CNTO1275SLE3001 Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 23 September 2020
1.5.
Randomization and Blinding
Randomization
Central randomization will be implemented in this study using an interactive web response 
system (IWRS).  Subjects will be randomly assigned to 1 of 2 treatment groups based upon a 
computer-generated randomization schedule prepared before the study under the supervision of 
the sponsor; however, the sponsor will not be privy to the actual randomization schedule. When 
a subject is eligible for randomization at a study site, the randomization requestor at that study 
site will contact the IWRS using the requester’s own user identification and personal 
identification number and provide the relevant subject details to uniquely identify that subject. 
Permuted block randomization with the following stratification factors will be used:

race (white, black, all other categories combined)

presence of Lupus Nephritis at baseline (Y/N)

composite of baseline SLE medications and clinical SLEDAI score (high medications 
and SLEDAI ≥ 10, high medications and SLEDAI < 10, medium medications and 
SLEDAI ≥ 10, medium medications and SLEDAI < 10)

Subjects will be defined as receiving high medications if they are receiving any of 
the following: ≥ 15 mg/wk MTX, or ≥ 1.5 mg/kg/day AZA/6-MP, or ≥1.5 g/day 
MMF/1.125 g/day MPA, and/or ≥ 15 mg/day prednisolone or equivalent 

Subjects receiving baseline medication(s) for SLE that do not meet the above 
criteria for the category of ‘high’ medications would be included in the ‘medium’ 
medication category   
Based upon the computer-generated randomization schedule, the IWRS will assign a unique 
treatment code, which will dictate the treatment assignment and matching study agent kit for that
subject.  The IWRS will be developed, validated, and administrated by the IWRS vendor.
Approximately 500 subjects will be randomly assigned in a 3:2 ratio to receive either 
ustekinumab or placebo, respectively.  Subjects assigned to the ustekinumab group will receive 
an initial, body weight-range based IV dose approximating 6 mg/kg of ustekinumab 
(ustekinumab 260 mg weight ≤55 kg; ustekinumab 390 mg weight >55 kg and ≤85 kg; 
ustekinumab 520 mg weight >85 kg), and subjects who were randomized to placebo will receive 
placebo treatment. Starting at Week 8, subjects will receive SC dosing with either placebo or 
ustekinumab 90 mg q8w through Week 48. Subjects entering the extension period will receive 
open-label ustekinumab 90 mg SC every 8 weeks through Week 160.  
Blinding
The study blind will be maintained for the duration of the study until after the primary Week 52 
DBL.  
The Investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the Investigator to break the blind for an 
individual subject in emergency situations where unblinding is deemed necessary.


STELARA®  (ustekinumab)
Statistical Analysis Plan CNTO1275SLE3001 Amendment 2
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Status: Approved, Date: 23 September 2020
Data that may potentially unblind the treatment assignment (e.g., study agent serum 
concentrations, anti- ustekinumab antibodies, study agent preparation/accountability data, 
treatment 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 database lock and 
unblinding.
The blind will be maintained during the extension period until the last subject completes the 
Week 52 evaluations and the 52-week database is locked. At the Week 52 DBL, the data will be 
unblinded for analysis to the sponsor. Investigative study sites and subjects will remain blinded 
to initial treatment assignment until after the final database (Study Extension Week 176) is 
locked.
Under normal circumstances, the blind should not be broken until all subjects have completed 
the study and the database is finalized. The Investigator may in an emergency determine the 
identity of the study agent by contacting the IWRS. While the responsibility to break the 
treatment assignment 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 and reason for the unblinding must be 
documented by the IWRS, in the appropriate section of the case report form (CRF), and in the 
source document. The documentation received from the IWRS indicating the code break must be 
retained with the subject's source documents in a secure manner.
The external independent DMC and Statistical Support Group (SSG: an external independent 
team supporting analytical and operational aspects of the DMC as described in the DMC 
Charter) are unblinded to subject treatment groups. The contents of the unblinded data to which 
the DMC and SSG have access should not be divulged, in any way, to members of the study 
team or to any members of the Sponsor Committee unless specifically requested by the Sponsor 
Committee Chairperson, until the study has completed.  The Sponsor Committee Chairperson 
will only request unblinded data to access safety if absolutely needed and those individuals 
unblinded to the data will be documented in advance and not directly involved in study conduct.  
More detailed information is included in the DMC Charter.
Subjects who have had their treatment assignment unblinded should continue to return for 
scheduled evaluations.
For the specified interim analyses, the randomization codes and the translation of randomization 
codes into treatment and control groups will be disclosed to those authorized as detailed in the 
DMC Charter.   
1.6.
Coronavirus 2019 (COVID-19) 
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact 
on the conduct of this clinical study due to, for example, self-isolation/quarantine by subjects and 
study-site personnel; travel restrictions/limited access to public places, including hospitals; study 
site personnel being reassigned to critical tasks.


STELARA®  (ustekinumab)
Statistical Analysis Plan CNTO1275SLE3001 Amendment 2
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Status: Approved, Date: 23 September 2020
On May 8th, 2020 a study specific guidance was created to document approaches that are being 
implemented to maintain continuity of patient care and minimize risks to trial integrity during the 
COVID-19 pandemic. These modifications to study procedure were to be implemented on an as-
needed (subject-by-subject or site-by-site) basis. More details about study operational procedures 
related to COVID-19 are described in the guidance and the COVID-19 Appendix to the study 
protocol.
Note that references throughout the SAP to COVID-19 and any impact it may have on a 
subject’s data handling rules is NOT in reference to the coronavirus disease but instead to
operational and logistic issues related to COVID-19 (e.g. inability to access a site for dosing or 
regularly scheduled visits).
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
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 and the associated COVID-19 study specific guidance.
For PK analyses, if a subject has an administration of study agent more than +/- 7 days of the 
scheduled dosing date, the concentration data collected between such a dosing visit and the 
subsequent dosing visit will be excluded from the by-visit data analyses.  For the Week 52 visit, 
if the PK sampling time deviates more than +/- 3 days of the scheduled date of study agent 
administration, the PK concentration at this visit will be excluded from the by-visit data analyses.
2.2.
Pooling Algorithm for Analysis Centers
Unless otherwise specified, data from all investigational centers/sites will be pooled by region 
for analyses.
2.3.
Analysis Sets
2.3.1.
Randomized Analysis Set
The randomized analysis set includes all randomized subjects.  
In the demographics and disposition analyses, subjects will be analyzed according to their 
assigned treatment group.
2.3.2.
Efficacy Analysis Set(s)
2.3.2.1.
Full Analysis Set 
The efficacy analysis set will be based upon the Full Analysis Set (FAS) and includes 
randomized subjects who received at least 1 dose (partial or complete, IV or SC) of study agent.  
In the efficacy analyses, subjects will be analyzed according to their assigned treatment group 
regardless of their actual treatment received.


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Unless otherwise stated, efficacy analyses will be limited to those FAS subjects who should have 
had a given visit based upon their latest scheduled study visit and the trial termination date of 
26th June 2020. To determine the latest visit where a subject should be included in an any 
analysis, use the following formula:

Identify the last scheduled and completed visit date for a subject. This will be classified 
as ‘Week A’ where ‘A’ is the numeric visit week.

Calculate the time from last schedule visit date to trial termination using the following 
formula:
o
[(trial termination date – last scheduled visit date) + 1] / 7 = value. Decimal 
places are removed, and the remaining value represents the weeks since last visit 
up to and including trial termination for a subject. This will be classified as ‘B’

Calculate their derived latest visit as Week (A+B)
The subject would be included in any analysis less than or equal to the derived latest visit 
above. For example, if a subject had their last scheduled and completed visit on January 20th, 
2020, and this was the Week 16 visit for the subject, the following would be their derived latest 
visit:

Subjects last scheduled and completed visit was Week 16

Trial termination date – last visit date: 26 June 2020 minus 20 Jan 2020 + 1 = 169 days

Weeks since last visit: 169 days / 7 = 24.1 weeks, after removing the decimal this is 24 
Weeks

Subjects derived latest visit is Week 16 + 24 weeks = Week 40 
Therefore, for this subject, they would be included through Week 40 in the analysis.  They would 
not be included in any analysis after Week 40.
2.3.3.
Safety Analysis Set
The safety analysis set includes all randomized subjects who received at least 1 dose (partial or 
complete, IV or SC) of study agent.
In the safety analyses, subjects will be analyzed according to the actual treatment received.  
2.3.4.
Pharmacokinetics Analysis Set
The PK analysis set is defined as subjects who have received at least 1 complete dose of 
ustekinumab and have at least one valid blood sample drawn for PK analysis.
In the PK analyses, subjects will be analyzed according to the actual treatment received.


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2.3.5.
Immunogenicity Analysis Set
The immunogenicity analysis set is defined as all subjects who received at least one dose (partial 
or complete, IV or SC) of ustekinumab and have appropriate samples for detection of antibodies 
to ustekinumab (i.e. subjects with at least 1 appropriate sample obtained after their first dose of 
ustekinumab).
In the immunogenicity analyses, subjects will be analyzed according to the actual treatment 
received.
2.3.6.
Pharmacodynamics Analysis Set
The PD analysis set is defined as all subjects who received at least one dose (complete or partial, 
IV or SC) of study agent.  Subjects will be analyzed according to the actual treatment received.
2.4.
Definition of Subgroups
To evaluate the consistency of the primary efficacy endpoint (proportion of subjects with SRI-4 
composite response at Week 52) subgroup analyses may be performed when the number of 
subjects in the subset permits (at least 15 subjects for each treatment group within a subset).  
The subgroups for subgroup analysis may include, but are not limited to, the following:  
1.
Subgroups defined by demographics
a.
Region (APAC, LA, EEU, Africa, NA, WEU)
b.
Race (White, Black, Asian, All other categories)
c.
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
d.
Age (16-25, 26-55, Over 55)
e.
Body Weight (≤ 55 kg, > 55 and ≤85 kg, > 85 kg)
f.
BMI (Normal [< 25 kg/m2], Overweight [≥ 25 to < 30 kg/m2], Obese [≥ 30 kg/m2])
g.
Sex (Male, Female)
h.
Subjects age at SLE diagnosis (≤ 21 Years, > 21 Years)
2.
Subgroups defined by baseline characteristics
a.
Combined factor of baseline SLE Medication (High, Medium) and SLEDAI-2K 
score (≥ 10, <10)
b.
SLEDAI-2K Score (< Median, ≥ Median)
c.
PGA Score (< Median, ≥ Median)
d.
Presence of lupus nephritis at baseline (Y, N)
e.
Urine Protein/Creatinine Ratio at baseline (< Median, ≥ Median)


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f.
Serologic status individually and collectively for anti-dsDNA, C3 and C4 
i.
dsDNA (positive, negative)
ii.
Complement C3, C4 (normal, abnormal)
g.
SLE medication use at baseline 
For analysis 2g (SLE medication use at baseline), the following categories will be analyzed
given at least 15 subjects for each treatment group within a subset:
SLE Concomitant Medication Therapy at Baseline
Glucocorticoids ONLY
Antimalarials ONLY
Immunosuppressants ONLY
Antimalarials + Glucocorticoids only
Antimalarials + Immunosuppressant only
Immunosuppressants + Glucocorticoids only
Glucocorticoids + Antimalarials + Immunosuppressant
(APAC = Asia Pacific, LA = Latin America, EEU = Eastern European Union, NA = North 
America, WEU = Western European Union)
2.5.
Study Day and Relative Day
The Reference Date is the date of the first study agent administration. If the date of the first study 
agent administration is missing or the first study agent administration is not done, then the 
Reference Date equals the corresponding visit date (e.g., Week 0 visit date). If the corresponding 
visit date is also missing, then the Reference Date equals the randomization date.  Study Day 1 or 
Day 1 refers to the reference date (there is no Study Day 0).  All efficacy and safety assessments 
at all visits will be assigned a day relative to this date.
Study day or relative day for a visit is defined as:

Visit date - (date of Study Day 1) +1, if visit date is ≥date of Day 1

Visit date - Date of Day 1, if visit date <date of Day 1
There is no 'Day 0'
2.6.
Baseline
Unless otherwise stated, baseline is defined as the last observation prior to the start of the first 
study agent administration.


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2.7.
Imputation Rules for Missing AE Date/Time of Onset/Resolution
Partial AE onset dates will be imputed as follows:

If the onset date of an adverse event is missing day only, it will be set to:

First day of the month that the AE occurred, if month/year of the onset of AE is 
different than the month/year of the study agent start

The day of study agent start, if the month/year of the onset of AE is the same as 
month/year of the study agent start date and month/year of the AE resolution date is 
different

The day of study agent start or day of AE resolution date, whichever is earliest, if 
month/year of the onset of AE and month/year of the study agent start date and 
month/year of the AE resolution date are same

If the onset date of an adverse event is missing both day and month, it will be set to the 
earliest of:

January 1 of the year of onset, as long as this date is on or after the study agent start 
date

Month and day of the study agent start date, if this date is the same year that the AE 
occurred

Last day of the year if the year of the AE onset is prior to the year of the study 
agent start date,

The AE resolution date.

Completely missing onset dates will not be imputed.
Partial AE resolution dates not marked as ongoing will be imputed as follows:

If the resolution date of an adverse event is missing day only, it will be set to the earliest 
of the last day of the month of occurrence of resolution or the day of the date of death, if 
the death occurred in that month.

If the resolution date of an adverse event is missing both day and month, it will be set to 
the earliest of December 31 of the year or the day and month of the date of death, if the 
death occurred in that year.

Completely missing resolution dates will not be imputed.
AE onset/resolution dates with missing times will be imputed as follows:

A missing time of onset of an adverse event will be set to:

00:01 if the onset date does not occur on the same day as a study agent 
administration. 

The start time of the corresponding study agent administration if onset date does
occur on the same day as study agent administration. 

The missing time of resolution of an adverse event will be set to 23:59.


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If a missing time is associated with a partial or missing date, the date will be imputed first prior 
to imputing the time.
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
Details of the Data Monitoring Committee (DMC) safety reviews and interim analysis 
assessments are included in a separate DMC Charter and DMC SAP.  The DMC SAP contains 
definitions of analysis sets, derived variables, scope and objects of the DMC, data-cutoff points, 
statistical methods and output to be produced for the safety reviews and interim analyses of 
efficacy as required by the DMC Charter.  Additionally, a dedicated DMC Data Presentation 
Specifications (DPS) document details output and programming specifications.
The follow offers a high-level summary of Interim Analysis activities.
3.1.
Interim Analysis
The interim analysis will be performed 24 weeks after 50% of the planned subjects have been
randomized. This is expected to be approximately a year and a half after the first subject is 
dosed.
The objective of the Interim Analysis is to decide whether to terminate the study for futility, by 
evaluating the absolute difference in proportion of subjects achieving a SLEDAI-2K SRI-4 
response and who do not meet treatment failure criteria (targeting SRI-4 Primary estimand) in an 
unblinded fashion by the unblinded DMC.
At the time of the interim analysis, the DMC will make a nonbinding recommendation to either 
(1) continue the study without modification or (2) terminate the study because of lack of 
efficacy.
The interim analysis for futility will be a two-step process consisting of the following:

Step 1:  The DMC will assess whether the proportion of subjects achieving SRI-4 
composite response at Week 24 in the ustekinumab treated group is ≤ 2% greater than 
the proportion in the placebo treated group.  If the difference is greater than 2%, the 
DMC will recommend to continue the study without modification.  If the difference is 
≤2%, the DMC will continue to Step #2.

Step 2:  Using the same dataset, the DMC will assess whether the proportion of subjects 
achieving SRI-4 composite response at Week 52 in the ustekinumab treated group is 
≤2% greater than the proportion in the placebo treated group.  If the difference is 
greater than 2%, the DMC will recommend to continue the study without modification.  
If the difference is ≤ 2%, the DMC will recommend to terminate the study.
The decision to use a cutoff of 2% is based upon the observed differences in proportion of SRI-4 
composite responders at Week 24 in the completed Phase 2 study (CNTO1275SLE2001), 
estimated clinically significant differences in response rate as well as minimizing the risk to 
incorrectly claim futility.  Operating characteristics of the futility analysis are shown in Table 2
below: 


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Table 2:
Operating Characteristics of Interim Analysis for Futility
Assume True Delta 
in Population
Threshold for Decision Rulea
Probability of 
Claiming Futility
Powerb
0
2%
50.1%
4.5%
5
2%
30.1%
19.4%
10
2%
12.3%
51.2%
15
2%
4.9%
82.6%
20
2%
1.3%
96.0%
25
2%
0.1%
99.9%
30
2%
0.0%
100.0%
0
4%
65.1%
3.5%
5
4%
39.9%
17.1%
10
4%
20.6%
47.4%
15
4%
7.9%
80.4%
20
4%
2.8%
94.7%
25
4%
0.2%
99.8%
30
4%
0.1%
99.8%
Futility analysis performed 24 weeks after 50% of the planned subjects have been randomized.
The futility analysis probabilities are based upon observing the cutoff at both Weeks 24 and 52 for the sample.
Delta represents the Difference in Proportions between ustekinumab and placebo (ustekinumab minus placebo)
a Observed delta to claim futility (i.e., if observed Week 24 delta is < threshold and observed Week 52 delta is 
< the threshold)
b Power at Week 52 primary DBL for the study given that the futility analysis is performed
Although the DMC will make a recommendation to the Sponsor, the Sponsor will make the final 
decision of the action taken.  The use of an independent, external DMC and Statistical Support 
Group as well as the communication plan discussed throughout the DMC Charter result in 
limited interactions of the independent DMC and the study team.  Additionally, unblinding 
information used for reviews is sequestered from the study team.  This should ensure protection
of study integrity.  The fact that the DMC is only privy to the difference in proportions of 
responders between the treatment groups during the interim analysis for futility and not the 
individual or group level response rates is an additional measure in place to ensure study 
integrity. 
If the recommendation from the DMC is to terminate the study, initially, the Sponsor Committee
would be unblinded to confirm that the futility criteria were met.  If additional analysis were to 
be performed to support continuing the study unmodified, those involved in the unblinding 
would not be involved in the conduct of the study and the list of personnel would be documented 
prior to any analysis.  Further details for the Interim Analysis are included in the DMC Charter 
and DMC SAP.
3.2.
Data Monitoring Committee
The independent DMC will monitor data on an ongoing basis to ensure the continuing safety of 
the subjects enrolled in the study.  The committee will meet periodically to review interim data.  
After the review, the DMC will make recommendations regarding the continuation of the study.  
Any safety concerns will be communicated to the Sponsor Committee Chairperson.


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None of the DMC members will be participating in the study; they will be independent of the 
Sponsor.  The independent DMC consists of at least 2 medical experts in relevant therapeutic 
areas and 1 statistician and are to be specified before study initiation.  The major function of the 
DMC is to monitor the safety of the study agent and to perform the interim analysis and provide 
recommendations for placing the study on hold or stopping the study in the event of serious 
safety concerns or futility.
Periodic safety reviews will occur as outlined in the DMC Charter, initiating when the 30th
subject reaches their Week 12 visit and then occurring approximately 6-monthly until the last 
meeting is within 6 months of the Week 52 database lock.  The Interim Analysis described in
Section 3.1 will coincide with the 3rd DMC scheduled meeting.
Serious adverse events will be reported to the DMC members on an ongoing basis.  The DMC 
will have access to the unblinded data and review tabulated safety summaries (if appropriate) and 
any additional safety data that the DMC may request.
The content of the safety summaries and interim analysis, the DMC roles and responsibilities and 
the general procedures (including communication plan) and their possible recommendations on 
study conduct will be defined and documented in the DMC Charter prior to the first DMC 
review.
4.
SUBJECT INFORMATION
The number of subjects in each analysis set will be summarized and listed by treatment group, 
and overall. In addition, the distribution of subjects by region, and country will be presented.
4.1.
Demographics and Baseline Characteristics
Table 3 presents a list of the demographic variables and disease characteristics that will be 
summarized by treatment group and overall for the randomized analysis set.  Prior and 
concomitant medications used at baseline will be listed.
Age will be calculated as (date of informed consent – date of birth + 1) / 365.25 in units of years.
BMI will be calculated as weight/height2 with units of kg/m2.


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Table 3:
Demographic Variables and Disease Characteristics at Baseline
Continuous Variables:
Summary Type
Age (years)
Descriptive statistics 
(N, mean, standard 
deviation [SD], median 
and range [minimum and 
maximum]
Weight (kg)
Height (cm)
Body Mass Index (BMI) (kg/m2)
SLEDAI-2K score (0-105)
PGA score (0-3)
SLE Duration (years)
Number of Active Joints (0-62)
Number of Tender Joints (0-64)
Number of Swollen Joints (0-62)
CLASI Activity Score (0-70)
Categorical Variables
Summary Type
Age ([16-25 years, 26-50 years, 51-64 years, and >65 years])
Frequency distribution 
with the number and 
percentage of subjects in 
each category.
Sex (male, female)
Racea (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or other Pacific Islander, White, Other, Multiple)
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
BMI ([normal ≤25 kg/m2, overweight 25-<30 kg/m2, obese ≥30 kg/m2])
Proportion with Lupus Nephritis Present (%)
Proportion with Anti-dsDNA Antibody Positivity (%)
Proportion with Anti-Smith Antibody Positivity (%)
Proportion with Anti-Nuclear Antibody Positivity (%)
Proportion with Low Complement C3 (%)
Proportion with Low Complement C4 (%)
Proportion with at least 1 BILAG A Score (%)
Proportion with at least 2 BILAG B Scores (%)
Proportion with at least 1 BILAG A Score or at least 2 BILAG B Scores (%)
aIf multiple race categories are indicated, the Race is recorded as 'Multiple'
Additionally, the proportion of subjects receiving selected concomitant medications at baseline 
(e.g. glucocorticoids, anti-malarials, mycophenolate mofetil [MMF]/Mycophenolic Acid [MPA], 
azathioprine [AZA]/6-mercaptopurine [6-MP], methotrexate [MTX]) and average dose of 
concomitant medication(s) will be summarized by treatment group.
4.2.
Disposition Information
Disposition information will be based upon the randomized analysis set.
The number of subjects in the following disposition categories will be summarized by treatment 
group:

Subjects randomized

Subjects treated

Subjects completing the study

Subjects who discontinued study agent and reasons for discontinuation


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
Subjects who terminated study prematurely and reasons for termination

Subjects who met treatment failure criteria and reason
4.3.
Treatment Compliance
During the double-blinded study period, study agent will be administered as an IV (initial dose) 
and SC injection by authorized and qualified staff personnel and the details of each 
administration will be recorded in the electronic case report form (eCRF) including date, start 
and stop times for infusion, and start time for injection.  Compliance with the treatment agent 
will be controlled by the study site personnel.
Study agent compliance will be summarized descriptively. Compliance to randomized treatment 
versus actual treatment will be presented in a summary table.  Additionally, subjects may be 
summarized by the study agent lot(s) received.  
4.4.
Extent of Exposure
The number of subjects exposed to study agent, the number of administrations of study agent by 
type of administration (IV and SC), and cumulative dose (IV and SC) of study agent will be 
summarized by randomized treatment group.
4.5.
Protocol Deviations
In general, the following list of major protocol deviations may have the potential to impact 
subjects’ rights, safety or well-being, or the integrity and/or result of the clinical study. Subjects 
with major protocol deviations will be identified prior to database lock and the subjects with 
major protocol deviations will be summarized by category.

Subjects who entered but did not satisfy entry criteria

Subjects who received the wrong treatment or incorrect dose

Subjects who developed withdrawal criteria but were not withdrawn

Subjects who received a disallowed concomitant medication

Other deviations (e.g. missed visits for reasons other than AEs, unblinding error, actions 
deemed as major deviations by the study team)
4.6.
Prior and Concomitant Medications
Background medication use for active SLE will be summarized by treatment group.  New 
medication, prohibited medication or medication dose increased from baseline dose for SLE will 
be listed and the dose of that medication will be summarized.
Prior and concomitant medications will be coded according to the World Health Organization 
(WHO) encoding dictionary, and the number and percent of subjects receiving each medication 
in each treatment group will be summarized by Level 3 Anatomical Therapeutic Chemical 
Classification (ATC) code (first four numbers in the code).


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Prior medications are defined as any therapy used before the day of first dose (partial or 
complete) of study agent. Concomitant medications are defined as any therapy used on or after 
the same day as the first dose of study agent, including those that started before and continue
after the first dose (partial or complete) of study agent.
4.7.
COVID-19 Related Summaries
Subject disposition as related to COVID-19 will be summarized by treatment group. This 
includes the following COVID-19 related disposition events:

Termination of study due to COVID-19 (pandemic and/or disease) and reason

Discontinuation of study agent due to COVID-19 and reason

Death related to COVID-19
Subjects discontinuing treatment or terminating study participation due to COVID-19 and 
reason(s) will be listed.
Assessment of study compliance as related to COVID-19 will be summarized, including number 
of missed visits, and number of remote visits conducted.  Subjects whose visit compliance was
impacted by COVID-19 will be listed.
Depending on the extent of the COVID-19 impact on the study, subgroup analyses may be 
defined on a study level to evaluate the impact (e.g., different periods of the pandemic: pre-
COVID-19, during COVID-19, post-COVID-19)
Subjects receiving concomitant medications related to COVID-19 infection will be listed.
Major protocol deviations as related to COVID-19 will be summarized and listed.
Study agent modifications due to COVID-19 will be summarized and listed.
5.
EFFICACY
5.1.
Analysis Specifications
5.1.1.
Level of Significance
Unless otherwise stated, the statistical significance is set to a 2-sided α-level of 0.05 as per 
protocol.  Where appropriate, 95% confidence intervals will be provided.
Unless otherwise stated, efficacy analyses will be performed on the FAS subjects who should 
have had a given visit based upon their latest scheduled study visit and the trial termination date 
of 26th June 2020 (See Section 2.3.2.1).
5.1.2.
Multiplicity Adjustment for Testing Procedures
The primary endpoint of this study is the proportion of subjects achieving a SRI-4 composite 
response at Week 52.


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There are 6 major secondary endpoints in this study:
1.
Time to first flare based on the proportion of subjects with a flare occurring at any time 
after the baseline visit through Week 52, with flare defined as either 1 or more new 
BILAG A or 2 or more new BILAG B scores.
2.
The proportion of subjects with a SRI-4 composite response at Week 24
3.
The proportion of subjects achieving at least a 50% improvement in the number of 
joints with pain and signs of inflammation (active joints) at Week 52 in subjects with at 
least 4 affected joints at baseline 
4.
The proportion of subjects who achieve reduction in glucocorticoid dose by Week 40 
and sustain that reduction through Week 52 in those subjects receiving glucocorticoids 
at baseline (See Section 5.3.1.6 for definitions of reduction of glucocorticoid dose and 
sustained reduction of glucocorticoid dose.)
5.
The proportion of subjects achieving at least a 50% improvement in the CLASI Activity 
Score at Week 52 in subjects with a CLASI Activity Score of 4 or greater at baseline
6.
The proportion of subjects who (1) achieved reduction in glucocorticoid dose by 
Week 40 and sustained that reduction through Week 52 and (2) achieved a SRI-4 
composite response at Week 52 (Subjects must meet both criteria #1 and #2) in those 
subjects receiving glucocorticoids at baseline
A serial gatekeeping (fixed sequence) approach will be applied to adjust for multiplicity and to 
strongly control type I error across the primary and major secondary endpoints.  First, the 
primary endpoint will be tested to compare ustekinumab with the placebo group at a 2-sided α-
level of 0.05.  If the test is significant, the hypotheses of the major secondary endpoints will be 
tested in a fixed sequence at the 2-sided α-level of 0.05 as follows (Figure 2).  If a given 
comparison is not significant at the 2-sided α level of 0.05, the remaining treatment group 
comparisons will be considered supportive analysis.


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Figure 2:
Primary and Secondary Testing Hierarchy


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5.1.3.
Data Handling Rules
No imputation will be performed for missing baseline values.
If an investigational site is closed for non-compliance with study processes and procedures as 
outline in the protocol and training materials, the following actions will be taken regarding all 
subject data collected at the site;

All efficacy data collected will be considered un-evaluable and will be excluded from 
any efficacy analysis.  No imputation for the missing subject data will be performed.

All safety and PK data collected will be included in safety and PK analyses (except 
those PK analyses regarding efficacy).
Primary Endpoint:

For the primary endpoint, subjects meeting treatment failure criteria will be imputed as 
non-responders from the point of treatment failure onward. Missing data will be imputed 
as non-response.  Sensitivity analyses will be performed using observed data regardless 
of whether the subject met treatment failure criteria. 
Binary major secondary endpoints:

Analyses will be similar to the main analysis of the primary endpoint:  subjects meeting 
treatment failure criteria will be imputed as non-responders from the point of treatment 
failure onward. Missing data will be imputed as non-response. 
Continuous endpoints, if applicable:

Observations after meeting treatment failure criteria will be set to missing for subjects 
who met the criteria. No imputation will be performed for missing post baseline
continuous values; the statistical model (i.e., MMRM) will adjust for missing post 
baseline data.
For all other binary endpoints, analyses will be similar to the main analysis of the primary 
endpoint:  subjects meeting treatment failure criteria will be imputed as non-responders from the 
point of treatment failure onward. Missing data will be imputed as non-response.
In addition, selected data may also be reported using observed data without applying these data 
handling rules.
5.1.3.1.
Treatment Failure
Treatment failure criteria is applied during the double-blind portion of the study.  
Treatment Failure Criteria:  Subjects who have 1 or more of the following events (due to 
increased SLE disease activity) will be defined as treatment failures from the point of the 
occurrence of the event onward:


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*Note:  Where replacement of a medication (i.e. dose equivalent is equal or less than current 
dose) is permitted, the reason for replacement should not be due to SLE worsening. If the 
replacement is due to SLE worsening, the subject may be classified as a treatment failure.  
Antimalarial Medications

Between the Week 12 and the Week 52 visit either; (a) exceeding the baseline dose of 
antimalarial treatment, or (b) initiation of a new (not present at randomization) 
antimalarial treatment and this antimalarial does not replace a current antimalarial 
(i.e. dose equivalent is equal or less than current dose)

Addition of a new antimalarial to the existing treatment regimen (not present at 
randomization) before Week 12 and the subject still was receiving that antimalarial after 
Week 12 and this antimalarial does not replace a current antimalarial (i.e. dose 
equivalent is equal or less than current dose)
Oral Glucocorticoids for SLE Disease Activity

Between the Week 12 and the Week 52 visit either; (a) exceeding the baseline average 
daily dose of oral glucocorticoid treatment, or (b) initiation of a new (not present at 
randomization) oral glucocorticoid treatment and this glucocorticoid does not replace a 
current glucocorticoid (i.e. dose equivalent is equal or less than current dose)

Addition of a new oral glucocorticoid treatment to the existing treatment regimen (not 
present at randomization) before Week 12 and the subject still was receiving that oral 
glucocorticoid after Week 12 and this glucocorticoid does not replace a current 
glucocorticoid (i.e. dose equivalent is equal or less than current dose)
Non-biologic Immunomodulators (Mycophenolate mofetil [MMF], Mycophenolic acid [MPA], 
Azathioprine [AZA], 6-mercaptopurine [6-MP], Methotrexate [MTX])

Between the Week 12 and the Week 52 visit either; (a) exceeding the baseline dose of 
immunomodulator treatment, or (b) initiation of a new (not present at randomization) 
immunomodulator treatment and this immunomodulator does not replace a current 
immunomodulator (i.e. dose equivalent is equal or less than current dose) of similar 
mechanism of action (e.g. MMF substitution for MPA or vice versa, AZA substitution 
for 6-MP or vice versa, MTX oral can replace MTX subcutaneous (or intramuscular) or 
MTX subcutaneous (or intramuscular ) can replace MTX oral)

Addition of a new immunomodulator treatment to the existing treatment regimen (not 
present at randomization) before Week 12 and the subject still was receiving that 
immunomodulator after Week 12 and this immunomodulator does not replace a current 
immunomodulator (i.e. dose equivalent is equal or less than current dose) of similar 
mechanism of action (e.g. MMF substitution for MPA or vice versa, AZA substitution 
for 6-MP or vice versa)


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Prohibited medications

Between randomization and Week 52, initiation of any protocol prohibited medication 
with the following exceptions: 

If clinically necessary, a total of 1 or 2 IA injections may be permitted for SLE up 
to the Week 12 visit and will be recorded as a medical procedure and as 
concomitant medication

Up to the Week 12 visit, short-term (≤2 weeks) epidural, IV, IM, intrabursal, or 
intralesional glucocorticoid for the treatment of conditions other than SLE is 
permitted and should be limited to situations where, in the opinion of the 
Investigator, there are no adequate alternatives.  However, intravenous 
glucocorticoid exceeding 625 mg prednisone equivalent/day for 2 or more days are 
not permitted at any time
Discontinuation:

Subjects who discontinue study agent for any reason prior to Week 52 will be classified 
as a treatment failure from the point of discontinuation forward
Depending on the estimand of interest, different data handling rules will be applied to Treatment 
Failures.
Subjects who met treatment failure criteria and reason for meeting criteria will be listed.
Periodic review for subjects meeting the above treatment failure criteria is performed by the 
blinded sponsor medical monitors.  The periodic review process consists of (1) applying 
programmatic definitions of treatment failure based upon the above criteria to the collected data 
to generate listings of subject meeting treatment failure criteria and (2) medical monitor in-depth 
assessment of clinical data including concomitant medications, medical history, laboratory 
assessments, and potentially other pertinent information to confirm the treatment failure criteria 
met and (3) maintaining results of the reviews within a tracking document.  All subjects meeting 
treatment failure criteria will be reviewed in a blinded manner. Within the programmed 
dataset(s), there will exist variables for the programmed treatment failure criteria met, the 
confirmed treatment failure criteria met after medical review, as well as a detailed summary 
reason for any differences between the programmed and clinically reviewed treatment failure
criteria.  The medically reviewed and confirmed treatment failure variables will serve as the 
basis for all analyses where treatment failure rules are in effect.
Subjects who met treatment failure criteria, reason for meeting criteria, confirmed treatment
failure criteria, and detailed summary of reason for any differences between the programmed and 
clinically reviewed treatment failure criteria will be listed.
5.2.
Primary Efficacy Endpoint(s)
The primary efficacy endpoint is the proportion of SRI-4 composite responders at Week 52.


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5.2.1.
Definition
SLEDAI-2K SRI-4 response is defined as ≥4-point reduction from baseline in SLEDAI-2K score
(see Section 5.3.1.3), no new BILAG A and no more than 1 new BILAG B domain score, and no 
worsening from baseline in the Physician’s Global Assessment (PGA) of Disease Activity 
(<10% worsening from baseline).4 For the primary endpoint analysis, SRI-4 composite response 
is the proportion of subjects who achieve a SLEDAI-2K SRI-4 response at Week 52 and do not 
meet treatment failure criteria prior to Week 52.
5.2.2.
Estimands
Primary Endpoint Analysis:
The Primary Estimand will be targeted for the primary endpoint.  The Primary Estimand for the 
primary endpoint is defined by the following:

Population:  Subjects in the FAS with active SLE who have not adequately responded to 
one or more standard-of-care treatments.

Variable:  Proportion of SRI-4 composite response at Week 52

Intercurrent event: The following intercurrent events are to be taken into account:
1. If a subject takes medication that meets treatment failure criteria or discontinues 
treatment (see treatment failure rules for details), assume non-response from the 
point of treatment failure onward.

Population-level summary:  Difference in the proportion of subjects achieving SRI-4 
composite response at Week 52 between the ustekinumab and placebo treatment groups.
Supplementary Estimands:
A supplementary Treatment Policy (de Facto) Estimand is also considered.  The Treatment 
Policy (de Facto) Estimand for the primary endpoint is defined by the following:

Population:  Subjects in the FAS with active SLE who have not adequately responded to 
one or more standard-of-care treatments.

Variable:  Proportion of SRI-4 composite response at Week 52

Intercurrent event:  The occurrence of an intercurrent event is irrelevant.  All observed 
values will be used regardless of occurrence of an intercurrent event.

Population-level summary:  Difference in the proportion of subjects achieving SRI-4 
composite response at Week 52 between the ustekinumab and placebo treatment groups.
5.2.3.
Analysis Methods:  Primary Endpoint
In general, the statistical software SAS® will be used for all data analysis.


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Analysis of the primary efficacy endpoint (SRI-4 composite response at Week 52) will utilize the 
Primary Estimand and be based upon the FAS excluding those subjects whose projected Week 
52 visit occurred after study termination (see Section 2.3.2.1).  
Sensitivity analyses will be performed and include an analysis based upon the entire FAS (See 
Section 5.2.3.2). 
The following outlines the analysis method:
As per the primary estimand, if a subject takes medication that meets treatment failure criteria or 
discontinues treatment (see treatment failure rules in Section 5.1.3.1 for details), assume non-
response from the point of treatment failure or treatment discontinuation onward.  Additionally, 
if a subject is lost to follow-up (i.e. missing data) assume non-response.
Logistic regression, adjusting for baseline stratification factors, region and baseline SLEDAI-2K
score (continuous variable), will be used to analyze the primary endpoint. The logistic regression 
model will include treatment group, region, stratification factors as described in Section 1.5
(race, presence of lupus nephritis at baseline, composite of baseline SLE medications [high/low] 
and clinical SLEDAI score [<10, ≥10] at baseline) and baseline SLEDAI-2K score (continuous 
variable). The baseline SLEDAI-2K score will be defined as the closest non-missing 
measurement taken prior to the Week 0 infusion.
The metric utilized for comparison across treatment groups will be the odds ratio.  The odds ratio
associated 95% Wald, asymptotic method confidence intervals1 and the statistical significance of 
the difference in treatment effect will be reported. In addition to the odds ratios and confidence 
interval, the difference in proportions and associated confidence interval1 will be provided as 
supplementary results.
5.2.3.1.
Subgroup Analyses
Subgroup analysis of the primary endpoint based on region will be performed. This is due to 
potential regional differences in efficacy, safety, treatment practices and higher placebo response 
rates in certain regions. Subgroup analysis of the primary endpoint by other selected baseline 
characteristics may be presented when the number of subjects in the subset permits (at least 15 
subjects for each treatment group within a subset):
1.
Subgroups defined by demographics
a.
Region (APAC, LA, EEU, Africa, NA, WEU)
b.
Race (White, Black, Asian, All other categories)
c.
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
d.
Age (16-25, 26-55, Over 55)
e.
Body Weight (≤ 55 kg, > 55 and ≤85 kg, > 85 kg)


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f.
BMI (Normal [< 25 kg/m2], Overweight [≥ 25 to < 30 kg/m2], Obese [≥ 30 kg/m2])
g.
Sex (Male, Female)
h.
Subjects age at SLE diagnosis (≤ 21 Years, > 21 Years)
2.
Subgroups defined by baseline characteristics
a.
Combined factor of baseline SLE Medication (High, Medium) and SLEDAI-2K 
score (≥ 10, <10)
b.
SLEDAI-2K Score (< Median, ≥ Median)
c.
PGA Score (< Median, ≥ Median)
d.
Presence of lupus nephritis at baseline (Y, N)
e.
Urine Protein/Creatinine Ratio at baseline (< Median, ≥ Median)
f.
Serologic status individually and collectively for anti-dsDNA, C3 and C4 
i.
dsDNA (positive, negative)
ii.
Complement C3, C4 (normal, abnormal)
g.
SLE medication use at baseline
For subgroup analyses, odds ratios and corresponding 95% confidence intervals will be 
presented graphically. Additionally, nominal p-values for the comparison across treatment 
groups for the subgroups as well as for the interaction between treatment groups will be 
presented.
5.2.3.2.
Sensitivity Analyses
Termination of the study due to futility resulted in a significant change to the planned sensitivity 
analyses in this section.  Please see SAP Amendment #1, dated January 8th, 2020 for originally 
planned analyses.
Sensitivity Analysis 1 (Treatment Policy Estimand):  In order to assess both components of the 
primary endpoint (1) subjects remaining in the study at week 52, on treatment, and not meeting 
treatment failure criteria and then in that subset (2) those achieving a SRI-4 response at Week 52 
the following analyses will be performed:

Analysis 1A:  To assess component #1 of the primary endpoint we will include a 
summary (number and percentage of subjects in each treatment group) of subjects who 
remain in the study at Week 52, on treatment and do not meet treatment failure criteria.

Analysis 1B:  To address component #2 of the primary endpoint, subjects who have an 
observed SRI-4 value at Week 52 will be included.    
Sensitivity Analysis 2 (Primary Estimand): The primary endpoint will be analyzed utilizing the 
FAS.  In this analysis, subjects whose projected Week 52 visit occurs after study termination will 
not be excluded from the analysis set.


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Sensitivity Analysis 3 (Primary Estimand): In the event that mis-stratification occurs in greater 
than 10% of subjects, the primary endpoint will be analyzed using stratification factors taken 
from the electronic data capture (EDC) system instead of the IWRS system.
See Section 5.2.4 for further details on these analyses.
Table 4 below shows the assumptions of each considered analysis for the primary efficacy 
endpoint, all applied to the full analysis set defined in Section 2.3.2:
Table 4:
Analysis Types and Assumptions
Analysis Type
Estimand
Analysis Method
Assumption
Primary Analysis
Primary (FAS
excluding Week 
52 projected after 
termination)
Non-responder imputation for 
data after intercurrent event and 
missing data. Logistic 
regression.
Missing not at Random:  
Missing data and intercurrent 
event indicates lack of 
response
Sensitivity Analysis 
#1A (component 1)
Treatment Policy
No imputation, summary of 
data
No assumptions
Sensitivity Analysis 
#1B (component 2)
Treatment Policy
No imputation for missing data, 
logistic regression
Missing Completely at 
Random:  completers are 
representative of non-
completers
Sensitivity Analysis #2
Primary (FAS)
Non-responder imputation for 
data after intercurrent event and 
missing data. Logistic 
regression. 
Missing not at Random:  
Missing data and intercurrent 
event indicates lack of 
response
Sensitivity Analysis #3
Primary (FAS 
excluding Week 
52 projected after 
termination)
Non-responder imputation for 
data after intercurrent event and 
missing data. Logistic 
regression.
Missing not at Random:  
Missing data and intercurrent 
event indicates lack of 
response
5.2.4.
Analysis Methods:  Sensitivity Analyses
5.2.4.1.
Component Analysis (Sensitivity Analysis 1)
Analysis 1A: The primary endpoint will be summarized (number and percentage in each 
treatment group) utilizing the Treatment Policy (de Facto) Estimand.
Analysis 1B:  The primary endpoint will be analyzed utilizing the Treatment Policy (de Facto) 
Estimand.  Logistic regression similar to the primary analysis as outlined in Section 5.2.3 will be 
performed.
5.2.4.2.
Primary Endpoint using the Full Analysis Set (Sensitivity Analysis 2)
The primary endpoint will be analyzed using the entire FAS where subjects whose projected 
Week 52 visit occurs after study termination will be included in the analysis set. Therefore, all 
subjects who were randomized and received at least 1 dose (partial or complete, IV or SC) of 
study agent will be included in the analysis.


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5.2.4.3.
Stratification Analysis (Sensitivity Analysis 3)
The primary endpoint will be analyzed as outlined in Section 5.2.3 using logistic regression, 
adjusting for baseline stratification factors, region and baseline SLEDAI-2K score (continuous 
variable).  Based upon the ITT principle, the primary analysis uses the IWRS data for categorical 
stratification factors.  For this sensitivity analysis, the categorical stratification factors (race, 
presence of lupus nephritis at baseline, composite of baseline SLE medications [high/low] and 
clinical SLEDAI score [<10, ≥10] at baseline) will be taken from the electronic data capture 
(EDC) system instead of the ‘as stratified’ data within the IWRS system.  
5.3.
Major Secondary Endpoints
The secondary endpoints are the following:
1.
Time to first flare based on the proportion of subjects with a flare occurring at any time 
after the baseline visit through Week 52, with flare defined as either 1 or more new 
BILAG A or 2 or more new BILAG B scores
2.
The proportion of subjects with a SRI-4 composite response at Week 24
3.
The proportion of subjects achieving at least a 50% improvement in the number of 
joints with pain and signs of inflammation (active joints) at Week 52 in subjects with at 
least 4 affected joints at baseline 
4.
The proportion of subjects receiving glucocorticoids at baseline who achieve reduction 
in glucocorticoid dose by Week 40 and sustain that reduction through Week 52 
(See Section 5.3.1.6 for definitions of reduction of glucocorticoid dose and sustained 
reduction of glucocorticoid dose.)
5.
The proportion of subjects achieving at least a 50% improvement in the CLASI Activity 
Score at Week 52 in subjects with a CLASI Activity Score of 4 or greater at baseline
6.
The proportion of subjects receiving glucocorticoids at baseline who achieve reduction 
in glucocorticoid dose by Week 40, sustain that reduction through Week 52 and achieve 
a SRI-4 composite response at Week 52 (Subjects must meet all criteria)
5.3.1.
Definition
5.3.1.1.
British Isles Lupus Assessment Group (BILAG)
The British Isles Lupus Assessment Group (BILAG)5,6 index scores subjects based on the need 
for alterations or intensification of therapy. The assessing physician will evaluate 97 items 
divided into 9 organ system domains. The physician considers presence of each item in the past 4 
weeks and answers 0=not present, 1=improving, 2=same, 3=worse, or 4=new. Each 
organ/system domain is classified programmatically or by data reviewers as BILAG A, B, C, D, 
or E based upon criteria specific to the domain.6 The BILAG index was designed to give 
practicing physicians a tool to help in decision-making based on amount of activity in each 
organ/system. The baseline measurement for the BILAG is defined as the closest measurement 
taken during the study and prior to administration of study agent at Week 0.


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Adjudicated Flare:  Adjudication for a flare is performed by a blinded adjudication committee 
consisting of clinicians with expertise in lupus disease features and clinical assessment tools.  
The adjudication process consists of (1) applying programmatic definitions of BILAG and 
modified SELENA Flare Index (mSFI) flares to the eCRF collected data to generate a listing of 
subjects with flares and (2) three independent and experienced blinded reviewers will then 
perform an in-depth assessment of clinical data including BILAG, SLEDAI-2K, PGA, modified 
SELENA flare index, CLASI, joint count assessments, concomitant medications, medical 
history, laboratory assessments, and potentially other pertinent information to confirm or 
adjudicate the flare. In the event that the primary reviewers disagree on the flare status the final 
determination of true vs. false flare for each case will be based on majority (2 out of 3 
evaluators) vote. In rare instances regarding complex cases, additional external subject matter 
expert(s) may be consulted to provide an evaluation of the flare, and consensus may be reached 
by committee after a discussion amongst the reviewers and external experts.
All flares will be adjudicated regardless of whether it is the subject’s first flare or an additional 
flare occurring in either the same or a different organ system. Within the programmed dataset, 
there will exist variables for the programmed flare, adjudicated flare, as well as a detailed 
summary of the reason for adjudication. The adjudicated flare variables will serve as the basis for 
the flare endpoints. Details of the flare adjudication process will also be provided in a separate 
adjudication manual.  
Note:  Flares that are determined to be due to COVID-19 will be excluded from flare analyses 
(i.e. the subject will not be censored for a COVID-19 related flare and subject would not have 
been considered to have had a flare).  The reason(s) for exclusion will be discussed.  Any non 
COVID-19 related flare in the future would be included.  Analyses where these such flares are 
included may be conducted.  Note that adjudication of COVID-19 related flares is part of the 
formal adjudication process.
BILAG Flare:  Defined as at least 1 new BILAG A or at least 2 new BILAG B scores meeting at 
least one of the following criteria:

Not present at baseline

The occurrence of a new/worse manifestation in a different component of a domain that 
is already present

At least 1 A or 2 B scores in a domain which improves to B/C/D for at least 2 sequential 
study visits followed by new/worse disease activity
Refer to the Flare Charter for more detailed definitions and programming rules.
Time to First Flare:  Time to first flare is defined as the time (in days) after baseline when a 
given subject experiences his or her first flare. Time to first flare is calculated as the date of the 
first flare minus the date of randomization day + 1.


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5.3.1.2.
SRI-4 Composite Response
See Section 5.2.1 for definition
5.3.1.3.
Systemic Lupus Erythematosus Disease Activity Index 2000 
(SLEDAI-2K)
The SLE disease activity index 2000 (SLEDAI-2K/SLEDAI-2K RI-50) is an established, 
validated SLE activity index. It is based on the presence of 24 features in 9 organ systems and 
measures disease activity in SLE patients at the time of the visit or in the previous 30 days; the 
index is weighted according to the feature. Features are scored by the assessing physician if 
present at the time of the visit within the last 30 days, with more severe features having higher 
scores, and then simply added to determine the total SLEDAI-2K score, which ranges from 0 to 
105.7 The baseline measurement for each of the 24 features of the SLEDAI-2K is defined as the 
closest measurement taken prior to the initiation of the Week 0 study agent administration.  The 
baseline SLEDAI-2K score will be derived from these 24 features.  
The SLEDAI-2K has been adapted and developed into the SLEDAI-2K RI-50,8 a measure that 
can document partial improvement in the 24 disease features among SLEDAI-2K assessments. A 
threshold of 50% improvement was judged to reflect clinically significant improvement and is 
scored as half the weight for the feature. “When a descriptor is recorded as present at the initial 
visit, 1 of 3 situations can follow: (1) the descriptor achieves complete remission at follow-up, in 
which case the score would be “0”; (2) the descriptor does not achieve a minimum of 50% 
improvement at follow-up, in which case the score would be identical to its corresponding 
SLEDAI-2K value; or (3) the descriptor improves by ≥50% (according to the SLEDAI-2K RI-50 
definition) but has not achieved complete remission, in which case the score is evaluated as one-
half the score that would be assigned for SLEDAI-2K.” The SLEDAI-2K RI-50 score is the sum 
of the 24 scored items, which ranges from 0 to 105.
For this study, the developer of the SLEDAI-2K/SLEDAI-2K RI-50 instrument has modified 
scoring disease activity on S2K RI-50 based solely on physician encounter at the time of the 
study visit for the following 8 items: Visual disturbance, Cranial nerve disorder, CVA, 
Vasculitis, Arthritis, Myositis, Rash and Alopecia. This was to ensure reliability of the disease 
activity assessment by the investigators and reduce patient self-reporting bias. Unless otherwise 
specified, all references to the SLEDAI-2K within this SAP refer to this modified version.
SLEDAI improvement is defined as a reduction from baseline in total SLEDAI-2K score. No 
worsening of total SLEDAI-2K from baseline is defined as a change ≤0 in SLEDAI-2K score. At 
baseline, the features assessed in the SLEDAI-2K are used for comparison to the SLEDAI-2K 
RI-50 [Follow-up] described above.
5.3.1.4.
Physicians Global Assessment (PGA) of Disease Activity  
The Physician’s Global Assessment of Disease Activity3 independent of subjects’ assessment is 
recorded on a 10-cm visual analogue scale (VAS) with responses ranging from 0-3, and verbal 
anchors “No Lupus Activity” (0) on the far-left side of the scale and “Extremely Active Lupus” 
(3) on the far right of the scale. Disease activity can range from 0 representing no disease 


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activity, 1 representing mild disease activity, 2 representing moderate disease activity, to 3 
representing extremely active disease. The baseline measurement for the PGA is defined as the 
closest measurement taken prior to the initiation of the Week 0 administration.
5.3.1.5.
Joints with Pain and Signs of Inflammation  
Joints with ‘pain and signs of inflammation’ will be classified as ‘active’ and be defined as those
joints which are tender (i.e. subject reports pain as assessor applies pressure) on examination and
exhibit at least one sign of inflammation (e.g. edema of effusion to be considered swollen) on 
physical examination as determined by the joint assessor.  
Assessment of tender, swollen, and both tender and swollen joints will be performed by an 
adequately trained joint assessor at all visits indicated in the protocol. Joint counts will be 
assessed using a 64 tender and 62 swollen joint count in accordance with the SLEDAI-2K RI-50 
electronic case report form (eCRF), which includes a homunculus depicting the bilateral 
temporomandibular, sternoclavicular, shoulder, elbow, wrist, metacarpophalangeal, hand 
proximal interphalangeal, hand distal interphalangeal, hip (only tenderness assessed), knee, 
ankle, metatarsophalangeal, and foot interphalangeal joints. The joint assessor will record the 
number of tender, swollen, and both tender and swollen joints and then assess whether the joints 
demonstrating both tenderness and swelling meet the above definition of ‘pain and signs of 
inflammation’ and therefore be considered ‘active’. The number of active joints will then be 
entered on the S2K-RI50 eCRF under the arthritis section. A 50% improvement in the number of 
active joints is defined as a 50% reduction from baseline in the number of active joints for those 
subjects with active joints at baseline.  The analysis of at least 50% improvement will be 
performed on subjects with at least 4 active joints at baseline (e.g. subjects with 4 or 5 active 
joints at baseline would show 50% improvement if the number of joints were reduced to 0,1 
or 2).  
Local intra-articular injections into joints will deem the joints to be imputed as active (having 
pain and signs of inflammation) from the point of injection thereafter for the purpose of joint 
count assessments.
5.3.1.6.
Glucocorticoid Reduction
For this study, average daily dose for any given day is the average of the last 7 days dosing, 
including the day of interest.  Note that the dosing days do not have to be consecutive.  The 
average is of the last 7 days where the subject was dosed.
For this study, reduction of glucocorticoid dose is defined as:

A reduction in average daily oral glucocorticoid dose by at least 50% (relative to the 
baseline dose) 
OR

Reduction of average daily oral glucocorticoid dose by at least 25% (relative to the 
baseline dose) so that the average daily dose is reduced to ≤7.5 mg (prednisone or 
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For this study, sustained reduction of glucocorticoid dose is defined as:
Achieving average daily oral glucocorticoid dose reduction (as described above) between 
Weeks 24 and 40, and sustaining that reduction through Week 52, in those subjects who, at 
baseline, were receiving oral glucocorticoids. Note that this will be performed in the subset of 
randomized subjects who were receiving oral glucocorticoids at baseline.
Minor dose adjustments after reducing glucocorticoid dose are permitted and subjects will still 
be considered to have sustained reduction.  These dose adjustments are permitted after the 
Week 40 visit up to and including the Week 48 visit.  Any dose increase after the Week 48 visit 
would deem the subject as a non-responder for the endpoint from the point of dose increase 
onward.  These dose adjustments include the following:

An increase in average daily dose to a maximum of 5 mg (averaged across the period of 
increase) above the dose reduction achieved and the increased dose does not return to or 
exceed the baseline dose, that meets the above criteria is permitted.  Only one increase 
in average daily dose (maximum of 5 mg average daily dose above dose reduction 
achieved and the increased dose does not return to or exceed the baseline dose) for a 
period of no longer than 7 consecutive days is permitted. The subject will not be 
considered to have achieved sustained reduction in glucocorticoid dose if either of the 
following conditions occur:
1.
Average daily dose increase continues for longer than 7 consecutive days
2.
Greater than 1 (> 1) distinct episode of average daily dose increase occurs  

Table 5 below provides examples of possible scenarios.  
Table 5:
Glucocorticoid Dosing (mg) Examples Within Range of Sustaining Reduction
Baseline 
Dose
Criteria Achieved
Reduced 
Dose*
Maximum Increase 
Allowed *
Maximum Adjusted Dose 
Allowed 
20
50% reduction
10.0
5
15.0
17.5
50% reduction
9.0
5
14.0
15
50% reduction
7.5
5
12.5
10
25% reduction to ≤ 7.5 mg
7.5
2
9.5
7.5
25% reduction to ≤ 7.5 mg
6.0
1
7.0
5
25% reduction to ≤ 7.5 mg
4.0
1
5.0
*Note that maximum increases allowed (column 4) are presented in possible dosing increments, as GC doses are 
available in 1, 2, 2.5 and 5 mg doses.  Reduced doses (column 3) are rounded up to the next possible clinical dose.
Note that a subject meeting the allowed dose adjustment criteria must taper back to their Week 40 reduced dose by 
the end of the dose increase period.


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Missing Glucocorticoid Dosing:
Missing glucocorticoid dosing will only be interpolated for the glucocorticoid efficacy analyses
(i.e. Major Secondary endpoints #4 and #6 described in Section 5.3), all other analyses (e.g. 
safety, concomitant medications) will not interpolate missing values.  
In general, if a subject or investigator indicates that a dose was skipped (i.e. dose data is not 
missing, dose of medication was not taken) the dose will be entered as a 0 mg dose.
If glucocorticoid dosing is missing at baseline, no interpolation will be performed.
If a subject has baseline and at least 1 post baseline dose measurement, the following 
interpolation will be performed:

Unless otherwise specified, missing dose will be interpolated as the average of (1) the 
actual dose taken on the last day before the missing value(s) and (2) the actual dose 
taken on first day after the missing value(s).  

Although the missing dose data will be interpolated, in those analyses where treatment 
failure rules are in effect, a subject’s response status will either be set to non-response 
(Primary Estimand analyses) or missing (Hypothetical Estimand) from the point of 
treatment failure onwards. 
5.3.1.7.
Cutaneous Lupus Erythematosus Disease Area and Severity Index
(CLASI)
Cutaneous lupus disease activity and severity will be measured by the Cutaneous Lupus 
Erythematosus Disease Area and Severity Index (CLASI). The CLASI is an instrument to assess 
the disease activity and damage caused to the skin for cutaneous lupus erythematosus (CLE)
patients with or without systemic involvement. The CLASI consists of 2 scores; the first 
summarizes the activity of the disease while the second is a measure of the damage caused by the 
disease (CLASI Activity and CLASI Damage scores). Activity is scored by the Investigator
based on erythema, scale/hyperkeratosis, mucous membrane involvement, acute hair loss, and 
non-scarring alopecia. Damage is scored in terms of dyspigmentation and scarring, including 
scarring alopecia. The scores are calculated by simple addition based on the extent of the 
symptoms.9

CLASI scores range from 0-70 for activity and 0-56 for damage, with higher scores 
indicating worse disease activity.
5.3.2.
Analysis Methods:  Secondary Endpoints
Analyses for binary secondary endpoints (proportion of response, improvement, reduction) will 
be based upon the Primary Estimand and utilize the FAS excluding those subjects whose 
projected Week 52 visit occurred after study termination.  (see Section 2.3.2.1)  
Supportive analyses will be performed and include an analysis based upon the entire FAS (See 
Section 5.4).  Time to flare analyses will also be based upon the Primary Estimand and FAS 
excluding those subjects whose projected Week 52 visit occurred after study termination where 


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loss to follow-up patients will be censored and patients who discontinue study treatment (as 
described below) or initiate rescue therapy will be considered to have a flare.

For this study, reasons for discontinuation of study treatment include: (1) adverse event 
(2) death (3) prohibited medication (4) lack of efficacy (5) loss to follow up (6) non-
compliance with study drug (7) physician decision (8) protocol deviation (9) pregnancy 
(10) study terminated by sponsor (11) withdrawal by parent or guardian (12) withdrawal 
by subject and (13) other.  For the primary time to flare analysis those who discontinue 
study treatment for the following reasons: (1) adverse event (2) death (3) prohibited 
medication or (4) lack of efficacy will be considered to have a flare, while subjects who 
discontinue study treatment for the remaining reasons will not be considered to have a 
flare and their observed data will be used, unless they initiate rescue therapy.
Note:  Flares that are determined to be due to COVID-19 will be excluded from flare analyses 
(i.e. the subject will not be censored for a COVID-19 related flare and subject would not have 
been considered to have had a flare).  The reason(s) for exclusion will be discussed.  Any non 
COVID-19 related flare in the future would be included.  Analyses where these such flares are 
included may be conducted.  Note that adjudication of COVID-19 related flares is part of the 
formal adjudication process.
The hazard ratio for time to flare data (secondary endpoint #1 in Section 5.3 above) will be 
estimated using the Cox proportional hazards model, adjusting for baseline SLEDAI-2K score 
(continuous variable), and its 95% confidence interval will be calculated. The proportional 
hazards assumption will be verified with appropriate methods (e.g. log-minus-log plots) as part 
of the analysis.  The reported p-values for time to first flare analyses will be derived from a log-
rank test and will also be used for multiplicity control. The survival curves will be estimated 
using Kaplan-Meier estimates.
Binary endpoints (secondary endpoints #2, 3, 4, 5, and 6 in Section 5.3 above) will be analyzed 
using the same approach as the primary endpoint.  Logistic regression, adjusting for baseline 
stratification factors, region and baseline SLEDAI-2K score (continuous variable) as described in 
Section 5.2.3 will be used.
In general, point estimates and 95% confidence intervals for comparison between treatment 
groups will be reported.
5.4.
Additional Efficacy Endpoints
As supportive analyses to the primary composite endpoint, the following analyses will be 
performed on the Primary Estimand (both a FAS analyses excluding those subjects whose 
projected Week 52 visit occurred after study termination as well as a the entire FAS analyses 
including those subjects will be performed) as well as the Treatment Policy Estimand.  Summary 
statistics including point estimates, odds ratios and 95% Wald confidence intervals1 will be 
reported.  


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
The proportion of subjects with at least a 4-point improvement compared with baseline in 
SLEDAI-2K at Week 52

The proportion of subjects with no worsening from baseline in PGA at Week 52 

The proportion of subjects with no BILAG worsening from baseline (defined as no new 
BILAG A scores and ≤1 new BILAG B score) at Week 52 

The proportion of subjects with SRI-4, SRI-5, SRI-6, SRI-7, or SRI-8 composite response at 
Week 52 
As supportive analyses to the key secondary endpoints, the following analyses will be 
performed:

For the binary key secondary endpoints (#2, 3, 4, 5, and 6 in Section 5.3) a similar 
analyses as outlined in Section 5.2.3 for the primary endpoint will be performed 
utilizing the Treatment Policy (de Facto) Estimand.  

For the binary key secondary endpoints (#2, 3, 4, 5, and 6 in Section 5.3) a similar 
analyses as outlined in Section 5.2.3 for the primary endpoint will be performed 
utilizing the Primary Estimand and the entire FAS.  
As supportive analysis to the time to flare key secondary endpoint, the following 2 analyses will 
be performed:
1.
An analysis using the Treatment Policy Estimand will be performed censoring subjects 
who are lost-to-follow-up.  Patients who continue to be followed in the study, regardless 
of adherence to study drug or use of ancillary therapies, will be evaluated for flare. 
2.
An analysis using the modified Treatment Policy Estimand where those who 
discontinue study treatment for the following reason: (1) adverse event (2) death (3) 
prohibited medication (4) lack of efficacy (11) withdrawal by parent or guardian (12) 
withdrawal by subject and (13) other, will be considered to have a flare, while subjects 
who discontinue study treatment for the remaining reasons will not be considered to 
have a flare and their observed data will be used, unless they initiate rescue therapy.  
(See Section 5.3.2 for complete list of possible reasons for discontinuation)
5.4.1.
Definition
5.4.1.1.
Measures of Improvement in Global Disease Activity
SLEDAI-2K: See Section 5.3.1.3.
SRI-4 Composite Response:  SLEDAI-2K SRI-4 response is defined as ≥4-point reduction from 
baseline in SLEDAI-2K score, no new BILAG A and no more than 1 new BILAG B domain 
score, and no worsening from baseline in the Physician’s Global Assessment (PGA) of Disease 
Activity (<10% worsening from baseline).4 SRI-4 composite response is the proportion of 
subjects who achieve a SLEDAI-2K SRI-4 response and do not meet treatment failure criteria
prior to the visit of interest.  


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SRI-5, SRI-6, SRI-7, SRI-8 Composite Response:  Defined as SRI-4 response above however a 
≥5-point, ≥6-point, ≥7-point and ≥8-point reduction from baseline in SLEDAI-2K score is 
required.
Note that for any given SRI composite response, the subset of subjects included in the analysis 
are those who have a SLEDAI score at baseline greater than or equal to the reduction required 
for the response (e.g. For the SRI-7 composite response, only subjects with a baseline SLEDAI 
score ≥ 7 are included in the analysis)
BILAG No Worsening:  Defined as no new BILAG A scores and ≤1 new BILAG B score.
No Worsening in PGA:  Defined as no significant deterioration (< 1.0 cm increase) in 10 cm 
visual analogue scale, or < 0.3 point increase on a 0-3 point scale.
5.4.2.
Analysis Methods
Unless otherwise specified, the analysis population will be the FAS excluding those subjects 
whose projected Week 52 visit occurred after study termination as defined in Section 2.3.2.  The 
endpoints will be summarized by treatment groups.
P-values provided for analyses will be nominal.
Binary endpoints (e.g. responder analysis) will be analyzed using the same approach as the 
primary endpoint.  Logistic regression, adjusting for baseline stratification factors, region and 
baseline SLEDAI-2K score (continuous variable) as described in Section 5.2.3 will be used.  
If applicable, continuous endpoints will be analyzed using a Mixed Model for Repeated 
Measures (MMRM) model to test the difference between treatment groups and adjust for missing 
data.  The models will include baseline SLEDAI score as a covariate and treatment, baseline 
medication use for SLE (high, medium), race, visit, and an interaction of treatment and visit as 
fixed effects. The within-subject covariance between visits will be estimated via an unstructured 
variance-covariance matrix. In case of convergence problems, alternative variance-covariance 
structures will be tried in the following order, with the first structure that converges being used in 
the analysis: heterogeneous Toeplitz, standard Toeplitz, and AR(1) with separate subject random 
effect. Comparison of the ustekinumab arm versus placebo will be performed using the 
appropriate contrast.  The normality and equal variance assumptions underlying the MMRM 
model will be assessed graphically. Residuals from the primary models will be plotted against 
the predicted values and a QQ plot of the residuals versus the expected quantiles of the standard 
normal distribution will be presented. If either the equal variance or the normality assumption 
appears to be grossly violated, other methods including an ANCOVA on ranks model or an 
appropriate transformation of the primary endpoint might be considered.  
The hazard ratio for time to event data will be estimated using the Cox proportional hazards 
model and its 95% confidence interval will be calculated. The proportional hazards assumption 
will be verified with appropriate methods (e.g. log-minus-log plots) as part of the analysis.  The 
reported p-values for time to event analyses will be derived from a log-rank test and will also be 


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used for multiplicity control. The survival curves will be estimated using Kaplan-Meier 
estimates.
The following Table 6 outlines the efficacy endpoints, types of the analyses, and the data 
handling rules used through Week 52 for Additional Efficacy Endpoints listed in Section 5.4.
Table 6:
Analysis and Data Handling Rules for Supportive Endpoints Listed in Section 5.4
Endpoint
Estimand
Missing Data 
Imputation
Type
Measures of Improvement in Global Disease Activity
1
The proportion of subjects with SRI-4, SRI-
5, SRI-6, SRI-7, and SRI-8 composite 
response at Week 52
Primary (FAS 
including/excluding 
Week 52 projected 
after termination)
Yes – TF considered 
non-responders. 
Missing assume 
non-response.
Binary
Treatment Policy
No
Binary
2
The proportion of subjects with SRI-4 
response at Week 24
Primary (FAS 
including/excluding 
Week 24 projected 
after termination)
Yes – TF considered 
non-responders. 
Missing assume 
non-response.
Binary
Treatment Policy
No
Binary
3
The proportion of subjects with at least a 4-, 
5-, 6-, 7-, or 8-point improvement compared
with baseline in SLEDAI-2K at 52
Primary (FAS 
including/excluding 
Week 52 projected 
after termination)
Yes – TF considered 
non-responders. 
Missing assume 
non-response.
Binary
Treatment Policy
No
Binary
4
The proportion of subjects with no 
worsening in PGA at Week 52
Primary (FAS 
including/excluding 
Week 52 projected 
after termination)
Yes – TF considered 
non-responders. 
Missing assume 
non-response.
Binary
Treatment Policy
No
Binary
5
The proportion of subjects with no BILAG 
worsening compared with baseline at Week 
52
Primary (FAS 
including/excluding 
Week 52 projected 
after termination)
Yes – TF considered 
non-responders. 
Missing assume 
non-response.
Binary
Treatment Policy
No
Binary
Flare
6
Time to first flare based on the proportion of 
subjects with a flare occurring at any time 
after baseline visit through Week 52, with 
flare defined as either 1 or more new BILAG 
A or 2 or more BILAG B scores
Treatment Policy
No
Binary
7
Time to first flare based on the proportion of 
subjects with a flare occurring at any time 
Modified 
No
Binary


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Table 6:
Analysis and Data Handling Rules for Supportive Endpoints Listed in Section 5.4
Endpoint
Estimand
Missing Data 
Imputation
Type
after baseline visit through Week 52, with 
flare defined as either 1 or more new BILAG 
A or 2 or more BILAG B scores
Treatment Policy
Glucocorticoid Sparing (Tapering)
8
The proportion of subjects receiving 
glucocorticoids at baseline who achieve 
reduction in glucocorticoid dose by Week 40 
and sustain that reduction through Week 52
Treatment Policy
No
Binary
9
The proportion of subjects receiving 
glucocorticoids at baseline who achieve 
reduction in glucocorticoid dose by Week 40, 
sustain that reduction through Week 52 and 
achieve SRI-4 composite response at Week 
52
Treatment Policy
No
Binary
Musculoskeletal Disease
10
The proportion of subjects achieving at least 
a 50% improvement in the number of active 
joints (defined as joints with pain and signs 
of inflammation) at Week 52 in subjects with 
at least 4 active joints at baseline
Treatment Policy
No
Binary
Mucocutaneous Disease
11
The proportion of subjects who achieve a 
50% reduction from baseline in CLASI 
activity score at Week 52 in those subjects 
with a baseline CLASI activity score of at 
least 4
Treatment Policy
No
Binary
5.5.
SLEDAI-2K Supportive Analyses
The S2K RI-50 was developed based on the SLEDAI-2K, which in general scores post-baseline 
disease activity if present at the time of the physician encounter or in the preceding 30 days. 
However, for this study, the developer of the SLEDAI-2K/SLEDAI-2K RI-50 instrument has 
modified scoring disease activity on S2K RI-50 based solely on physician encounter at the time 
of the study visit for the following 8 items: Visual disturbance, Cranial nerve disorder, CVA, 
Vasculitis, Arthritis, Myositis, Rash and Alopecia. This was to ensure reliability of the disease 
activity assessment by the investigators and reduce patient self-reporting bias. Unless otherwise 
specified, all references to the SLEDAI-2K within this SAP refer to this modified version.  The 
remaining 16 items are scored utilizing the 30 day look back. Therefore, post-baseline SLEDAI-
2K assessments are based upon this modified S2K RI-50.  This was to ensure reliability of the 
disease activity assessment by the investigators and reduce patient self-reporting bias. In 
addition, we are able to collect more information around partial improvement of disease activity.  


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On March 30th of 2020, the originally developed SLEDAI-2K utilizing the 30 day look back was 
implemented in the study and data was to be captured from implementation of the form through 
the end of the study.  This data is in addition to the modified S2K/S2K RI-50 data to be collected 
from study start through the end of the study.
The primary endpoint, SRI-4, as well as all SLEDAI-2K analyses for CNTO1275SLE3001 are
based upon the modified instrument utilizing the day of study visit for the 8 items reference 
above.  As supportive information, and to demonstrate consistency between utilization of the 
modified instrument and the originally developed S2K RI-50 we will perform various supportive 
analysis as outlined in this section.
5.5.1.
Definition
5.5.1.1.
SLEDAI-2K v10Oct2015 (modified SLEDAI-2K/S2K- RI-50)
The SLEDAI-2K v10Oct2015, hereafter referenced as modified SLEDAI-2K/S2K RI-50 is the 
endpoint in both the CNTO1275SLE2001 and CNTO1275SLE3001 studies as defined in 
Section 5.3.1.3.  For 8 of the 24 SLEDAI-2K domains, the post-baseline disease activity score is
based solely on physician encounter on the day of study visit.  These 8 domains include the 
Alopecia, Arthritis, Cranial Nerve Disorder, CVA, Myositis, Rash, Vasculitis and Visual 
Disturbance
domains. The first utilization of the modified
instrument was in the 
CNTO1275SLE2001 study where it was implemented from study start.  The date of that 
implementation was 10 Oct 2015, therefore the naming convention of this endpoint.  All analyses 
concerning SLEDAI-2K in both the CNTO1275SLE2001 and CNTO1275SLE3001 studies
utilize the modified SLEDAI-2K data.  This includes the SLEDAI-2K component of the primary 
endpoint, SRI-4.
5.5.1.2.
SLEDAI-2K Pre-v2015 (Traditional SLEDAI-2K)
SLEDAI-2K based upon data being obtained from the March 30, 2020 implementation of the 
originally developed SLEDAI-2K questionnaire and associated eCRF page utilizing the 30 day 
look back on all SLEDAI-2K components.
However, given the limited data collected for the Traditional SLEDAI-2K due to the study 
termination, no analyses concerning the Traditional SLEDAI-2K will be performed.
5.5.1.3.
SLEDAI-2K Recode
SLEDAI-2K based upon utilizing BILAG to recode the 8 domains (Alopecia, Arthritis, Cranial 
Nerve Disorder, CVA, Myositis, Rash, Vasculitis and Visual Disturbance) where the disease 
activity score was based upon physician encounter on the day of study visit.  For the other 16 
SLEDAI domains, the SLEDAI-2K v10Oct2015 data as collected is utilized.  
The following steps were taken in order to re-code the SLEDAI-2K v10Oct2015 into the 
SLEDAI-2K Recode based upon a BILAG re-coding algorithm:
1.
Define mapping of BILAG components to SLEDAI-2K Domains as follows:
SLEDAI Domain
BILAG Components Utilized in Mapping


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Alopecia
Alopecia severe, Alopecia mild
Arthritis
Arthritis severe, Arthritis moderate
Cranial Nerve Disorder
Cranial neuropathy
CVA
Cerebrovascular disease
Myositis
Myositis severe, Myositis mild
Rash
Skin eruption severe, Skin eruption mild, Panniculitis/bullous 
lupus severe, Panniculitis/bullous lupus mild, Peri-ungal 
erythema/chilblains
Vasculitis
Major cutaneous vasculitis/thrombosis, Digital infarcts or 
nodular vasculitis, Splinter haemorrhages, Cerebral vasculitis, 
Pulmonary haemorrhage/vasculitis, Aortitis, Coronary 
vasculitis, Lupus enteritis/colitis
Visual Disturbance
Severe keratitis, Posterior uveitis/retinal vasculitis severe, 
Retinal/choroidal vaso-occlusive disease, Isolated cotton-wool 
spots, Optic neuritis, Anterior ischaemic optic neuropathy
2.
Define algorithm for re-coding the SLEDAI-2K v10Oct2015 values
a.
BILAG ‘New’ or ‘Worse’ or ‘Same’ or ‘Improving’ for any one of the BILAG 
components included in a specific SLEDAI domain result in a re-coding of a 
‘PRESENT’ value for that specific SLEDAI-2K Recode domain.   
b.
BILAG ‘Not Present’ or missing for all of the BILAG components in a specific 
SLEDAI domain = ‘ABSENT’ for that specific SLEDAI-2K Recode domain.
3.
Using steps #1-#2 above, re-code the 8 SLEDAI-2K v10Oct2015 domains that did not 
utilize the 30 day look back as either ‘ABSENT’ or ‘PRESENT’.  For the remaining 16 
SLEDAI-2K domains, utilize the SLEDAI-2K v10Oct2015 responses as collected. 
4.
Database the SLEDAI-2K Recode domain values in addition to the original SLEDAI-
2K v10Oct2015 responses to be used in exploratory analyses
5.
Utilize the 8 SLEDAI-2K Recode domain values in addition to the original 16 
SLEDAI-2K v10Oct2015 responses to calculate a new variable, SLEDAI-2K Recode 
Total Score.
5.5.2.
Analysis Specifications
5.5.2.1.
SLEDAI-2K v10Oct2015 (modified SLEDAI-2K)
For the purposes of this SAP, ALL analyses referencing SLEDAI-2K are those based upon the 
modified SLEDAI-2K and will be performed as outlined in this SAP.


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5.5.2.2.
SLEDAI-2K Re-Code
The following analyses will be performed utilizing the SLEDAI-2K Re-Code data.  
SRI-4 Composite Response at Week 52 Using SLEDAI-2K Re-Code:  Defined as ≥4-point 
reduction from baseline in SLEDAI-2K Re-Code score, no new BILAG A and no more than 1 
new BILAG B domain score, and no worsening from baseline in the Physician’s Global 
Assessment (PGA) of Disease Activity (<10% worsening from baseline). For the primary 
endpoint analysis, SRI-4 composite response is the proportion of subjects who achieve a 
response at Week 52 and do not meet treatment failure criteria to Week 52.
Sensitivity Analysis 1 (Treatment Policy Estimand) Using SLEDAI-2K Re-Code:  Sensitivity 
analysis #1B, see Section 5.2.3.2, will be performed on the population of subjects who have 
Week 52 SLEDAI-2K Re-Code data.
Sensitivity Analysis 2 (Primary Estimand) Using SLEDAI-2K Re-Code:  Sensitivity analysis #2, 
see Section 5.2.3.2, based upon the entire FAS will be performed on the population of subjects 
who have Week 52 SLEDAI-2K Re-Code data.
5.5.3.
Analysis Methods
Unless otherwise stated, the analysis population for the SLEDAI-2K Re-Code analysis will be 
the FAS excluding those subjects whose projected Week 52 visit occurs after study termination 
as defined in Section 2.3.2.  The endpoints will be summarized by treatment groups.
P-values provided will be nominal.
Binary endpoints (e.g. responder analysis) will be analyzed using the same approach as the 
primary endpoint.  Logistic regression, adjusting for baseline stratification factors, region and 
baseline SLEDAI-2K score (continuous variable) as described in Section 5.2.3 will be used. 
Consistency across the analyses may be displayed graphically.
6.
SAFETY
Unless otherwise stated, all safety analyses will be based upon the safety analysis set as 
described in Section 2.3.3 above.  No formal statistical comparison is planned.  
6.1.
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Any AE occurring at or after 
the initial administration of study agent is considered to be a treatment emergent adverse event 
(TEAE). If the event occurs on the day of the initial administration of study agent, 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 agent based on partial onset date or resolution date. AEs that occur prior to the 
administration of study agent but then increase in intensity after dosing are also considered to be 
treatment emergent.  All reported treatment-emergent adverse events will be included in the 


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analysis.  For each adverse event, the number and percentage of subjects who experience at least 
1 occurrence of the given event will be summarized by treatment group. 
TEAEs will be tabulated by treatment group and Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Class (SOC) and be sorted in descending frequency of the Preferred 
Term (PT) within the SOC.  The following TEAEs will be summarized by treatment group:
Summary tables will be provided for:

All TEAEs

Serious TEAEs

TEAEs reasonably related to study agent

TEAEs by severity (mild, moderate, severe)

Treatment emergent infections including serious infections

Treatment emergent opportunistic infection

Treatment emergent infusion/injection site reactions

Treatment emergent hypersensitivity reactions

Treatment emergent occurrences of Tuberculosis
In addition to the summary tables, the following will be listed by subject:

Serious TEAEs

TEAEs leading to discontinuation of study agent

Major Adverse Cardiovascular Events (MACE)

Any deaths
A reasonably related AE is defined as any event with the relationship to study agent as ‘very 
likely’, ‘probable’, or ‘possible’ on the AE eCRF page or if the relationship to study agent is 
missing.
Infusion reaction is defined as the following:
Refer only to the adverse event dataset.  An infusion reaction is defined as an AE that occurs 
during or within 1 hour following the infusion of study agent and the event must be included 
within the MedDRA narrow Hypersensitivity Reactions SMQ, with the exception of laboratory 
abnormalities. 


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Use the following rationale to exclude lab abnormality events:
Exclude all AEs coded to the SOC of Investigations with the exception of the following 2 Higher 
Level Grouped Terms (HLGTs).  Include only the following 2 HLGTs from the Investigation 
SOC as infusion reactions:

Cardiac and vascular investigations (excl enzyme tests)

Physical examination and organ system status topics
If the AE onset time is missing and the AE onset date is the same as the infusion date, the 
missing time will be imputed with the time of the infusion
An injection site reaction is defined as an AE with the question on the AE eCRF page ‘Was this 
an injection site reaction’ = ‘Yes’.
An infection is defined as any AE that was characterized by the investigator as an infection on 
the eCRF.
An opportunistic infection is defined as infection by an organism that normally is not pathogenic 
or does not cause invasive infection in immunocompetent hosts (e.g. cytomegalovirus, 
pneumocystosis, or aspergillosis).
Since safety should be assessed relative to exposure and follow-up, all AE summary tables will 
summarize the average weeks of follow-up and average exposure for each treatment group.
6.2.
Clinical Laboratory Tests
Routine laboratory data from clinical chemistry, hematology, serology and urinalysis will be 
collected at screening and at Visits according to the time and events schedule in the study 
protocol.  The laboratory data to be summarized are as follows:
Clinical Blood Chemistry: Chemistry panel including alanine aminotransferase (ALT), albumin, 
aldolase (if creatinine kinase is elevated at screening then perform aldolase test at screening, 
Week 0 and follow-up as needed), alkaline phosphatase, aspartate aminotransferase (AST), 
bicarbonate, blood urea nitrogen (BUN), calcium, chloride, creatinine, creatinine kinase, FSH as 
needed, glucose (non-fasting), phosphorous, potassium, sodium, total bilirubin, total protein.  If 
total bilirubin is abnormally elevated, both direct and indirect bilirubin will be assessed.
Hematology:  hemoglobin, hematocrit, platelet count, white blood cell (WBC) total and 
differential (basophils, eosinophils, lymphocytes, monocytes, neutrophils), CD19 B-cell analyses 
by flow cytometry during screening only if needed for subjects previously exposed to B-cell 
depleting therapies, Coomb’s direct test
Coagulation Laboratories:  prothrombin time (PT), partial prothrombin time (PTT), international 
normalized ratio (INR)


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Urinalysis:  Dipstick (bilirubin, blood, glucose, ketones, leukocytes, nitrite, pH, specific gravity, 
and urobilinogen), urine sediment microscopy (bacteria, crystals, epithelial cells, granular casts, 
heme casts, RBC, RBC casts, WBC, WBC casts) and urinary protein/creatinine ratio
Additional lab data may be summarized as needed.
Descriptive statistics for selected clinical laboratory analyte and for change from baseline at each 
scheduled post-baseline visit will be provided by treatment group. The National Cancer 
Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE; version 4.0) will be 
used in the summary of laboratory data (Grade 0-4).  The proportion of subjects with post-
baseline values by maximum toxicity grade for clinical laboratory tests will be summarized by 
treatment group.  Subjects with toxicity grades ≥ 2 will be listed.
Proportion of subjects with maximum ALT/AST will be provided for the categories:  

1 to < 2xULN

≥ 2 to < 3xULN

≥ 3 to < 5xULN

≥ 5xULN
For those labs without CTCAE toxicity grades, the incidence of markedly abnormal laboratory 
values will be presented by treatment group.  Additionally, the markedly abnormal laboratory 
values will be listed.  Markedly abnormal criteria will be defined in the Data Presentation 
Specifications (DPS) document.
6.3.
Vital Signs and Physical Examination Findings
Weight, blood pressure, temperature, respiratory rate and heart rate will be assessed with a 
completely automated device. 
Descriptive statistics of changes from baseline will be summarized by visit and treatment group.  
Abnormal findings will be summarized by treatment group.  In addition, a listing of subjects with 
abnormal vital signs will be presented.  Vital sign parameters will be considered abnormal using 
the criteria below:


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Vital Sign
Abnormally Low
Abnormally High
Systolic BP (mm Hg)
Absolute value < 90 mmHg and a 
decrease from baseline ≥ 20 mmHg
Absolute value > 180 mmHg and an 
increase from baseline ≥ 20 mmHg
Diastolic BP (mm Hg)
Absolute value < 50 mmHg and a 
decrease from baseline ≥ 15 mm Hg
Absolute value > 105 and an increase 
from baseline ≥ 15 mm Hg
Respiratory Rate             
(beats/minute)
< 12
> 24
Heart Rate             
(beats/minute)
Absolute value < 50 bpm and a 
decrease from baseline ≥ 15 bpm
Absolute value > 120 bpm and an 
increase from baseline ≥ 15 bpm
Temperature (°C)
< 36°C
> 38°C
6.4.
Electrocardiogram
This section does not apply to this study.
6.5.
Other Safety Parameters
This section does not apply to this study.
6.6.
COVID-19 Summaries
Included in the adverse event summaries discussed in this section will be events related to 
COVID-19.  These will be identified and coded using the MedDRA coding guidance for 
COVID-19.  Summary tables will be provided for:

COVID-19 related TEAEs

Selected TEAEs of interest related to COVID-19

Selected TEAEs of interest related to COVID-19
In addition to the summary tables, the following will be listed by subject:

TEAEs related to COVID-19

Serious TEAEs related to COVID-19

Deaths related to COVID-19
7.
PHARMACOKINETICS/PHARMACODYNAMICS
7.1.
Pharmacokinetics
PK analyses will be performed on the PK analysis set (see Section 2.3.4).  No imputation for 
missing concentration data will be performed.


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PK concentrations will be summarized by treatment group among PK evaluable subjects. 
Descriptive statistics, including arithmetic mean, SD, coefficient of variation, median, minimum, 
and maximum will be calculated for ustekinumab concentrations at each sampling time. 
Concentrations below the lowest quantifiable concentration in a sample will be treated as zero in 
the summary statistics.  All subjects excluded from the analysis will be clearly documented in the 
study report.  Once a subject meets one of the following dosing deviation criteria, the subject’s 
data will be excluded from the by-visit data analyses from that point onwards:

Discontinued ustekinumab administrations.

Skipped an ustekinumab administration.

Received an incomplete/ incorrect ustekinumab dose.

Received an incorrect study agent.

Received an additional ustekinumab dose.

Received an administration outside of visit windows (For PK analyses, the visit and the 
study agent administration should occur within +/- 7 days of the scheduled visit day 
relative to Week 0). 
The definition of treatment group at Week 52 analysis is as follows:

Ustekinumab: Subjects who received ustekinumab at any time from Week 0.  
PK data may be displayed graphically.  Plots of mean (SD) serum concentrations of ustekinumab 
over time, using semi-logarithmic scales, may be provided. 
The relationship between PK and antibody to ustekinumab status may be assessed.
If feasible, a population PK analysis using nonlinear mixed effects modeling may be used to 
characterize the disposition characteristics of ustekinumab in the current study. The influence of 
important variables such as body weight and antibodies to ustekinumab status on the population 
PK parameter estimates may be evaluated. Details will be given in a population PK analysis 
plan, and results of the population PK analysis will be presented in a separate technical report.
7.2.
Immune Response
Blood samples will be collected to examine the formation of antibodies to ustekinumab at the 
specified visits as shown in the schedule of events in the protocol.  For subjects who discontinue 
study agent administrations, samples will be collected at their final safety visit, 16 weeks after 
the last study agent administration.
The data analysis includes the following:

The incidence and titers of antibodies to ustekinumab will be summarized for all 
subjects who received at least one dose of ustekinumab and had appropriate serum 
samples for antibody detection.  


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
The incidence of neutralizing antibody status (NAbs) to ustekinumab will be 
summarized for subjects who are positive for antibodies to ustekinumab and have 
samples evaluable for NAbs. 

A listing of subjects positive for antibodies to ustekinumab at any time.

The relationship between antibody to ustekinumab and efficacy at Week 52 (SRI-4 
composite response).

Infusion/injection-site reactions by antibody to ustekinumab status and treatment group.
The definition of treatment group at Week 52 analysis is as follows:

Ustekinumab: Subjects who received ustekinumab at any time from Week 0.   
7.3.
Pharmacodynamics
Anti-Nuclear Antibody (ANA) levels and proportion of subjects with positive ANA over time 
will be summarized for those subjects positive at baseline.
Changes in the concentration and proportion of subjects with abnormalities of individual 
pharmacodynamics markers from baseline to the selected post treatment time points will be 
summarized.  These include but are not limited to ANA, anti-ds-DNA, C3 and C4 complement, 
IgA, IgG, and IgM.  
7.4.
Pharmacokinetic/Pharmacodynamic Relationships
If data permit, the relationships between serum ustekinumab concentration and efficacy or 
pharmacodynamic measures may be analyzed graphically.
8.
LONG TERM EXTENSION (THROUGH WEEK 176) SUMMARIES
Eligible subjects could enter the study extension after their Week 52 visit.  However, due to the 
early termination of the study a formal Week 176 DBL (i.e. the end of the extension period of the 
study) will not occur.  The following summaries are to evaluate the entirety of safety data for the 
trial through the trial termination and 16 weeks of safety follow up as well as demographics and 
disposition for those subjects entering the study extension. 
There is no formal statistical hypothesis testing for the Week 176 DBL, neither are there efficacy 
summaries after Week 52.  Due to the early termination of the trial, the data from the Week 176
DBL are supportive to Week 52 and will evaluate longer term safety.
8.1.
Demographics
Demographics and baseline characteristics for those subjects entering the study extension will be 
summarized based upon the randomized analysis set.  
8.2.
Disposition
Disposition information will be summarized by treatment group in terms of numbers of subjects 
randomized, treated, entering study extension and completing scheduled study extension visits.  


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Disposition information will be based upon the randomized analysis set. Additionally, the 
number of subjects who discontinued study agent after entering the study extension and the 
reason for discontinuation as well as those who terminated the study and reason for termination 
will be summarized.
8.3.
Protocol Deviations
Protocol deviations will be summarized as described in Section 4.5.
8.4.
Concomitant Medications
Concomitant medications will be summarized as described in Section 4.6.
8.5.
Efficacy 
Efficacy data after Week 52 will not be summarized.
8.6.
Adverse Events
Adverse Events (AEs) will be summarized in similar fashion as described in Section 6.1.  
For the placebo group, AEs that occur before entering the LTE and receiving the first dose of 
ustekinumab (before entering LTE) will be considered to have occurred while on placebo 
treatment.  AEs that occur in the placebo group during or after the first dose of ustekinumab 
(after entering LTE and receiving first dose of ustekinumab) will be considered to have occurred 
while on ustekinumab treatment.  Summaries will clearly describe this separation (e.g. example 
heading below).  
Placebo – Ustekinumab
Placebo
(Before LTE Entry)
Ustekinumab
(After LTE Entry)
8.7.
Clinical Laboratory Tests
Clinical labs will be summarized as described in Section 6.2.
8.8.
Vital Signs and Physical Examination Findings
Vital signs will be summarized as described in Section 6.3.
8.9.
Pharmacokinetics/Immunogenicity/Pharmacodynamics
PK and immunogenicity will be summarized as described in Sections 7.1 and 7.2 excluding any 
analysis of efficacy and immune response.


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