Conditions: Scleroderma, Systemic
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 56
Healthy volunteers: no

Brief summary:
The purpose of the study is to evaluate the efficacy of guselkumab in participants with systemic sclerosis (SSc).

Detailed description:

Arms:
arm 1: Participants will receive intravenous (IV) injection of Guselkumab Dose 1 at Week 0, 4, and 8 followed by subcutaneous (SC) injection of Dose 2 Guselkumab every 4 weeks (Q4W) from Week 12 to Week 48 (end of maintenance phase). Participants will receive SC injection of Guselkumab Dose 2 and IV injection of placebo at long-term extension (LTE) Weeks 52, 56, and 60 followed by SC injection of Guselkumab Dose 2 Q4W from LTE Week 64 until Week 100. arm 2: Participants will receive IV injection of matching placebo at Week 0, 4, and 8 followed by SC injection of matching placebo Q4W from Week 12 to Week 48 (end of maintenance phase). Participants will receive SC injection of Placebo and IV injection of Guselkumab Dose 1 at LTE Weeks 52, 56, and 60 followed by SC injection of Guselkumab Dose 2 Q4W from LTE Week 64 until Week 100.

Interventions: intervention 1: Guselkumab Dose 1 intervention 2: Guselkumab Dose 2 intervention 3: Placebo
Intervention descriptions: intervention 1: Guselkumab Dose 1 will be administered intravenously. intervention 2: Guselkumab Dose 2 will be administered subcutaneously. intervention 3: Placebo will be administered intravenously or subcutaneously.

Protocol document:
Prot_000.pdf: 
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
1
Status: Approved,  Date:  15 November 2022
Janssen Pharmaceutical K.K.*
Clinical Protocol
Protocol Title
A Multicenter, Randomized, Placebo-controlled, Double-blind, Proof-of-concept Study of
Guselkumab in Participants with Systemic Sclerosis
Protocol CNTO1959SSC2001; Phase 2a
AMENDMENT 5
 CNTO1959  (guselkumab)
 
* This study is being conducted by Janssen Pharmaceutical K.K. in Japan. The term “sponsor” is used
throughout the protocol to represent Janssen Pharmaceutical K.K.
Status: 
Approved
Date: 
15 November 2022
Prepared by: Janssen Pharmaceutical K.K.
EDMS number: 
EDMS-RIM-152487, 7.0
GCP Compliance:  This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory
requirements.
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or
otherwise.
NCT04683029


CNTO1959  (guselkumab)  
Clinical Protocol CNTO1959SSC2001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
2
Status: Approved,  Date:  15 November 2022
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 5 
15 November 2022
Amendment 4 
25 August 2022
Amendment 3 
30 September 2021
Amendment 2 
20 Ma y 2021
Amendment 1 
25 March 2021
Original Protocol 
20 October 2020
Amendment 5 (15 November 2022)
Overall Rationale for the Amendment: To Abolish Week 24 DBL and Internal Decision Committee
(IDC).
The changes made to the clinical protocol CNTO1959SSC2001 as part of Protocol Amendment 5 are listed
below, including the rationale of each change and a list of all applicable sections.
Section Number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis
OVERALL DESIGN
4.1 Overall Design
The following text was modified:
TwoThree planned database locks (DBLs) will occur:
when all participants complete the Week 24 visit
(hereinafter referred to as “Week 24 DBL”), EOS of the
main study (Week 52 visit for participants who entered
LTE or Week 60 safety follow up visit for participants
who did not enter LTE, hereinafter referred to as “Week
52 DBL”), and EOS of LTE (Week 112 visit, hereinafter
referred to as “Final DBL”). Of note: if the LTE is
terminated as per the IDC’s (Internal Decision
Committee) recommendation (Section 9.5), there will be
2 DBLs (Week 24 and Week 52 DBLs) only and the LTE
data collected for the participants who already entered
LTE at the time of Week 24 DBL will be analyzed at
Week 52 DBL, along with the data through Week 52 or
60 visit.
To Abolish Week 24
DBL and IDC in order
to avoid unblinding for
part of the sponsor
personnel during
double-blind period
(until Week 52) from
data integrity
perspective.
1.2 Schema 
Figure 1
 
Week 24 DBL was deleted.
4.1.1 Long-term Extension 
The following text was deleted:
An internal decision committee (IDC) will be established
to determine whether the LTE can continue or not based
on the data from Week 24 DBL, as a risk mitigation if
few benefits of guselkumab has been observed (Section
9.5). The decision will be informed to investigators by
sponsor’s study site monitor, only if LTE is terminated.
Investigators must inform all participants to take the
following actions;
 
Participants who have already entered LTE will
discontinue study intervention, and perform Early
termination visit and safety follow up visit
NCT04683029


CNTO1959  (guselkumab)  
Clinical Protocol CNTO1959SSC2001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
3
Status: Approved,  Date:  15 November 2022
Section Number 
and Name
Description of Change 
Brief Rationale
(Week 112) as per Section 1.3.
 
Participants who are still in the main study will
continue study intervention until Week 52, and
follow up visit (Week 60) to complete the study as
per Section 1.3, unless there is any safety concern.
 
If the termination decision is made for safety
concern, then all participants will be discontinued
from both LTE and main study.
6.3 Measure to Minimize 
Bias: Randomization and 
Blinding 
Blinding 
The following text was modified:
Under normal circumstances, the blind should not be
broken until the Week 52 DBL. However, selected
sponsor personnel will be unblinded for analysis after the
Week 24 DBL has occurred. All sponsor personnel, site
personnel and participants will remain blinded to the
treatment assignments until the Week 52 DBL. An
unblinding plan will be developed and finalized prior to
any unblinding to designate sponsor personnel who will
have access to the unblinded data during the period from
the Week 24 DBL to the Week 52 DBL.
An internal decision committee (IDC) will be established
to determine whether the LTE can continue or not with
the data from Week 24 DBL and the IDC member will
be unblinded to all Week 24 data to facilitate the decision
making (Section 9.5).
9.4.1 General 
Considerations 
The following text was modified:
The primary An interim analysis will be performed
when all participants have completed the Week 52
24visit or discontinued earlier. The final analysis will
be performed when all participants have completed the
last study visit or discontinued earlier. Other analysis
timepoints are described in Section 9.4.6.
9.4.6 Other Analyses 
Interim Analyses 
The following text was modified:
The primary analysis will be performed when all
participants have completed Week 24 or discontinued
earlier. Internal Decision Committee (IDC) will
determine whether the LTE can continue or not based on
the primary analysis results. In addition, selected sponsor
personnel will be unblinded at the primary analysis for
internal decision making. Details of the unblinding will
be specified in SAP.
If LTE continues, aAn interim analysis will be
performed when all participants have completed EOS of
the main study Week 52 or discontinued earlier. All
sponsor personnel will be unblinded at the analyses for
internal decision-making and/or interactions with health
authorities.
9.5 Internal Decision 
Committee
Section deleted.
 
NCT04683029


CNTO1959  (guselkumab)  
Clinical Protocol CNTO1959SSC2001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
4
Status: Approved,  Date:  15 November 2022
Section Number 
and Name
Description of Change 
Brief Rationale
6.8 Concomitant Therapy 
NSAIDs or Other 
Analgesics 
The following text was modified: 
For participants who receive corticosteroids and/or 
NSAIDs, prophylactic treatment with such as
rebamipide, proton pump inhibitors or H2-receptor
blockers should be considered. Prophylactic treatment
should be added according to the investigator’s
discretion.
Change to appropriate
prophylaxis.
NCT04683029


CNTO1959  (guselkumab)  
Clinical Protocol CNTO1959SSC2001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
5
Status: Approved,  Date:  15 November 2022
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................. 2
TABLE OF CONTENTS .......................................................................................................................... 5 
LIST OF IN-TEXT TABLES AND FIGURES ............................................................................................ 7
1. 
PROTOCOL SUMMARY ................................................................................................................ 8
1.1. 
Synopsis ..................................................................................................................................... 8
1.2. 
Schema .................................................................................................................................... 16
1.3. 
Schedule of Activities (SoA) ...................................................................................................... 17
2. 
INTRODUCTION .......................................................................................................................... 22
2.1. 
Study Rationale......................................................................................................................... 23
2.2. 
Background............................................................................................................................... 24
2.3. 
Benefit-Risk Assessment .......................................................................................................... 25
2.3.1. 
Risks for Study Participation .................................................................................................. 25
2.3.2. 
Benefits for Study Participation .............................................................................................. 28
2.3.3. 
Benefit-Risk Assessment for Study Participation .................................................................... 28
3. 
OBJECTIVES AND ENDPOINTS ................................................................................................. 29
4. 
STUDY DESIGN ........................................................................................................................... 31
4.1. 
Overall Design .......................................................................................................................... 31
4.1.1. 
Long-term Extension .............................................................................................................. 33
4.1.2. 
Self-Administration of Study Intervention ................................................................................ 33
4.2. 
Scientific Rationale for Study Design ......................................................................................... 34
4.2.1. 
Study-specific Ethical Design Considerations ......................................................................... 34
4.3. 
Justification for Dose ................................................................................................................. 35
4.4. 
End of Study Definition .............................................................................................................. 36
5. 
STUDY POPULATION ................................................................................................................. 37
5.1. 
Inclusion Criteria ....................................................................................................................... 37
5.2. 
Exclusion Criteria ...................................................................................................................... 41
5.3. 
Lifestyle Considerations ............................................................................................................ 46
5.4. 
Screen Failures ......................................................................................................................... 46
5.5. 
Criteria for Temporary Delaying Enrollment/Randomization/Administration of Study
Intervention Administration ........................................................................................................ 46
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY ......................................................... 46
6.1. 
Study Intervention(s) Administered ............................................................................................ 46
6.1.1. 
Combination Products ............................................................................................................ 47
6.2. 
Preparation/Handling/Storage/Accountability ............................................................................. 48
6.3. 
Measures to Minimize Bias: Randomization and Blinding .......................................................... 49
6.4. 
Study Intervention Compliance .................................................................................................. 50
6.5. 
Dose Modification ..................................................................................................................... 50
6.6. 
Continued Access to Study Intervention After the End of the Study............................................ 51
6.7. 
Treatment of Overdose ............................................................................................................. 51
6.8. 
Concomitant Therapy ................................................................................................................ 51
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL ........................................................................................... 53
7.1. 
Discontinuation of Study Intervention ........................................................................................ 53
7.1.1. 
Liver Chemistry Stopping Criteria ........................................................................................... 55
7.2. 
Participant Discontinuation/Withdrawal From the Study ............................................................. 55
7.2.1. 
Withdrawal From the Use of Research Samples .................................................................... 55
7.3. 
Lost to Follow-up ....................................................................................................................... 56
NCT04683029


CNTO1959  (guselkumab)  
Clinical Protocol CNTO1959SSC2001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
6
Status: Approved,  Date:  15 November 2022
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................ 57
8.1. 
Efficacy Assessments ............................................................................................................... 59
8.1.1. 
Modified Rodnan Skin Score .................................................................................................. 60
8.1.2. 
American College of Rheumatology Combined Response Index in Diffuse Cutaneous
Systemic Sclerosis Score ....................................................................................................... 60
8.1.3. 
Pulmonary Function Tests ..................................................................................................... 60
8.1.4. 
Physician Global Assessment ................................................................................................ 60
8.1.5. 
Patient-reported Outcomes .................................................................................................... 61
8.1.6. 
Digital Ulcer Assessments ..................................................................................................... 61
8.1.7. 
Nailfold Capillaroscopy .......................................................................................................... 62
8.1.8. 
High-resolution Computed Tomography (HRCT) Assessment ................................................ 62
8.2. 
Safety Assessments .................................................................................................................. 62
8.2.1. 
Physical Examinations ........................................................................................................... 62
8.2.2. 
Vital Signs ............................................................................................................................. 62
8.2.3. 
Electrocardiograms ................................................................................................................ 63
8.2.4. 
Clinical Safety Laboratory Assessments ................................................................................. 63
8.2.5. 
Interstitial Lung Disease Monitoring........................................................................................ 63
8.2.6. 
Adverse Events Temporally Associated with Infusion ............................................................. 63
8.2.7. 
Injection-site Reactions .......................................................................................................... 63
8.2.8. 
Hypersensitivity Reactions ..................................................................................................... 63
8.2.9. 
Tuberculosis evaluations........................................................................................................ 64
8.2.9.1. 
Initial Tuberculosis Evaluation ............................................................................................. 64
8.2.9.2. 
Ongoing Tuberculosis Evaluation ........................................................................................ 65
8.2.10. 
Infections ............................................................................................................................... 65
8.2.11. 
Hepatitis B Monitoring ............................................................................................................ 66
8.2.12. 
Concomitant Medication Review ............................................................................................ 66
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting...................................... 66
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information ............................................................................................................................ 66
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events ......................................... 67
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events ..................................................... 67
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events ........................................... 67
8.3.5. 
Pregnancy ............................................................................................................................. 68
8.3.6. 
Adverse Events of Special Interest (AESI).............................................................................. 68
8.4. 
Pharmacokinetics ...................................................................................................................... 68
8.4.1. 
Evaluations ............................................................................................................................ 68
8.4.2. 
Analytical Procedures ............................................................................................................ 68
8.4.3. 
Pharmacokinetic Parameters and Evaluations........................................................................ 69
8.5. 
Pharmacogenomics .................................................................................................................. 69
8.6. 
Biomarkers ............................................................................................................................... 69
8.6.1. 
Pharmacodynamics ............................................................................................................... 69
8.7. 
Immunogenicity Assessments ................................................................................................... 69
8.8. 
Autoantibodies .......................................................................................................................... 70
9. 
STATISTICAL CONSIDERATIONS .............................................................................................. 70
9.1. 
Statistical Hypotheses ............................................................................................................... 70
9.2. 
Sample Size Determination ....................................................................................................... 70
9.3. 
Populations for Analysis Sets .................................................................................................... 71
9.4. 
Statistical Analyses ................................................................................................................... 72
9.4.1. 
General Considerations ......................................................................................................... 72
9.4.2. 
Primary Endpoint ................................................................................................................... 72
9.4.3. 
Secondary Endpoints ............................................................................................................. 72
9.4.4. 
Exploratory Endpoints ............................................................................................................ 73
9.4.5. 
Safety Analyses ..................................................................................................................... 73
9.4.6. 
Other Analyses ...................................................................................................................... 73
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................... 76
10.1. 
Appendix 1: Abbreviations and Definitions ................................................................................. 76
NCT04683029


CNTO1959  (guselkumab)  
Clinical Protocol CNTO1959SSC2001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
7
Status: Approved,  Date:  15 November 2022
10.2. 
Appendix 2: Clinical Laboratory Tests........................................................................................ 78
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations ....................................... 79
10.3.1. 
Regulatory and Ethical Considerations ................................................................................... 79
10.3.2. 
Financial Disclosure ............................................................................................................... 82
10.3.3. 
Informed Consent Process ..................................................................................................... 82
10.3.4. 
Data Protection ...................................................................................................................... 83
10.3.5. 
Publication Policy/Dissemination of Clinical Study Data .......................................................... 84
10.3.6. 
Data Quality Assurance ......................................................................................................... 85
10.3.7. 
Case Report Form Completion ............................................................................................... 85
10.3.8. 
Source Documents ................................................................................................................ 86
10.3.9. 
Monitoring.............................................................................................................................. 87
10.3.10. On-Site Audits ....................................................................................................................... 87
10.3.11. Record Retention ................................................................................................................... 88
10.3.12. Study and Site Start and Closure ........................................................................................... 88
10.4. 
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and
Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up,
and Reporting ........................................................................................................................... 90
10.4.1. 
Adverse Event Definitions and Classifications ........................................................................ 90
10.4.2. 
Attribution Definitions ............................................................................................................. 91
10.4.3. 
Severity Criteria ..................................................................................................................... 91
10.4.4. 
Special Reporting Situations .................................................................................................. 91
10.4.5. 
Procedures ............................................................................................................................ 92
10.4.6. 
Product Quality Complaint Handling ....................................................................................... 93
10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality ........................................... 94
10.5. 
Appendix 5: Contraceptive and Barrier Guidance ...................................................................... 95
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ................................ 97
10.7. 
Appendix 7: Hepatitis B Virus (HBV) Screening with HBV DNA Testing ................................... 101
10.8. 
Appendix 8: Study Conduct During a Natural Disaster ............................................................. 102
10.9. 
Appendix 9: Protocol Amendment History................................................................................ 104
11. REFERENCES ........................................................................................................................... 121
INVESTIGATOR AGREEMENT .......................................................................................................... 123
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Schedule of Activities (SoA) of Screening and Double-Blind Study Intervention (Main
Study) .................................................................................................................................. 17
Table 2: 
Long-Term Extension for Eligible Participants Who Have Completed the Main Study
(LTE) ................................................................................................................................... 20
Table 3: 
Volume of Blood to be Collected from Each Participant ........................................................ 57
Table 4: 
Eligibility based on hepatitis B virus test results .................................................................. 101
FIGURES
Figure 1: Schematic Overview of the Main Study ................................................................................ 16
Figure 2: Schematic Overview of LTE ................................................................................................. 16
NCT04683029


CNTO1959  (guselkumab)  
Clinical Protocol CNTO1959SSC2001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
8
Status: Approved,  Date:  15 November 2022
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
A Multicenter, Randomized, Placebo-controlled, Double-blind, Proof-of-concept Study of Guselkumab in
Participants with Systemic Sclerosis
Guselkumab (CNTO1959) is a fully human immunoglobulin G1 lambda (IgG1λ) monoclonal antibody
(mAb) that binds to human interleukin (IL)-23 with high specificity and affinity. The binding of
guselkumab to the IL-23p19 subunit blocks the binding of extracellular IL-23 to the cell surface IL-23
receptor, inhibiting IL-23-specific intracellular signaling and subsequent activation and cytokine
production. In this manner, guselkumab inhibits the biological activity of IL-23 in all in vitro assays
examined.
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary 
 
To evaluate the efficacy of guselkumab in
participants with systemic sclerosis (SSc)
 
Change from baseline in Modified Rodnan Skin
Score (mRSS) at Week 24
Secondary
 
To evaluate the additional efficacy of
guselkumab in participants with SSc
 
Change from baseline in mRSS at Week 52
 
The proportion of participants who experience
worsening of mRSS at Week 24 and Week 52
 
The proportion of participants achieving a score
of 0.6 in American College of Rheumatology
Combined 
Response 
Index 
in 
dcSSc
(ACR CRISS) at Week 24 and Week 52
 
Change from baseline in forced vital capacity
(FVC) and percent predicted FVC at Week 24
and Week 52
 
Change from baseline in the measured absolute
diffusing capacity of the lung for carbon
monoxide (DLCO) and the derived percent
predicted DLCO at Week 24 and Week 52
 
Change from baseline in digital ulcer counts at
Week 24 and Week 52
 
Change from baseline in Health Assessment
Questionnaire-Disability Index (HAQ-DI) score
at Week 24 and Week 52
 
To evaluate the safety and tolerability of
guselkumab in participants with SSc
 
Number and proportion of participants with
treatment-emergent adverse events (AEs) and
serious adverse events (SAEs) or adverse events
of special interest (AESI) from baseline through
Week 24, Week 52, Week 76 and Week 104.
 
To evaluate the pharmacokinetic (PK) and
immunogenicity of guselkumab
 
Serum guselkumab concentrations
 
Incidence of anti-guselkumab antibody
NCT04683029


CNTO1959  (guselkumab)  
Clinical Protocol CNTO1959SSC2001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
9
Status: Approved,  Date:  15 November 2022
Objectives 
Endpoints
Exploratory
 
To evaluate the other efficacy of 
guselkumab in participants with SSc 
 
Time to disease worsening: Increase from
baseline ≥5 and ≥20% in mRSS OR decrease
>10% from baseline in percent predicted FVC
 
The proportion of participants who experience
FVC decline compared with baseline at Week 24
and Week 52
 
The proportion of participants who experience
worsening of FVC at Week 24 and Week 52
 
Change from baseline in fibrotic change assessed
with high-resolution computed tomography
(HRCT) at Week 24 and Week 52 in participants
with baseline fibrosis/fibrotic changes
 
The proportion of participants who experience
worsening of fibrotic change assessed with
HRCT at Week 24 and Week 52
 
Change from baseline in Frequency Scale for the
Symptoms of Gastroesophageal reflux disease
(FSSG) score at Week 24 and Week 52
 
Assessment of nailfold capillaries at Week 24
and Week 52
 
Change from baseline in Patient global
assessment (PGA) at Week 24 and Week 52
 
Change from baseline in Physician global
assessment (PhGA) at Week 24 and Week 52
 
To evaluate the long-term efficacy of 
guselkumab in participant with SSc 
 
Change from baseline and Week 52 in mRSS at
Week 76 and Week 104
 
The proportion of participants who experience
worsening of mRSS at Week 76 and Week 104
 
The proportion of participants achieving a score
of 0.6 in American College of Rheumatology
Combined 
Response 
Index 
in 
dcSSc
(ACR CRISS) at Week 76 and Week 104
 
Change from baseline in forced vital capacity
(FVC) and percent predicted FVC at Week 76
and Week 104
 
The proportion of participants who experience
worsening of FVC at Week 76 and Week 104
 
Change from baseline in the measured absolute
diffusing capacity of the lung for carbon
monoxide (DLCO) and the derived percent
predicted DLCO at Week 76 and Week 104
NCT04683029


CNTO1959  (guselkumab)  
Clinical Protocol CNTO1959SSC2001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
10
Status: Approved,  Date:  15 November 2022
Objectives 
Endpoints
 
Change from baseline in Health Assessment
Questionnaire-Disability Index (HAQ-DI) score
at Week 76 and Week 104
 
Change from baseline in digital ulcer counts at
Week 76 and Week 104
 
Change from baseline in fibrotic change assessed
with high-resolution computed tomography
(HRCT) at Week 76 and Week 104 in
participants 
with 
baseline 
fibrosis/fibrotic
changes
 
The proportion of participants who experience
worsening of fibrotic change assessed with
HRCT at Week 76 and Week 104
 
Change from baseline in Frequency Scale for the
Symptoms of Gastroesophageal reflux disease
(FSSG) score at Week 76 and Week 104
 
To evaluate the effect of guselkumab vs
placebo on the pharmacodynamic (PD) and
SSc disease biomarkers
 
Change from baseline levels of skin (optional)
and circulating (blood based) biomarkers over
time to enable:
Evaluation 
of 
target 
engagement 
in
tissue/efficacy pharmacodynamic (PD) readouts
 
Single 
nucleotide 
polymorphisms 
(SNPs)
frequency associated with IL-23 pathway
Hypothesis
This is a proof-of-concept (PoC) study aimed at detecting an early efficacy signal of guselkumab in
participants with SSc, compared to placebo, to support further clinical development.
 
The null hypothesis is that the treatment difference between guselkumab and placebo for the primary
endpoint is =0.
 
The alternative hypothesis is that the treatment difference between guselkumab and placebo for the
primary endpoint is ≠0.
Due to the PoC nature of this study, a 2-sided alpha of 0.2 is allocated for testing this PoC hypothesis. The
PoC objective will be considered met if the calculated p-value for testing this PoC hypothesis is less than
0.2.
OVERALL DESIGN
This is a randomized, double-blind, placebo-controlled, parallel, multicenter, interventional study to
evaluate the efficacy of guselkumab in men and women between the ages of 18 to 75 years, inclusive, with
a diagnosis of SSc according to American College of Rheumatology (ACR) and European League Against
Rheumatism (EULAR) 2013 criteria with a disease duration of ≤36 months (defined as time from first non-
Raynaud phenomenon manifestation), and mRSS ≥10 to ≤22 units.
Participants will be randomly assigned in a 1:1 ratio, based on randomization strata of presence of ILD (yes,
no), baseline mRSS (low [≥10 to ≤15] or high [≥16 to ≤22]), and baseline anti-topoisomerase I antibody
status (positive, negative), to one of the following treatment groups:
NCT04683029


CNTO1959  (guselkumab)  
Clinical Protocol CNTO1959SSC2001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
11
Status: Approved,  Date:  15 November 2022
 
Guselkumab (Group/Arm A): Guselkumab 400 mg intravenous (IV) administration at Weeks 0, 4, and
8 (induction) followed by guselkumab 200 mg subcutaneous (SC) administration every 4 weeks
(Q4W) from Week 12 until Week 48 (maintenance)
 
Placebo (Group/Arm B): Matching placebo IV administration at Weeks 0, 4, and 8 (induction)
followed by matching placebo SC administration Q4W from Week 12 until Week 48 (maintenance)
The main study will be conducted in 3 phases: a maximum 6-week screening phase, a 52-week double-blind
intervention phase, and a safety follow-up phase with a post-intervention follow-up visit at 12 weeks after
the participant’s last dose of study intervention to collect any AEs since the last study visit.
Participants who complete the main study (Week 0 through 52: ie, after the Week 48 evaluation, prior to
Week 52 evaluation) and who, in the opinion of the investigator, may benefit from continued treatment,
will participate in the LTE by signing the ICF before or at Week 52. The duration of individual participation
will be approximately 66 weeks without LTE and 118 weeks with LTE.
Two planned database locks (DBLs) will occur: EOS of the main study (Week 52 visit for participants who
entered LTE or safety follow up visit for participants who did not enter LTE, hereinafter referred to as
“Week 52 DBL”), and EOS of LTE (Week 112 visit, hereinafter referred to as “Final DBL”).
Key efficacy assessments will include mRSS, ACR CRISS score; pulmonary function tests: FVC and % of
predicted FVC, and DLCO (ml/min/mm Hg) and % of predicted DLCO (hemoglobin-corrected); PhGA;
and PGA. Key safety assessments include the monitoring of AEs (including SAEs, AEs of special interest
[AESIs], infections, injection-site reactions, adverse events temporally associated with infusion, and
hypersensitivity reactions), physical examinations, vital sign measurements, electrocardiogram (ECG)
measurements, clinical laboratory tests, ILD (assessed by centrally read HRCT), and tuberculosis (TB)
evaluations. Additionally, PK, biomarker, and immunogenicity assessments will also be performed in this
study
NUMBER OF PARTICIPANTS
The study will target to enroll a total of approximately 56 participants with 28 participants planned per
intervention group.
INTERVENTION GROUPS AND DURATION
Participants will be randomly assigned in a 1:1 ratio to 1 of the following study intervention groups:
 
Guselkumab (Group/Arm A): Guselkumab 400 mg IV administration Weeks 0, 4, and 8 (induction)
followed by guselkumab 200 mg SC administration Q4W from Week 12 until Week 48 (maintenance)
 
Placebo (Group/Arm B): Matching placebo IV administration Weeks 0, 4, and 8 (induction) followed
by matching placebo SC administration Q4W from Week 12 until Week 48 (maintenance)
During the LTE, all participants will receive guselkumab treatment in LTE as below depending on the arms
they were in the main study:
 
Group/Arm A (guselkumab arm from the main study): Guselkumab 200 mg SC and placebo IV at LTE
Weeks 52, 56, and 60 followed by guselkumab 200 mg SC Q4W from LTE Week 64 until Week 100.
 
Group/Arm B (placebo arm from the main study): Placebo SC and guselkumab 400 mg IV at LTE
Weeks 52, 56, and 60 followed by guselkumab 200 mg SC Q4W from LTE Week 64 until Week 100.
The duration of individual participation will be approximately 66 weeks without LTE and 118 weeks with
LTE.
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Clinical Protocol CNTO1959SSC2001 Amendment 5
 
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Status: Approved,  Date:  15 November 2022
EFFICACY EVALUATIONS
Efficacy assessments will include the following:
 
mRSS
 
ACR CRISS score
 
Pulmonary function tests (PFTs):
 
FVC and % of predicted FVC
 
DLCO (ml/min/mm Hg) and % of predicted DLCO (hemoglobin-corrected)
 
PhGA
 
Patient-Reported Outcomes (PROs):
 
PGA
 
HAQ-DI
 
FSSG Questionnaire
 
Digital ulcer assessment
 
Nailfold Capillaroscopy
 
Lung HRCT (centrally read)
PHARMACOKINETIC EVALUATIONS
Serum samples will be analyzed to determine concentrations of guselkumab using respective validated,
specific, and sensitive methods by or under the supervision of the sponsor’s respective assay methods.
IMMUNOGENICITY EVALUATIONS
Serum samples will be screened for antibodies binding to guselkumab and the titer of confirmed positive
samples will be reported. Serum samples positive for anti-guselkumab antibodies will be further
characterized for neutralizing antibodies (Nabs) to guselkumab. Other analyses may be performed to verify
the stability of anti-guselkumab antibodies and/or further characterize the immunogenicity of guselkumab.
AUTOANTIBODIES
Samples will be collected at screening to evaluate the presence of autoantibodies (including, but not limited
to anti-ribonucleic acid [RNA] polymerase, anti-centromere, and anti-topoisomerase).
PHARMACODYNAMIC AND BIOMARKER
Peripheral blood mononuclear cell (PBMC) and serum samples will be collected at timepoints specified in
the Schedule of Assessments (SoA), to assess the blood cellular and molecular biomarkers to enable
evaluation of target engagement in tissue/efficacy PD readouts.
An optional biomarker sub-study will obtain a biopsy sample of non-lesional (unaffected) skin sample at
Week 0, and lesional (at Week 0) skin at Week 0 and 24 from all participants who consent.
PHARMACOGENOMIC EVALUATIONS
A pharmacogenomic blood sample will be collected from participants who consent separately to this
component of the study to allow for pharmacogenomic research, as necessary. Participant participation in
pharmacogenomic research is optional.
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CNTO1959  (guselkumab)  
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Status: Approved,  Date:  15 November 2022
SAFETY EVALUATIONS
Safety evaluations conducted at each study visit will include the assessment of AEs (at the visit and those
occurring between evaluation visits), ILD monitoring (assessed by centrally read HRCT), TB evaluation
and other infection assessments, clinical laboratory blood tests (hematology and serum chemistry including
C-reactive protein), pregnancy testing, physical examinations, ECG measurements, vital signs (as defined
in the Schedule of Activities), concomitant medication review, and observations for injection-site reactions,
hypersensitivity reactions, and AEs temporally associated with an infusion. In addition, for participants
who are eligible with surface antigen (HbsAg) negative, core antibody (anti-HBc) and/or surface antibody
(anti-HBs) positive, and HBV DNA test is negative, HBV DNA quantitation should be monitored at least
every 3 months or shorter.
STATISTICAL METHODS
Sample Size Determination
A 95% confidence interval (CI) of [−4.7, −1.7] in mRSS change from baseline to 6 months is considered a
clinically meaningful change. The lower bound of this 95% CI, -4.7, has been taken as the expected
treatment difference in the sample size calculation of this study, assuming guselkumab can achieve a
clinically meaningful change in most of guselkumab-treated participants.
Assuming a standard deviation (SD) of 8 points, an 80% power at a 2-sided significance level of 0.20, with
a 1:1 randomization ratio, to detect a treatment effect of -4.7 points, a total of at least 54 participants will
be required. Allowing for up to 2 participants randomized but without post-baseline efficacy assessments,
approximately 56 (28 each) randomized participants are planned.
Population for Analyses Sets
Efficacy and participant information analyses will include all randomized participants who received at least
1 dose (complete or partial) of study intervention and will be analyzed based on the randomized treatment
groups, regardless of the treatment they actually received.
Safety analysis set will include all randomized participants who receive at least 1 dose (partial or complete)
of study intervention and participants will be analyzed based on the treatment they receive, regardless of
the treatment groups to which they are assigned.
Pharmacokinetic analysis set will include all participants who received at least 1 complete dose of
guselkumab and have at least 1 observed post dose PK data.
Immunogenicity analysis set will include all participants who received at least 1 dose of guselkumab and
have at least 1 observed post dose immune response data.
Efficacy Analyses
Simple descriptive summary statistics, such as n, mean, SD, median, inter quantile range, minimum, and
maximum for continuous variables, and counts and percentages for discrete variables will be used to
summarize most data.
For primary endpoint (Change from baseline in mRSS at Week 24), treatment comparison will be
performed using a Mixed-Effect Model Repeated Measure (MMRM) model. The MMRM model includes
treatment group, baseline mRSS, stratification factors, visit, treatment group by visit interaction, and
baseline mRSS by visit interaction as fixed effects. Treatment effects will be estimated based on least-
square (LS) means of the differences. The p-values for the LS mean differences along with the 2-sided 80%
CI will be presented. Sensitivity and subgroup analyses for the primary endpoint will be performed, if
appropriate. The details of these analyses and data handling rules will be specified in the statistical analysis
plan (SAP).
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CNTO1959  (guselkumab)  
Clinical Protocol CNTO1959SSC2001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date:  15 November 2022
All other efficacy endpoints will be summarized over time by treatment group. Treatment comparisons will
be performed using an MMRM model where there are repeated continuous measurements or a logistic
model where there is a dichotomous response variable. No adjustments for multiple comparisons will be
made for the secondary endpoints and all p-values will be considered nominal. The detailed methods of
analysis and the data-handling rules will be provided in the SAP.
Safety Analyses
Routine safety evaluations will be performed based on the safety analysis set. Adverse events, SAEs, related
AEs, and AEs by severity will be summarized by treatment group. More specification of other AESIs such
as ILD will be described in the SAP.
The laboratory parameters and change from baseline in selected laboratory parameters (hematology and
chemistry), and the number of participants with abnormal laboratory parameters (hematology and
chemistry) based on National Cancer Institute Common-Terminology Criteria for Adverse Events
(NCI-CTCAE) toxicity grading will be summarized by treatment group.
Clinically relevant ECG abnormalities will be evaluated by frequency tabulations. Descriptive statistics of
temperature, pulse/heart rate, respiratory rate, and blood pressure (systolic and diastolic) values and changes
from baseline will be summarized at each scheduled time point. The percentage of participants with values
beyond clinically important limits will be summarized.
Pharmacokinetic Analyses
Unless otherwise noted, PK analyses will be based on the PK Analysis Set. Serum guselkumab
concentrations over time will be summarized with descriptive statistics at each nominal sampling timepoint.
All concentrations below the lowest quantifiable concentration or missing data will be labeled as such in
the concentration database or data presentations. Concentrations below the lowest quantifiable
concentration will be treated as zero in the summary statistics.
Detailed rules for the analysis including exclusion from the PK analyses will be specified in the SAP.
Population PK modeling may be conducted when appropriate. If population PK analysis is conducted, the
results will be presented in a separate report.
Immunogenicity Analyses
The incidence and titers of anti-guselkumab antibodies will be summarized for the immunogenicity analysis
set. A listing of participants who are positive for anti-guselkumab antibodies will be provided. The
maximum titers of anti-guselkumab antibodies will be summarized for participants who are positive for
antibodies to guselkumab.
The incidence of Nabs to guselkumab will be summarized for participants who are positive for antibodies
to guselkumab and have samples evaluable for neutralizing antibodies to guselkumab.
Pharmacodynamic Analyses
Serum will be collected from all subjects to assess PD markers associated with guselkumab as well as
markers related to SSc. Measurements may include but are not limited to serum levels of IL-17A, IL-17F,
IL-22, beta defensin-2 (BD-2), and SAA. Broader proteomic profiling (eg, via Olink method) for biomarker
discovery may be performed.
Blood samples for the isolation of PBMCs will also be collected for subsequent immunophenotyping
analyses by multiparameter flow cytometry or mass cytometry (CyTOF) analysis to measure immune cell
populations before and during treatment. Gene expression analysis may also be performed; this may include
single cell RNA-sequencing (RNA-seq) profiling.
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Status: Approved,  Date:  15 November 2022
Results of pharmacodynamic/biomarker analyses will be presented in a separate report.
Biomarkers Analyses
Characterization of gene expression changes in the skin during treatment would be analyzed as determined
by RNA-seq at Weeks 0 and 24. If feasible, a non-lesional (unaffected) skin sample will be collected at
Week 0; lesional (at Week 0) samples to be collected at both Weeks 0 and 24. If feasible, characterization
of the tissue immunopathological changes in the skin as determined by immunohistochemistry (IHC)/
immunofluorescence (IF)/ in situ hybridization (ISH), as well as histology analysis (eg, fibrosis) may be
performed. Multiparameter protein profiling (eg, imagine CyTOF) may be considered.
Pharmacokinetic/Pharmacodynamic Analyses
The relationship between serum concentrations of guselkumab and the efficacy measures and/or relevant
PD endpoints, including biomarkers in blood or in skin biopsies, may be explored graphically when
appropriate. If any visual trend is observed, additional analysis may be conducted if deemed necessary.
Pharmacogenomic Analyses
Genetic analysis may help to identify population subgroups that respond differently to a drug. A single
DNA sample at Week 0 will be used to explore genetic factors that may influence molecular effects, clinical
efficacy, or tolerability of guselkumab and to identify genetic factors associated with SSc. A locus of
interest is the IL12RB1 gene; a reported SSc risk allele has been identified in this gene and there is potential
association with expression of the gene product (encoding a receptor for IL-23). Analysis applied to DNA
samples may focus on genotyping, using molecular arrays to scan polymorphisms across the genome.
Participation in the DNA sampling is optional.
Results will be presented in a separate report.
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Status: Approved,  Date:  15 November 2022
1.2. 
Schema
Figure 1: 
Schematic Overview of the Main Study
Abbreviations: DBL=database lock; IV=intravenous; N=number of participants; PE=primary endpoint;
R=randomization; SC=subcutaneous; SE=secondary endpoints
Figure 2: 
Schematic Overview of LTE
Abbreviations: DBL=database lock; IV=intravenous; N=number of participants; PE=primary endpoint;
R=randomization; SC=subcutaneous; SE=secondary endpoints
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Clinical Protocol CNTO1959SSC2001 Amendment 5
 
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19
Status: Approved,  Date:  15 November 2022
long-term extension, mRSS= modified Rodnan skin score; PBMC= Peripheral blood mononuclear cells; PRO=patient-reported outcome; RNA=ribonucleic acid;
SoA=schedule of assessments
Footnotes:
a. 
Must be signed before first study-related activity.
b. 
Minimum criteria for the availability of documentation supporting the eligibility criteria will be described in the full protocol. Check clinical status again before
first dose of study medication.
c. 
All PRO assessments should be conducted before other assessments in the order listed in the above SoA table.
d. 
The pharmacogenomic sample should be collected at the specified time points, but it may be collected at a later time point without constituting a protocol
deviation.
e. 
For participants who are eligible with surface antigen (HbsAg) negative, core antibody (anti-HBc) and/or surface antibody (anti-HBs) positive, and HBV DNA test
is negative, HBV DNA quantitation should be monitored at least every 3 months or shorter.
f. 
For all visits where study intervention will be administered, 1 blood sample should be collected prior to study intervention administration for evaluation of serum
concentrations and/or antibodies to study intervention. In addition, for IV infusion-related visits (Week 0, 4, 8), another blood draw should be taken approximately
60 minutes after the completion of the IV infusion for serum concentration measurement.
g. 
mRSS must be assessed by the same investigator longitudinally throughout the study
h. 
Screening should occur within 6 weeks prior to W0 visit. The study visit week are indicated and calculated based on the day of randomization/first administration
of the study intervention (W0 visit). Visit window should be ±7 days for each visit (Visit window for W0 visit should be -7 days).
i. 
Pulmonary function tests include forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO). If decline in % predicted FVC ≥
15 % (relative) is seen, another FVC test needs to be performed within a month.
j. 
To be measured at a central laboratory
k. 
Participants with potential active tuberculosis need to pause the study intervention administration until the tuberculosis assessment is completed.
l. 
For participants with stent, HRCT cannot be centrally read.
m. For screening, information on ACR CRISS step 1 will be collected as SSc Condition of Interest.
n. 
For participants who will NOT enter LTE, refer to Week 52 in Table 1. For participants who will enter LTE, refer to Week 52 and the subsequent visits in Table 2.
o. 
Only participants who will NOT enter LTE should perform the safety follow up visit at Week 60.
p. 
ICF for participation of LTE should be obtained at the latest at Week 52.
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Status: Approved,  Date:  15 November 2022
2. 
INTRODUCTION
Systemic sclerosis (SSc) is a complex autoimmune disease characterized by a thickening and
tightening of the skin and involvement of internal organs (gastrointestinal tract, heart, lungs, and
kidneys) with a chronic and frequently progressive course. One of the clinical features of SSc is
its patient-to‑patient variability, and heterogeneity has been observed in clinical manifestations,
autoantibody profiles, disease progression, response to treatment, and survival. On the basis of the
extent of their skin involvement, patients are grouped into limited cutaneous SSc (lcSSc) and
diffuse cutaneous SSc (dcSSc) subsets. In lcSSc, skin fibrosis is restricted to the fingers
(sclerodactyly), distal extremities, and face. On the other hand, patients with dcSSc have skin
fibrosis in areas including trunk and proximal extremities, relatively rapid disease progression with
extensive skin changes and early development of visceral organ complications compared to lcSSc.
Systemic sclerosis is designated as an intractable disease in Japan and the number of moderate to
severe SSc patients was 26,740 in 2018 according to the Japan Intractable Diseases Information
Center. The prevalence of SSc ranged from 7-489/million and the incidence from
0.6-122/million/year worldwide (Chiffot 2007).
Systemic sclerosis has high disease burden and unmet medical needs due to the limited efficacy of
most current treatments. No drugs significantly influence the natural course of SSc and no
advanced treatment is approved for the treatment of overall SSc. Autologous hematopoietic stem
cell transplantation (HSCT) trials in dcSSc have demonstrated survival benefit including
meaningful improvement in skin, lung fibrosis, and health-related quality of life. These benefits,
however, must be weighed against the increased risk of transplant-related mortality, which limits
wider use of HSCT in the treatment for SSc.
Survival has improved in recent decades and correlates best with the clinical disease subtype
(dcSSc vs lcSSc) and with the extent of organ involvement. Five-year survival among patients
with dcSSc has improved significantly, from 69% in the 1990-1993 cohort to 84% in the
2000-2003 cohort. Five-year survival among the patients with lcSSc remained very high and
unchanged for the same periods (93% and 91%, respectively) (Nihtyanova 2010).
Mortality associated with scleroderma renal crisis has declined significantly during the last
decades, as use of angiotensin-converting enzyme inhibitors. In contrast, pulmonary involvement
(ILD and/or pulmonary arterial hypertension) has become the most common cause of death in
patients with SSc. Contrary to rheumatoid arthritis (RA), the concept and use of disease-modifying
therapies that attenuate or reverse pathology and clinical impact are not currently applied to SSc.
Various drugs are used to treat specific symptoms or organ systems. Low dose corticosteroids may
be helpful for skin tightening of acute progressive patients but may predispose to renal crisis and
thus are used only if necessary. Nintedanib, a tyrosine kinase inhibitor was approved for the
treatment of ILD associated with SSc. Various immunosuppressants, including methotrexate,
azathioprine, mycophenolate mofetil, and cyclophosphamide, may help pulmonary alveolitis.
Mycophenolate mofetil is also effective for the treatment of ILD. Prostacyclin and endothelin
receptor antagonists are used for pulmonary hypertension. Calcium-channel blockers may help
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Status: Approved,  Date:  15 November 2022
Raynaud phenomenon. Intravenous (IV) infusions of prostaglandin E1 or prostacyclin or
sympathetic blockers can be used for digital ischemia. Reflux esophagitis is relieved by proton
pump inhibitors.
While the variety of medications are used to treat some of the SSc symptoms, there are still high
unmet medical needs for disease-modifying therapies with unequivocal efficacy and safety profile
for SSc.
Guselkumab (CNTO1959) is a fully human immunoglobulin G1 lambda (IgG1λ) monoclonal
antibody (mAb) that binds to human interleukin (IL)-23 with high specificity and affinity. The
binding of guselkumab to the IL-23p19 subunit blocks the binding of extracellular IL-23 to the
cell surface IL-23 receptor, inhibiting IL-23-specific intracellular signaling and subsequent
activation, and cytokine production. In this manner, guselkumab inhibits the biological activity of
IL-23 in all in vitro assays examined.
Guselkumab has been approved for the treatment of adults with moderate to severe plaque
psoriasis (PsO) in the United States (US), European Union, Canada, Japan and several other
countries worldwide, and for the treatment of psoriatic arthritis (PsA) in US, Canada, Brazil, and
Japan. In addition, guselkumab has been approved for the treatment of generalized pustular PsO,
erythrodermic PsO, and palmoplantar pustulosis in Japan.
Guselkumab is currently being developed worldwide in other diseases including for the treatment
of patients with PsA, hidradenitis suppurativa (HS), familial adenomatous polyposis, Crohn’s
disease (CD), lupus nephritis (LN), ulcerative colitis (UC), and giant cell arteritis (GCA). A
Phase 3 study in PsA, a Phase 2/3 program in CD, a Phase 2b/3 study in UC, and Phase 2 studies
in HS, LN, and GCA are currently ongoing or planned globally.
For the most comprehensive nonclinical and clinical information regarding guselkumab, refer to
the latest version of the Investigator’s Brochure (IB) for guselkumab. (IB guselkumab 2020)
The term “study intervention” throughout the protocol, refers to guselkumab and placebo as
defined in Section 6.1, Study Intervention(s) Administered.
The term “sponsor” used throughout this document refers to the entities listed in the ‘Protocol
Supplementary Information’, which will be provided as a separate document.
The term “participant” throughout the protocol refers to the common term “subject”.
2.1. 
Study Rationale
While the pathogenesis of SSc is complex and multifactorial, accumulated evidence suggests that
IL23/IL-17 pathway is involved in the pathophysiology of SSc. Several clinical studies have
shown that serum IL-23/IL-17 and skin IL-23 are increased in SSc patients compared with healthy
volunteers (Komura 2008; Kurasawa 2000). Correlation between serum IL-23 levels and
severity/extent of interstitial lung involvement was observed in patients with SSc (Rolla 2016). In
addition, internal analysis of ribonucleic acid (RNA)-sequencing (RNA-seq) data obtained from
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Status: Approved,  Date:  15 November 2022
recent onset SSc patient skin samples indicated upregulation of IL-23/IL17 related genes (analysis
from global Translational Science Medicine team). A case report has shown that ustekinumab
(mAb against IL-12 and IL-23) successfully improved skin tightening in a patient with both
psoriasis and SSc (Ichihara 2017). There is an ongoing Phase 3 clinical trial to evaluate
brodalumab, IL-17R antibody in subjects with SSc in Japan (NCT03957681). Although the results
of preceding brodalumab Phase 1b study (n 8) (NCT04368403) has not been publicly available,
efficacy and safety outcome of the Phase 1 study was evaluated and currently ongoing Phase 3
study was initiated.
These results suggest that reducing IL-23-mediated inflammation with guselkumab may improve
the signs and symptoms of active SSc. Taken together, these observations provide sufficient
rationale to explore the role of IL-23 in the pathogenesis of SSc in this proof-of-concept (PoC)
study of guselkumab in participants with SSc.
2.2. 
Background
Nonclinical Studies
A comprehensive overview of the nonclinical development program for guselkumab to support
the initiation of the study has been completed and the information is available in Section 3 of the
latest version of the guselkumab IB (IB guselkumab 2020).
Details regarding the proposed dose regimen and dose rationale are described in Section 6.1 and
Section 4.3.
Clinical Studies
As of 12 July 2020, 31 clinical studies of guselkumab have been completed or are ongoing. An
estimated 348 healthy subjects, 4,034 subjects with PsO, 109 subjects with RA, 1,471 subjects
with PsA, 182 subjects with palmoplantar pustulosis, 230 subjects with CD, 173 subjects with HS,
117 subjects with UC, and 19 subjects with familial adenomatous polyposis have been exposed to
guselkumab. Overall, an estimated 6,683 subjects have been exposed to guselkumab in the clinical
development program.
The largest clinical experience to date with guselkumab has been in PsO. The safety profile of
guselkumab in subjects with moderate to severe PsO is based on data from the Phase 2 study
CNTO1959PSO2001 and Phase 3 studies CNTO1959PSO3001, CNTO1959PSO3002,
CNTO1959PSO3003, CNTO1959PSO3006, and CNTO1959PSO3009. Of the 2,711
guselkumab-treated subjects, 2,255 subjects were exposed for at least 1 year, 1,516 were exposed
for at least 2 years, and 692 subjects and were exposed for 3 years. Long-term extensions of 2 of
the studies (CNTO1959PSO3001 and CNTO1959PSO3002) are ongoing and will continue
through up to 5 years of follow-up.
This section provides a summary of the sponsor’s assessment of how the overall clinical
experience with guselkumab across various indications supports the investigation of guselkumab
in SSc. Details about these guselkumab clinical development programs across various indications
are provided in Section 4 of the latest version of the guselkumab IB (IB guselkumab 2020).
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2.3. 
Benefit-Risk Assessment
More detailed information about the known and expected benefits and risks of guselkumab may
be found in the IB.
2.3.1. 
Risks for Study Participation
Potential Risks of Clinical
Significance
Summary of Data/
Rationale for Risk
Mitigation Strategy
Clinical worsening of systemic
sclerosis (SSc)
The benefit-risk of guselkumab in
the treatment of SSc has not been
established.
Participants will discontinue study
intervention if it is not in their best
interest or if they need to initiate
protocol-prohibited medications
including certain biologics
(Section 6.8 and Section 7.1).
Potential Risks Due to Study Intervention Guselkumab
Serious infections and reactivation 
of latent infections 
Available animal and human data 
suggest that blockade of IL-23 may 
be associated with an increased 
infection risk.  
 Participants with a history of, or
ongoing, chronic or recurrent
infectious disease, including
human immunodeficiency virus
(HIV), Hepatitis B or C, will be
excluded from the study.
Similarly, participants with
evidence of active or untreated
latent tuberculosis (TB) will be
excluded from the study
(Section 5.2).
 Participants who have received
Bacille Calmette-Guérin (BCG)
vaccination within 12 months or
any other live viral or bacterial
vaccination within 12 weeks
from randomization will be
excluded from the study. In
addition, participants must agree
not to receive a live viral or live
bacterial vaccination during the
study and for 12 weeks after
receiving the last dose of study
intervention.
 Participants will be instructed to
seek medical attention if they
develop signs or symptoms
suggestive of an infection, and
investigators are instructed in
the protocol to monitor for signs
or symptoms of infections,
including TB (Section 8.2.9 and
Section 8.2.10).
 Discontinuation of a
participant’s study intervention
must be strongly considered if
the participant develops a
serious infection, includin  g but
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not limited to sepsis or
pneumonia. In addition, any
serious infection should be
discussed with the medical
monitor or designee, and study
intervention should be withheld
until the clinical assessment is
complete (Section 8.2.10).
Hypersensitivity reactions, 
including serious hypersensitivity 
reactions. 
Serious hypersensitivity reactions 
including anaphylaxis have been 
reported in postmarketing 
experience with guselkumab in 
psoriasis patients. 
 Participants with known allergy,
hypersensitivity, or intolerance
to guselkumab or its excipients
will be excluded from the study.
 Sites are instructed that before
any administration of study
intervention, appropriately
trained personnel and
medications (eg, injectable
epinephrine) must be available
to treat hypersensitivity
reactions, including
anaphylaxis. In addition, all
participants must be observed
carefully for signs and
symptoms of a hypersensitivity
reaction (eg, urticaria, pruritis,
angioedema, wheezing,
dyspnea, or hypotension)
(Section 8.2.8).
 Any participant who develops a
serious hypersensitivity reaction
such as anaphylaxis must
discontinue study intervention
(Section 7.1).
Malignancy 
The preponderance of preclinical 
data suggests that blockade of 
endogenous interleukin (IL)-23 
would not be detrimental and may 
in fact be beneficial in tumor 
immunosurveillance and host 
protection; however, a risk of 
malignancy cannot be excluded. 
 Those participants who
currently have a malignancy or
have a history of malignancy
within 5 years prior to screening
(with exceptions noted in
Section 5.2) will be excluded
from the study. Additionally,
participants who have a history
of lymphoproliferative disease,
including lymphoma; a history
of monoclonal gammopathy of
undetermined significance or
signs and symptoms suggestive
of possible lymphoproliferative
disease, such as
lymphadenopathy or
splenomegaly will be excluded
from the study (Section 5.2).
 During the conduct of the study,
participants will undergo regular
clinical monitoring including
routine safety laboratory tests to
assess for an  y changes in health
NCT04683029


CNTO1959  (guselkumab)  
Clinical Protocol CNTO1959SSC2001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
27
Status: Approved,  Date:  15 November 2022
status that may indicate a
possible malignancy.
 Participants who develop a
malignancy during the study
(with the exception of no more
than 2 localized basal cell skin
cancers that are treated with no
evidence of recurrence or
residual disease) will be
discontinued from study
intervention (Section 7.1).
Liver injury 
A serious adverse event (SAE) of 
‘toxic hepatitis’ was reported in the 
ongoing Phase 2/3 guselkumab 
Crohn’s disease program in a 
participant who received 
guselkumab 1200 mg intravenous 
(IV) at Weeks 0, 4, and 8, and 
200 mg subcutaneous (SC) at 
Week 12. Based on the 
hepatocellular pattern of injury, 
temporal relationship of the event 
to guselkumab exposure, and the 
exclusion of alternative etiologies, 
this event may represent drug- 
induced liver injury possibly 
related to guselkumab. 
Alanine aminotransferase (ALT)/ 
aspartate aminotransferase AST 
abnormailities are a known risk for 
guselkumab, and that in the 
psoriatic arthritis studies, patients 
receiving guselkumab every 4 
weeks (Q4W) were more likely to
experience transaminase elevations
than those receiving it every 8
weeks (Q8W).
 During the conduct of the study,
liver function tests will be
monitored at regular intervals in
accordance with regulatory
guidance (FDA 2009). In
addition, the induction doses
evaluated in this clinical
program will not exceed 400 mg
IV.
 Participants with marked liver
enzyme elevations or symptoms
or signs of liver dysfunction (eg,
jaundice), should undergo a
thorough investigation for
possible causes of liver injury.
A participant must have their
study intervention discontinued
if the participant has severe liver
test abnormalities that are not
transient and are not explained
by other etiologies (Section 7.1
and Section 10.6).
Immunosuppression 
It is unknown if guselkumab in 
combination with other 
immunosuppressives increases the 
risk of diseases associated with 
immunosuppression, such as 
infections or malignancy. 
 In order to minimize the
theoretical increased risk of
infection or malignancy with the
combination of guselkumab
with immunosuppressive
therapy, the baseline dose of
oral corticosteroids on study
entry is limited ≤10 mg of
prednisolone or equivalent per
day which must be at a stable
dose ≥4 weeks prior to first dose
of study intervention.
Furthermore, participants
receiving investigational or
approved immunomodulatory
agents like IL-23 inhibitor
therapy, IL-12/23 inhibitors, or
IL-17 inhibitors, failed for
efficacy in SSc or within
12 weeks or 5 half-lives
NCT04683029


CNTO1959  (guselkumab)  
Clinical Protocol CNTO1959SSC2001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
28
Status: Approved,  Date:  15 November 2022
(whichever is longer) of first
administration of the study
intervention, are excluded from
the study. Additionally,
participants are also excluded
from the study if they have
received IL-receptor inhibitors
(eg, Tocilizumab, sarilumab) or
tyrosine kinase inhibitors (eg,
Nintedanib) within 12 weeks or
5 half-lives (whichever is
longer) or anti-cluster of
differentiation 20 (anti-CD20)
antibodies (eg, Rituximab)
within 1 year or 5 half-lives
(whichever is longer) prior to
first administration of the study
intervention. Further details
regarding concomitant
medications is provided in
Section 5.1 and Section 5.2.
 During study participation, the
use of IL-23 inhibitor therapy,
IL-12/23 inhibitors, IL-17
inhibitors, tocilizumab,
sirukumab, sarilumab,
mavrilimumab, abatacept,
belimumab, or tyrosine kinase
inhibitors is prohibited.
Participants initiating these
treatments will be discontinued
from further study intervention
administration (Section 7.1).
2.3.2. 
Benefits for Study Participation
The efficacy and safety of guselkumab in the treatment of SSc has not been established. The
scientific and clinical rationale for IL-23 blockade in the treatment of SSc supports the clinical
evaluation of guselkumab in this disease population
2.3.3. 
Benefit-Risk Assessment for Study Participation
Taking into account the measures taken to minimize risk to participants of this study, the potential
risks identified in association with guselkumab are justified by the anticipated benefits that may
be afforded to participants with SSc.
NCT04683029


CNTO1959  (guselkumab)  
Clinical Protocol CNTO1959SSC2001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
29
Status: Approved,  Date:  15 November 2022
3. 
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
 
To evaluate the efficacy of guselkumab in
participants with systemic sclerosis (SSc)
 
Change from baseline in Modified Rodnan Skin
Score (mRSS) at Week 24
Secondary
 
To evaluate the additional efficacy of
guselkumab in participants with SSc
 
Change from baseline in mRSS at Week 52
 
The proportion of participants who experience
worsening of mRSS at Week 24 and Week 52
 
The proportion of participants achieving a score
of 0.6 in American College of Rheumatology
Combined 
Response 
Index 
in 
dcSSc
(ACR CRISS) at Week 24 and Week 52
 
Change from baseline in forced vital capacity
(FVC) and percent predicted FVC at Week 24
and Week 52
 
Change from baseline in the measured absolute
diffusing capacity of the lung for carbon
monoxide (DLCO) and the derived percent
predicted DLCO at Week 24 and Week 52
 
Change from baseline in digital ulcer counts at
Week 24 and Week 52
 
Change from baseline in Health Assessment
Questionnaire-Disability Index (HAQ-DI) score
at Week 24 and Week 52
 
To evaluate the safety and tolerability of
guselkumab in participants with SSc
 
Number and proportion of participants with
treatment-emergent adverse events (AEs) and
serious adverse events (SAEs) or adverse events
of special interest (AESI) from baseline through
Week 24, Week 52, Week 76 and Week 104
 
To evaluate the pharmacokinetic (PK) and
immunogenicity of guselkumab
 
Serum guselkumab concentrations
 
Incidence of anti-guselkumab antibody
Exploratory
 
To evaluate the other efficacy of
guselkumab in participants with SSc
 
Time to disease worsening: Increase from
baseline ≥5 and ≥20% in mRSS OR decrease
>10% from baseline in FVC %
 
The proportion of participants who experience
FVC decline compared with baseline at Week 24
and Week 52
 
The proportion of participants who experience
worsening of FVC at Week 24 and Week 52
 
Change from baseline in fibrotic change assessed
with high-resolution computed tomography
(HRCT) at Week 24 and Week 52 in participants
NCT04683029


CNTO1959  (guselkumab)  
Clinical Protocol CNTO1959SSC2001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
30
Status: Approved,  Date:  15 November 2022
Objectives 
Endpoints
with baseline fibrosis/fibrotic changes
 
The proportion of participants who experience
worsening of fibrotic change assessed with
HRCT at Week 24 and Week 52
 
Change from baseline in Frequency Scale for the
Symptoms of Gastroesophageal reflux disease
(FSSG) score at Week 24 and Week 52
 
Assessment of nailfold capillaries at Week 24
and Week 52
 
Change from baseline in Patient global
assessment (PGA) at Week 24 and Week 52
 
Change from baseline in Physician global
assessment (PhGA) at Week 24 and Week 52
 
To evaluate the long-term efficacy of
guselkumab in participant with SSc
 
Change from baseline and Week 52 in mRSS at
Week 76 and Week 104
 
The proportion of participants who experience
worsening of mRSS at Week 76 and Week 104
 
The proportion of participants achieving a score
of 0.6 in American College of Rheumatology
Combined 
Response 
Index 
in 
dcSSc
(ACR CRISS) at Week 76 and Week 104
 
Change from baseline in forced vital capacity
(FVC) and percent predicted FVC at Week 76
and Week 104
 
The proportion of participants who experience
worsening of FVC at Week 76 and Week 104
 
Change from baseline in the measured absolute
diffusing capacity of the lung for carbon
monoxide (DLCO) and the derived percent
predicted DLCO at Week 76 and Week 104
 
Change from baseline in Health Assessment
Questionnaire-Disability Index (HAQ-DI) score
at Week 76 and Week 104
 
Change from baseline in digital ulcer counts at
Week 76 and Week 104
 
Change from baseline in fibrotic change assessed
with high-resolution computed tomography
(HRCT) at Week 76 and Week 104 in
participants 
with 
baseline 
fibrosis/fibrotic
changes
 
The proportion of participants who experience
worsening of fibrotic change assessed with
HRCT at Week 76 and Week 104
NCT04683029


CNTO1959  (guselkumab)  
Clinical Protocol CNTO1959SSC2001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
31
Status: Approved,  Date:  15 November 2022
Objectives 
Endpoints
 
Change from baseline in Frequency Scale for the
Symptoms of Gastroesophageal reflux disease
(FSSG) score at Week 76 and Week 104
 
To evaluate the effect of guselkumab vs
placebo on the pharmacodynamic (PD) and
SSc disease biomarkers
 
Change from baseline levels of skin (optional)
and circulating (blood based) biomarkers over
time to enable:
Evaluation 
of 
target 
engagement 
in
tissue/efficacy pharmacodynamic (PD) readouts
 
Single 
nucleotide 
polymorphisms 
(SNPs)
frequency associated with IL-23 pathway
Refer to Section 8, STUDY ASSESSMENTS AND PROCEDURES for evaluations related to
endpoints.
HYPOTHESIS
This is a PoC study aimed at detecting an early efficacy signal of guselkumab in participants with
SSc, compared to placebo, to support further clinical development.
 
The null hypothesis is that the treatment difference between guselkumab and placebo for the
primary endpoint is 0.
 
The alternative hypothesis is that the treatment difference between guselkumab and placebo
for the primary endpoint is ≠0.
Due to the PoC nature of this study, a 2-sided alpha of 0.2 is allocated for testing this PoC
hypothesis. The PoC objective will be considered met if the calculated p-value for testing this PoC
hypothesis is less than 0.2.
4. 
STUDY DESIGN
4.1. 
Overall Design
This is a randomized, double-blind, placebo-controlled, parallel, multicenter, interventional study
to evaluate the efficacy of guselkumab in men and women between the ages of 18 to 75 years,
inclusive, with a diagnosis of SSc according to American College of Rheumatology (ACR) and
European League Against Rheumatism (EULAR) 2013 criteria with a disease duration of
≤36 months (defined as time from first non-Raynaud phenomenon manifestation), and Modified
Rodnan Skin Score (mRSS) of ≥10 to ≤22 units.
For the main study, participants will be randomly assigned in a 1:1 ratio, based on randomization
strata of presence of ILD (yes, no), baseline mRSS (low [≥10 to ≤15] or high [≥16 to ≤22]), and
baseline anti-topoisomerase I antibody status (positive, negative), to 1 of the following treatment
groups:
NCT04683029


CNTO1959  (guselkumab)  
Clinical Protocol CNTO1959SSC2001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
32
Status: Approved,  Date:  15 November 2022
 
Guselkumab (Group/Arm A): Guselkumab 400 mg IV administration at Weeks 0, 4, and 8
(induction) followed by guselkumab 200 mg subcutaneous (SC) administration every 4 weeks
(Q4W) from Week 12 until Week 48 (maintenance)
 
Placebo (Group/Arm B): Matching placebo IV administration at Weeks 0, 4, and 8 (induction)
followed by matching placebo SC administration Q4W from Week 12 until Week 48
(maintenance)
The main study will be conducted in 3 phases: a maximum 6-week screening phase, a 52-week
double blind intervention phase, and a safety follow-up phase with a post-intervention follow-up
visit at 12 weeks after the participant’s last dose of study intervention to collect any adverse events
(AEs) since the last study visit. The duration of individual participation will be approximately 66
weeks.
Participants who complete the main study (Week 0 through 52: ie, after the Week 48 evaluation,
prior to Week 52 evaluation) and who, in the opinion of the investigator, may benefit from
continued treatment, will participate in the LTE by signing the ICF before or at Week 52. The
duration of individual participation will be approximately 66 weeks without LTE and 118 weeks
with LTE. The detail is provided in Section 4.1.1 Long-term Extension. During the LTE, Self-
Administration will be allowed for participants who complete training. Refer to Section 4.1.2 Self-
Administration of Study Intervention.
Two planned database locks (DBLs) will occur: EOS of the main study (Week 52 visit for
participants who entered LTE or safety follow up visit for participants who did not enter LTE,
hereinafter referred to as “Week 52 DBL”), and EOS of LTE (Week 112 visit, hereinafter referred
to as “Final DBL”).
Key efficacy assessments will include mRSS, American College of Rheumatology Combined
Response Index in dcSSc (ACR CRISS) score; pulmonary function tests: forced vital capacity
(FVC) and % of predicted FVC, and diffusing capacity of the lung for carbon monoxide
(DLCO) (ml/min/mm Hg) and % of predicted DLCO (hemoglobin-corrected); physician global
assessment (PhGA); and patients global assessment (PGA) (refer to Section 8.1, Efficacy
Assessments). Key safety assessments include the monitoring of AEs (including serious adverse
events [SAEs], adverse events of special interest [AESIs], infections, injection-site reactions, AEs
temporally associated with infusion, and hypersensitivity reactions), physical examinations, vital
sign measurements, electrocardiogram (ECG) measurements, clinical laboratory tests, ILD
monitoring (assessed by centrally read high-resolution computed tomography [HRCT]), and TB
evaluations (refer to Section 8.2, Safety Assessments). Additionally, PK, biomarker, and
immunogenicity assessments will also be performed in this study.
A target of 56 participants will be randomly assigned in this study with 28 participants planned per
intervention group.
An optional biomarker sub-study will obtain a biopsy sample of non-lesional (unaffected) skin
sample at Week 0, and lesional (at Week 0) skin at Week 0 and 24 from all participants who consent.
NCT04683029


CNTO1959  (guselkumab)  
Clinical Protocol CNTO1959SSC2001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
33
Status: Approved,  Date:  15 November 2022
A diagram of the study design is provided in Section 1.2. Schema.
4.1.1. Long-term Extension
The objective of LTE is to evaluate the long-term safety and efficacy of guselkumab in SSc patients.
The LTE begins with the completion of the assessments at the Week 52, and LTE continues
through LTE Week 104. The LTE includes a safety follow-up phase with a post-intervention
follow-up visit at LTE Week 112 (12 weeks after the participant’s last dose of study intervention).
Participants who complete the main study and who, in the opinion of the investigator, may benefit
from continued treatment, will participate in the LTE by signing the ICF before or at Week 52,
will receive guselkumab treatment in LTE as below depending on the arms they were in the main
study (Week 0 through 52).
 
Group/Arm A (guselkumab arm from the main study): Guselkumab 200 mg SC and placebo
IV at LTE Weeks 52, 56, and 60 followed by guselkumab 200 mg SC Q4W from LTE Week
64 until Week 100.
 
Group/Arm B (placebo arm from the main study): Placebo SC and guselkumab 400 mg IV at
LTE Weeks 52, 56, and 60 followed by guselkumab 200 mg SC Q4W from LTE Week 64
until Week 100.
During the LTE, all protocol-allowed concomitant medications and rescue medications may be
administered at the discretion of the investigator. Prohibited medications listed in Section 6.1
continue to be prohibited in the LTE.
All study evaluations to be performed during the LTE are listed in the Section 1.3 Schedule of
Activities (SoA).
The study blind will be maintained until the Week 52 DBL and participants will continue to receive
study intervention in a blinded manner at all visits until that time.
The final DBL will occur when all participants complete the LTE (EOS for LTE period).
At selected visits during the LTE, at the discretion of the investigator and participant, and after
appropriate and documented training, participants will self-administer study intervention. Details
are provided in Section 4.1.2 Self-Administration of Study Intervention.
A diagram of the study design is provided in Section 1.2. Schema.
4.1.2. Self-Administration of Study Intervention
From the LTE, all participants who are willing to perform self-study intervention administration
can receive training on how to self-administer study intervention at the investigative site. Three
times trainings are required, and participants can start the training at any time after Week 56.
At-home administration can begin from the selected visit according to regional/local regulations
and instruction at the discretion of the investigator and participant, and upon completion of training.
NCT04683029


CNTO1959  (guselkumab)  
Clinical Protocol CNTO1959SSC2001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
34
Status: Approved,  Date:  15 November 2022
Participants who are eligible for self-intervention administration will be supplied with study
intervention for at-home administration at Week 80 and will have the first at-home administration
at Week 84. At-home administration can only be performed for the following visits (if applicable):
LTE Weeks 84, 92, and 100. Participants will record all at-home study intervention administrations
on a diary card. Participants will also be instructed to contact the investigator promptly in the event
of any signs of an allergic reaction, infection, or bleeding. Finally, participants will continue to
have study visits and assessments at the investigative sites through LTE, as outlined in Section 1.3.
Participants who are unable or unwilling to have injections administered away from the site will
be required to return to the site for administration of study intervention.
4.2. 
Scientific Rationale for Study Design
Blinding, Control, Study Phase/Periods, Intervention Groups
A placebo control will be used to establish the frequency and magnitude of changes in clinical
endpoints that may occur in the absence of active intervention. Randomization will be used to
minimize bias in the assignment of participants to intervention groups, to increase the likelihood
that known and unknown participant attributes (eg, demographic and baseline characteristics) are
evenly balanced across intervention groups, and to enhance the validity of statistical comparisons
across intervention groups. Blinded intervention will be used to reduce potential bias during data
collection and evaluation of clinical endpoints.
DNA and Biomarker Collection
It is recognized that genetic variation can be an important contributory factor to interindividual
differences in intervention distribution and response and can also serve as a marker for disease
susceptibility and prognosis. Pharmacogenomic research may help to explain interindividual
variability in clinical outcomes and may help to identify population subgroups that respond
differently to an intervention. The goal of the pharmacogenomic component is to collect DNA to
allow the identification of genetic factors that may influence the PK, immunogenicity,
pharmacodynamic (PD), efficacy, safety, or tolerability of guselkumab and to identify genetic
factors associated with SSc.
Biomarker samples will be collected to evaluate the mechanism of action of or help to explain
interindividual variability in clinical outcomes or may help to identify population subgroups that
respond differently to an intervention. The goal of the biomarker analyses is to evaluate the PD of
guselkumab and aid in evaluating the intervention-clinical response relationship.
DNA and biomarker samples may be used to help address emerging issues and to enable the
development of safer, more effective, and ultimately individualized therapies.
4.2.1. 
Study-specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study and, during
the study, participants will be given any new information that may affect their decision to continue
participation. They will be told that their consent to participate in the study is voluntary and may be
NCT04683029


CNTO1959  (guselkumab)  
Clinical Protocol CNTO1959SSC2001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
35
Status: Approved,  Date:  15 November 2022
withdrawn at any time with no reason given and without penalty or loss of benefits to which they
would otherwise be entitled. Only participants who are fully able to understand the risks, benefits,
and potential AEs of the study, and provide their consent voluntarily will be enrolled.
The total blood volume to be collected (up to 413 mL per participant through Week 52, and up to
567 mL per participant through Week 112) is considered to be an acceptable amount of blood to be
collected over this time period from the population in this study based upon the standard of the blood
donation rule by the Japanese Red Cross Society.
4.3. 
Justification for Dose
The following guselkumab dose regimen will be evaluated through Week 48:
 
Induction: 400 mg IV at Weeks 0, 4, and 8
 
Maintenance: 200 mg SC Q4W starting from Week 12
The guselkumab dose regimen for this Phase 2 study was selected based on the objective of
determining the efficacy of guselkumab for treatment of SSc with possibly maximum drug
exposure accompanied with no safety concerns based on benefit-risk profile of available
guselkumab clinical trial data.
The proposed choice of an IV induction dose of 400 mg guselkumab at Weeks 0, 4 and 8 follows
the typical induction-maintenance treatment approach that has been used for investigative studies
of guselkumab in inflammatory diseases with target tissue that is more difficult to penetrate (eg,
CD). Induction therapy is essential to control and reduce the inflammatory damage and the
maintenance therapy is important to stabilize disease activity of SSc. This dosing regimen aims
for complete target inhibition of IL-23 in the affected organs including skin in this PoC study.
Data from the ongoing guselkumab Phase 2/3 study with CD patients were considered in the
selection of the guselkumab IV induction dose regimens in this Phase 2 SSc study. In the Phase 2
CD dose-ranging study, 3 guselkumab IV induction doses of 200, 600, and 1200 mg IV Q4W were
assessed while in the Phase 2/3 UC study, 200 mg and 400 mg IV induction doses are being
evaluated. A Dose Selection Committee reviewed the unblinded Week 12 interim analysis of
efficacy, safety, PK, and PD data and recommended an induction dose of 200 mg IV for the Phase
3 CD study. However, since UC may need a higher induction dose as patients with UC may have
higher inflammatory burden and a “leakier” gut leading to increased drug clearance, the 400 mg
IV Q4W induction dose regimen was also selected for the Phase 2/3 UC study. In consideration of
induction dose for other inflammatory diseases, the 400 mg IV Q4W induction dose regimen was
selected for this Phase 2 SSc study in order to increase the opportunity of obtaining the maximum
clinical response.
The safety of 200 mg and 600 mg IV Q4W regimens in the Phase 2b CD study was acceptable. A
single case of potential drug-induced liver injury possibly related to guselkumab was reported in
a participant who received the guselkumab 1200 mg IV dose regimen. Compared to the
guselkumab 1200 mg IV dose previously investigated in CD, the guselkumab 400 mg IV dose
would provide an approximately 3-fold lower exposure. In addition, the predicted exposure margin
NCT04683029


CNTO1959  (guselkumab)  
Clinical Protocol CNTO1959SSC2001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
36
Status: Approved,  Date:  15 November 2022
for 400 mg IV relative to the no observed adverse event level (NOAEL) of 50 mg/kg/week in
cynomolgus monkeys is approximately 10- to 13-fold, which is considered adequate to support the
limited duration of IV dosing (ie, 3 doses over 12 weeks).
Guselkumab 200 mg SC Q4W was selected as the maintenance dose regimen for this study with
the goal of increasing the opportunity of obtaining the maximum clinical response for SSc. This
dose regimen is lower than the 400 mg IV dose regimen, taking into account dose level, dosing
frequency, and the SC bioavailability of approximately 50% (as reported in a Phase 1 study in
healthy subjects [refer to IB guselkumab 2020]).
With respect to safety of the maintenance dose regimens, the predicted exposure margins for the
200 mg SC Q4W dose regimen relative to the NOAEL of 50 mg/kg/week in cynomolgus monkeys
are approximately 33 to 40, which is considered adequate to support the long-term SC dosing (for
chronic maintenance) in the guselkumab SSc clinical development programs. Guselkumab is
approved for the treatment of plaque PsO with a good long-term clinical safety profile (with data
generated primarily at 100 mg SC Q8W), and dose regimens as high as 200 mg SC Q8W have
been shown to have favorable safety in a 6-month Phase 2 trial in RA and a 1-year Phase 3 trial in
subjects with PPP in Japan.
The available clinical safety data, along with acceptable safety margins and other studies
evaluating similar dose regimens from other ongoing studies, make it reasonable to study SSc with
this dose regimen.
4.4. 
End of Study Definition
End of Study Definition
The end of study is considered as the last visit for the last participant in the study. The final data
from the study site will be sent to the sponsor (or designee) after completion of the final participant
assessment at that study site, in the time frame specified in the Clinical Trial Agreement.
Study Completion Definition
A participant who will NOT enter LTE will be considered to have completed the main study if he
or she has completed all the assessments at Week 52 of the double-blind phase and completed the
final safety follow-up visit (EOS).
A participant who will enter LTE will be considered to have completed the main study if he or she
has completed all the assessments at Week 52 of the double-blind phase, and the participant will
be considered to have completed the LTE study if he or she has completed all the assessments at
LTE Week 104 and completed the final safety follow-up visit (LTE-EOS).
Participants who prematurely discontinue study intervention for any reason before completion of
the double-blind phase and LTE can be considered to have completed the study if they have
completed all the assessments at early termination visit and completed the final safety follow-up
visit.
NCT04683029


CNTO1959  (guselkumab)  
Clinical Protocol CNTO1959SSC2001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
37
Status: Approved,  Date:  15 November 2022
5. 
STUDY POPULATION
Screening for eligible participants will be performed within 6 weeks before administration of the
study intervention. Refer to Section 5.4, Screen Failures for conditions under which the repeat of
any screening procedures are allowed.
The inclusion and exclusion criteria for enrolling participants in this study are described below. If
there is a question about these criteria, the investigator must consult with the appropriate sponsor
representative and resolve any issues before enrolling a participant in the study. Waivers are not
allowed.
5.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1. 
Male or female (according to their reproductive organs and functions assigned by
chromosomal complement).
2. 
18 to 75 years of age, inclusive.
Type of Participant and Disease Characteristic
3. 
Medically stable on the basis of physical examination, medical history, vital signs, and
12-lead ECG performed at screening. Any abnormalities, must be consistent with the
underlying illness in the study population and this determination must be recorded in the
participant’s source documents and initialed by the investigator.
4. 
Medically stable on the basis of clinical laboratory tests performed at screening. If the
results of the serum chemistry panel including liver enzymes, blood coagulation,
hematology, or urinalysis are outside the normal reference ranges, the participant may
be included only if the investigator judges the abnormalities or deviations from normal
to be not clinically significant or to be appropriate and reasonable for the population
under study. This determination must be recorded in the participant’s source documents
and initialed by the investigator.
5. 
Diagnosis of SSc according to ACR and EULAR 2013 criteria.
6. 
Diffuse cutaneous SSc according to the LeRoy criteria ie, skin fibrosis proximal to the
elbows and knees in addition to acral fibrosis.
7. 
Disease duration of ≤36 months (defined as time from first non-Raynaud phenomenon
manifestation).
8. 
≥ 10 and ≤22 mRSS units at screening and Week 0.
9. 
FVC ≥60% of predicted at screening.
NCT04683029


CNTO1959  (guselkumab)  
Clinical Protocol CNTO1959SSC2001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
38
Status: Approved,  Date:  15 November 2022
10. 
DLCO ≥40% of predicted (hemoglobin-corrected) at screening.
11. 
Participants who meet 1 of the following criteria at screening:
a) Increase of ≥3 mRSS units, compared with an assessment performed within the
previous 2 to 6 months.*
b) Involvement of 1 new body area with an increase of ≥2 mRSS units compared with
an assessment performed within the previous 2 to 6 months.*
c) Involvement of 2 new body areas with increase of ≥1 mRSS units compared with
the assessment within the previous 2 to 6 months.*
*Excluding participants with decrease in mRSS within 2 months
12. 
Criterion modified per Amendment 1
12.1 Have screening laboratory test results within the following parameters, if 1 or more
of the laboratory parameters is out of range, a single retest of laboratory values is
permitted:
 
a. Hemoglobin 
≥9 g/dL 
SI: ≥90 mmol/L
b. White blood cells 
≥3.0 × 103/µL 
SI: ≥3.0 GI/L
c. Neutrophils 
≥1.5 × 103/µL 
SI: ≥1.5 GI/L
d. Platelets 
≥100 × 103/µL   
SI: ≥100 GI/L
e. Serum creatinine 
≤1.8 mg/dL 
SI: ≤159 μmol/L
f. Aspartate aminotransferase (AST) 
≤2 × ULN
g. Alanine aminotransferase (ALT) 
≤2 × ULN
 
Concomitant or previous medical therapies received
13. 
Regular treatment with the following agents with no changes in dose or frequency is
permitted as follows:
a) Oral glucocorticoids (average daily dose ≤10 mg of prednisolone or equivalent) for
≥6 weeks and at a stable dose ≥2 weeks prior to first dose of study intervention.
If currently not using oral glucocorticoids, must not have received them for
≥6 weeks prior to the first dose of study intervention.
b) Nonsteroidal anti-inflammatory drugs (NSAIDs) or other analgesics at a stable dose
≥2 weeks prior to first dose of study intervention.
c) Endothelin receptor antagonists (eg, bosentan, ambrisentan and macitentan) at a
stable dose ≥2 weeks prior to first dose of study intervention.
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d) Phosphodiesterase 5 inhibitors (eg, sildenafil and tadalafil) for at a stable dose
≥2 weeks prior to first dose of study intervention.
e) Prostacyclins (eg, epoprostenol, iloprost and treprostinil) for at a stable dose
≥2 weeks prior to first dose of study intervention.
f) Permitted topical medications for cutaneous disease for ≥4 weeks prior to first dose
of study intervention.
Tuberculosis
14. 
Are considered eligible according to the following TB screening criteria:
a) Have no history of latent or active TB before screening. An exception is made for
participants who have a history of latent TB and satisfy 1 of the following criteria:
 
are currently receiving treatment for latent TB,
OR
 
will initiate treatment for latent TB before the first administration of study
intervention,
OR
 
have documentation of having completed appropriate treatment for latent TB
within 5 years before the first administration of study intervention. It is the
responsibility of the investigator to verify the adequacy of previous anti-TB
treatment and provide appropriate documentation. Patients with a history and
documentation of having completed appropriate treatment for latent TB more
than 5 years before the first dose of study intervention are not eligible.
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
before the first administration of study intervention.
d) Within 2 months before the first administration of study intervention, have a
negative interferon gamma release assays (IGRAs; QuantiFERON-TB® or T-
SPOT®) result, or have a newly identified positive IGRA result (see Laboratory
Manual) in which active TB has been ruled out and for which appropriate treatment
for latent TB has been initiated before the first administration of study intervention.
A subject whose first IGRA result is indeterminate should have the test repeated. If
the second IGRA test result is also indeterminate, the subject may be enrolled
without treatment for latent TB, if active TB is ruled out, their chest radiograph
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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.
NOTE: IGRA is not required at screening for participants with a history of latent
TB and ongoing treatment for latent TB or documentation of having completed
adequate treatment as described above; participants with documentation of having
completed adequate treatment as described above are not required to initiate
additional treatment for latent TB.
e) Have a chest radiograph (both posterior-anterior and lateral views) taken ≤12 weeks
before the first administration of study intervention and read by a qualified
physician to read radiogram (eg, a radiologist or pulmonologist), with no evidence
of current, active TB or old, inactive TB. Chest computerized tomography (CT)
may also be performed if deemed appropriate by the investigator.
Sex and Contraceptive/Barrier Requirements
15. 
A woman of childbearing potential must have a negative urine pregnancy test result at
screening and baseline.
16. 
A woman must be (as defined in Section 10.5, Appendix 5: Contraceptive and Barrier
Guidance)
a. Not of childbearing potential
b. Of childbearing potential and
o 
Practicing a highly effective, preferably user-independent method of
contraception (failure rate of <1% per year when used consistently and
correctly) and agrees to remain on a highly effective method while
receiving study intervention and until 12 weeks after last dose  the end
of relevant systemic exposure. The investigator should evaluate the
potential for contraceptive method failure (eg, noncompliance, recently
initiated) in relationship to the first dose of study intervention. Examples
of highly effective methods of contraception are located in Section 10.5,
Appendix 5: Contraceptive and Barrier Guidance.
Note: If a participant’s childbearing potential changes after start of the study (eg, a
premenarchal woman experiences menarche) or the risk of pregnancy changes (eg, a
woman who is not heterosexually active becomes active), a woman must begin using a
highly effective method of contraception, as described throughout the inclusion and
exclusion criteria.
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17. 
A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted
reproduction during the study and for a period of 12 weeks after the last administration
of study intervention.
18. 
Criterion modified per Amendment 1
18.1 Male participants must agree to the following during the study and for at least 12
weeks after the last dose of study intervention:
 
Must agree not to donate sperm for the purpose of reproduction.
 
A male participant must wear a condom when engaging in any activity that allows
for passage of ejaculate to another person.
 
Male participants should also be advised of the benefit for a female partner to use
a highly effective method of contraception as condom may break or leak.
Informed Consent
19. 
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.
20. 
Must sign a separate informed consent if he or she agrees to provide an optional DNA
sample for research. Refusal to give consent for the optional DNA research sample does
not exclude a participant from participation in the study.
21. 
Willing and able to adhere to the lifestyle restrictions specified in this protocol.
5.2. 
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from
participating in the study:
Medical Conditions
1. 
History of liver or renal insufficiency (estimated creatinine clearance below
60 mL/min); significant cardiac, vascular, pulmonary, gastrointestinal, endocrine,
neurologic, hematologic, rheumatologic, psychiatric, or metabolic disturbances.
2. 
Has any known severe or uncontrolled SSc complications including hemoptysis,
pulmonary hemorrhage, renal crisis.
3. 
Has severe pulmonary hypertension as determined by echocardiogram and pulmonary
function test or right heart catheterization. Severe pulmonary hypertension includes but
not limited to;
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 
Left ventricular ejection fraction <40%
 
Peak tricuspid regurgitation velocity (m/s) >3.4
 
Resting heart rate <50 bpm
 
Systolic blood pressure < 90 mm Hg
 
ECG findings suggestive of significant conduction abnormalities
4. 
Has an interstitial lung disease requiring oxygen therapy.
5. 
Has any rheumatic disease other than SSc such as RA, polymyalgia rheumatica (PMR),
systemic lupus erythematosus, polymyositis/dermatomyositis that could interfere with
assessment of SSc.
6. 
Has a current diagnosis or signs or symptoms of severe, progressive, or uncontrolled
renal, cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic,
hematologic, rheumatologic, psychiatric, or metabolic disturbances. (or, in the
investigator’s opinion, any other concomitant medical condition that places the
participant at risk by participating in this study).
7. 
Has or has had any major ischemic event, within 12 weeks of first study intervention.
8. 
Has a history of lymphoproliferative disease, including lymphoma; a history of
monoclonal gammopathy of undetermined significance; or signs and symptoms
suggestive of possible lymphoproliferative disease, such as lymphadenopathy or
splenomegaly.
9. 
Has a history of, or ongoing, chronic or recurrent infectious disease, including but not
limited to chronic renal infection, chronic chest infection (eg, bronchiectasis), recurrent
urinary tract infection (recurrent pyelonephritis or chronic nonremitting cystitis), fungal
infection (eg, mucocutaneous candidiasis, but excluding fungal infections of the nail
beds), or open, draining, or infected skin wounds or ulcers.
10. 
Has or has had a serious infection (eg, sepsis, pneumonia, or pyelonephritis), or has
been hospitalized or received IV antibiotics for an infection during the 2 months before
first study intervention.
11. 
Has or has had a nontuberculous mycobacterial infection or clinically significant
opportunistic infection (eg, cytomegalovirus, pneumocystosis, invasive aspergillosis).
12. 
Has a history of latent or active granulomatous infection, including histoplasmosis or
coccidioidomycosis, before screening. Refer to inclusion criterion 14 for information
regarding eligibility with a history of latent TB.
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13. 
Has a history of an infected joint prosthesis or has received antibiotics for a suspected
infection of a joint prosthesis within 6 months of first study intervention, if that
prosthesis has not been removed or replaced.
14. 
Has a history of or is infected with human immunodeficiency virus (HIV [positive
serology for HIV antibody]); tests positive for hepatitis B virus (HBV) infection; has
antibodies to hepatitis C virus (HCV) at screening.
15. 
During the 6 weeks prior to baseline, have had any of (a) confirmed SARS-CoV-2
infection (test positive) (coronavirus disease 2019 [COVID-19]), 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.
An exception to this criterion maybe granted if a participant has 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, eg, 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:
 
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,
follow guidance from local health authorities when weighing the potential benefits
and risks of enrolling in the study, and during participation in the study.
16. 
Has experienced a recent single dermatomal herpes zoster eruption within the past 4
months. Has ever had multi-dermatomal herpes zoster (defined as appearance of lesion
outside the primary or adjacent dermatome) or central nervous system zoster infection.
17. 
Currently has a malignancy or has a history of malignancy within 5 years before
screening (with the exception of a non-melanoma skin cancer that has been adequately
treated with no evidence of recurrence for at least 3 months before the first study
intervention administration or cervical carcinoma in situ that has been treated with no
evidence of recurrence for at least 3 months before the first study intervention).
Note: premalignant lesions should be discussed with the sponsor medical monitor.
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18. 
Has a transplanted organ including HSCT (with exception of a corneal transplant
>3 months before the first study intervention).
19. 
Has known allergies, hypersensitivity, or intolerance to guselkumab or its excipients.
Diagnostic Assessments
20. 
Has had major surgery (eg, requiring general anesthesia and hospitalization) within 8
weeks before screening, or has not fully recovered from such surgery, or has such
surgery planned during the time the participant is expected to participate in the study.
Note: Participants with planned surgical procedures to be conducted under local
anesthesia may participate.
21. 
Has a history of drug or alcohol abuse according to the Diagnostic and Statistical
Manual of Mental Disorders, 5th edition, within 1 year before screening.
Prior/Concomitant Therapy
22. 
Has previously been treated with any investigational or approved immune-modulatory
biologic agent prior to first study intervention, including but not limited to:
 
Has received therapy:
 
IL-23 inhibitor therapy (including but not limited to guselkumab,
risankizumab, tildrakizumab, brazikumab, mirikizumab)
 
IL-12/23 inhibitors (ustekinumab)
 
IL-17 inhibitors (secukinumab, ixekizumab, brodalumab)
 
Has received therapy within 12 weeks, or 5 half-lives (whichever is longer):
 
Tocilizumab (Actemra)
 
Sirukumab, sarilumab, mavrilimumab, abatacept, belimumab
 
Tyrosine kinase inhibitor (nintedanib)
 
Systemic and topical Janus kinase inhibitor (eg, tofacitinib, upadacitinib)
 
Has received therapy within 1 year, or 5 half-lives (whichever is longer):
 
Rituximab
Note: Not listed biologic agents should be discussed and agreed with the sponsor
medical monitor.
23. 
Has been treated with:
 
Within 6 months of study intervention:
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Any cytotoxic agents (cyclophosphamide, chlorambucil, nitrogen mustard, or
other alkylating agents)
 
Intravenous immunoglobulin (IVIG), apheresis therapy (plasmapheresis or
leukopheresis)
 
Within 6 weeks of first study intervention:
 
Systemic immunosuppressive agents (including but not limited to cyclosporine
A, azathioprine, tacrolimus, sirolimus, sulfasalazine, leflunomide with
cholestyramine washout or mycophenolate mofetil/mycophenolic acid)
 
Intramuscular, intra-articular, intrabursal, epidural, intra-lesional or IV
glucocorticoids
Any questions or concerns with the use of these therapies should be discussed with the
study sponsor and/or medical monitor.
Prior/Concurrent Clinical Study Experience
24. 
Received an investigational intervention (including investigational vaccines) within
3 months or 5 half-lives (whichever is longer) or used an invasive investigational
medical device within 3 months before the planned first dose of study intervention or is
currently enrolled in an investigational study.
25. 
Bacille Calmette-Guérin (BCG) vaccination within 12 months or any other live bacterial
or live viral vaccination within 12 weeks of randomization.
26. 
Is a woman who is pregnant, or breastfeeding, or planning to become pregnant while
enrolled in this study or within 12 weeks after the last administration of study
intervention.
27. 
Is a man who plans to father a child while enrolled in this study or within 12 weeks after
the last administration of study intervention.
28. 
Any condition for which, in the opinion of the investigator, participation would not be
in the best interest of the participant (eg, compromise the well-being) or that could
prevent, limit, or confound the protocol-specified assessments.
Other Exclusions
29. 
Employee of the investigator or study site, with direct involvement in the proposed
study or other studies under the direction of that investigator or study site, as well as
family members of the employees or the investigator.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening.
If a participant’s clinical status changes (including any available laboratory results or receipt of
additional medical records) after screening but before the first dose of study intervention is given
such that he or she no longer meets all eligibility criteria, then the participant should be excluded
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from participation in the study. Section 5.4, Screen Failures, describes options for retesting. The
required source documentation to support meeting the enrollment criteria are noted in Section 10.3,
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations.
5.3. 
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions
during the course of the study to be eligible for participation:
1. 
Refer to Section 6.8, Concomitant Therapy for details regarding prohibited and
restricted therapy during the study.
2. 
Agree to follow all requirements that must be met during the study as noted in the
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
5.4. 
Screen Failures
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy
identification of each participant during and after the study. This document will be reviewed by
the sponsor study site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed
by the investigator in the study file. To ensure participant confidentiality, no copy will be made.
All reports and communications relating to the study will identify participants by participant
identification and age at initial informed consent. In cases where the participant is not randomized
into the study, the date seen and age at initial informed consent will be used.
Individuals who do not meet the criteria for participation in this study (screen failure) may be
rescreened.
Rescreening
Individuals who do not meet the criteria for participation in this study (screen failure) may be
rescreened 1 time.
5.5. 
Criteria for Temporary Delaying Enrollment/Randomization/Administration
of Study Intervention Administration
This section is not applicable for this study.
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY
6.1. 
Study Intervention(s) Administered
Participants will be randomly assigned in a 1:1 ratio to 1 of the following study intervention
groups:
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 
Guselkumab (Group/Arm A): Guselkumab 400 mg IV administration Weeks 0, 4, and 8
(induction) followed by guselkumab 200 mg SC administration Q4W from Week 12 until
Week 48 (maintenance).
 
Placebo (Group/Arm B): Matching placebo IV administration Weeks 0, 4, and 8 (induction)
followed by matching placebo SC administration Q4W from Week 12 until Week 48
(maintenance).
Intravenous study intervention (including the flush) should be administered over a period of not
less than 1 hour, and not more than 2 hours. The infusion (including the flush) should be completed
within 6 hours of preparation.
Since 2 SC injections by using 100 mg/mL prefilled syringe (PFS) are administered at visits, each
injection of study intervention should be given at a different location of the body.
Study intervention administration must be captured in the source documents and the electronic
case report form (eCRF).
Guselkumab will be manufactured and provided under the responsibility of the sponsor. Refer to
the IB for a list of excipients.
During the LTE, participants will receive guselkumab treatment in LTE as below depending on the
arms they were in the main study:
 
Group/Arm A (guselkumab arm from the main study) : Guselkumab 200 mg SC and placebo
IV at LTE Weeks 52, 56, and 60 followed by guselkumab 200 mg SC Q4W from LTE Week
64 until Week 100.
 
Group/Arm B (placebo arm from the main study): Placebo SC and guselkumab 400 mg IV at
LTE Weeks 52, 56, and 60 followed by guselkumab 200 mg SC Q4W from LTE Week 64 until
Week 100.
After Week 68 participants who have been appropriately trained in the self-administration of study
intervention may self-administer study intervention. At-home administration is allowed for
selected visits. More details are provided in Section 4.1.2 Self-Administration of Study
Intervention.
6.1.1. 
Combination Products
For this protocol, the term combination product refers to the single integral drug-device
combination.
The sponsor-manufactured combination product for use in this study is the prefilled syringe (PFS)
assembled with an UltraSafe Plus™ Passive Needle Guard (PFS-U). Additional details on the
PFS-U are provided in Section 6.2.
All combination product deficiencies (including failure, malfunction, improper or inadequate
design, manufacturer error, use error, and inadequate labeling) shall be documented and reported
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by the investigator throughout the study. These deficiencies will be reported as product quality
complaints (PQC) (see Section 10.4.6, Product Quality Complaint Handling) and appropriately
managed by the sponsor.
6.2. 
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
For IV administrations, guselkumab final vialed product (FVP [IV]) is supplied as a sterile solution
in a single-use glass vial containing 20 mL at a concentration of 10 mg/mL. Study intervention
will be prepared for IV administration based on the instructions provided to clinical sites in the
IPPI.
For SC administrations, guselkumab will be supplied as a 100 mg/mL sterile solution in a
single-use PFS assembled in an UltraSafe Plus™ Passive Needle Guard (PFS-U). For SC
administration, placebo for guselkumab will be supplied as a 1 mL sterile solution in a single-use
PFS assembled in a PFS-U.
Guselkumab and placebo for guselkumab should be clear and colorless to light yellow solution
that may contain small translucent particles. Do not use guselkumab or placebo for guselkumab if
the liquid is cloudy or discolored or has large particles. Protection from light is not required during
the preparation and administration of the study intervention material, but avoid direct exposure to
sunlight. Aseptic technique must be used during the preparation and administration of the study
intervention material.
Study personnel will instruct participants on how to transport, store, and administer study
intervention for at-home use during the LTE as indicated for this protocol.
Refer to the Investigational Product Procedures Manual (IPPM) and Investigational Product
Procedure Instructions (IPPI) for additional guidance on study intervention preparation, handling,
and storage.
Accountability
The investigator is responsible for ensuring that all study intervention received at the site is
inventoried and accounted for throughout the study. The study intervention administered to the
participant must be documented on the intervention accountability form. All study intervention
will be stored and disposed of according to the sponsor’s instructions. Study site personnel must
not combine contents of the study intervention containers.
Study intervention must be handled in strict accordance with the protocol and the container label,
and must be stored at the study site in a limited-access area or in a locked cabinet under appropriate
environmental conditions. Unused study intervention must be available for verification by the
sponsor’s study site monitor during on-site monitoring visits. The return to the sponsor of unused
study intervention will be documented on the intervention return form. When the study site is an
authorized destruction unit and study intervention supplies are destroyed on-site, this must also be
documented on the intervention return form.
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Potentially hazardous materials containing hazardous liquids, such as needles and syringes should
be disposed of immediately in a safe manner and therefore will not be retained for intervention
accountability purposes.
Study intervention should be dispensed under the supervision of the investigator or a qualified
member of the study site personnel, or by a hospital/clinic pharmacist. Study intervention will be
supplied only to participants participating in the study. Returned study intervention must not be
dispensed again, even to the same participant. Study intervention may not be relabeled or
reassigned for use by other participants. The investigator agrees neither to dispense the study
intervention from, nor store it at, any site other than the study sites agreed upon with the sponsor.
Further guidance and information for the final disposition of unused study interventions are
provided in the IPPI.
Participants who will be self-administering study intervention at home will receive detailed
instructions for study intervention storage and disposal of used syringes and handling of unused
study material. These participants will receive a sharps container to dispose of used syringed and
will be instructed to return the sharps container and/or unused cartons with syringes. Participants
who self-administer at home will record study intervention administrations with time and date
information on a diary card.
6.3. 
Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Participants will be randomly assigned
to 1 of 2 intervention groups based on a computer-generated randomization schedule prepared
before the study by or under the supervision of the sponsor. The randomization will be balanced
by using randomly permuted blocks and will be stratified by presence of ILD (yes, no), baseline
mRSS (low [≥10 to ≤15] or high [≥16 to ≤22]), and baseline anti-topoisomerase I antibody status
(positive, negative). The interactive web response system (IWRS) will assign a unique intervention
code, which will dictate the intervention assignment and matching study intervention kit for the
participant. The requestor must use his or her own user identification and personal identification
number when contacting the IWRS, and will then give the relevant participant details to uniquely
identify the participant.
Blinding
To maintain the study blind, the study intervention container will have a label containing the study
name, study intervention number, and reference number. A tear-off label is designed to be torn off,
separated from the study intervention container, and attached to the participant’s source documents.
The label will not identify the study intervention in the container. However, if it is necessary for a
participant’s safety, the study blind may be broken and the identity of the study intervention
ascertained. The study intervention number will be entered in the eCRF when the study
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intervention is administered. The study interventions will be identical in appearance and will be
packaged in identical containers.]
The investigator will not be provided with randomization codes. The codes will be maintained
within the IWRS, which has the functionality to allow the investigator to break the blind for an
individual participant.
Data that may potentially unblind the intervention assignment (ie, study intervention serum
concentrations, anti-guselkumab antibodies, study intervention preparation/accountability data,
intervention allocation, and 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 (DBL) and unblinding.
All sponsor personnel, site personnel and participants will remain blinded to the treatment
assignments until the Week 52 DBL.
The investigator may in an emergency determine the identity of the intervention by contacting the
IWRS. While the responsibility to break the intervention code in emergency situations resides
solely with the investigator, it is recommended that the investigator contact the sponsor or its
designee if possible, to discuss the particular situation, before breaking the blind. Telephone
contact with the sponsor or its designee will be available 24 hours per day, 7 days per week. In the
event the blind is broken, the sponsor must be informed as soon as possible. The date, time, and
reason for the unblinding must be documented by the IWRS, in the appropriate section of the eCRF
and in the source document. The documentation received from the IWRS indicating the code break
must be retained with the participant’s source documents in a secure manner.
Participants who have had their intervention assignment unblinded should continue to return for
scheduled evaluations.
6.4. 
Study Intervention Compliance
Study intervention will be administered at site as an IV infusion or SC injection by qualified staff.
The details of each administration will be recorded in the eCRF. For IV infusions, this will include
date and start and stop times of the IV infusion and volume infused; for SC injections, this will
include date and time of SC injection.
Study site personnel will maintain a log of all study intervention administered. Study intervention
supplies for each participant will be inventoried and accounted for.
6.5. 
Dose Modification
No treatment/dose adjustment of study intervention will be permitted throughout the study period.
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6.6. 
Continued Access to Study Intervention After the End of the Study
This protocol is designed to provide participants with up to approximately 104 weeks of treatment,
including LTE.
No continued access is proposed for this study as this is a PoC study. At the end of their
participation in the study, the participants will be instructed that they should return to their primary
physician to determine standard of care, if applicable.
6.7. 
Treatment of Overdose
For this study, any dose of guselkumab greater than the highest dose at a single visit specified in
this protocol will be considered an overdose. The sponsor does not recommend specific treatment
for an overdose.
In the event of an overdose, the investigator or treating physician should:
 
Contact the Medical Monitor immediately.
 
Evaluate the participant to determine, in consultation with the Medical Monitor, whether study
intervention should be interrupted or whether the dose should be reduced.
 
Closely monitor the participant for AE/SAE and laboratory abnormalities until guselkumab
can no longer be detected systemically.
 
Obtain a plasma sample for PK analysis if requested by the Medical Monitor (determined on
a case-by-case basis).
 
Document the quantity of the excess dose as well as the duration of the overdosing in the
eCRF.
6.8. 
Concomitant Therapy
Prestudy therapies including specific SSc therapies administered up to 60 days before first dose of
study intervention must be recorded at screening.
Concomitant therapies including specific SSc therapies must be recorded throughout the study
beginning with start of the screening to the final safety follow-up visit. Concomitant therapies
should also be recorded beyond the final safety follow-up visit only in conjunction with SAEs that
meet the criteria outlined in Serious Adverse Events in Section 8.3.1, Time Period and Frequency
for Collecting Adverse Event and Serious Adverse Event Information.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special
diets, exercise regimens, or other specific categories of interest) different from the study
intervention must be recorded in the eCRF. Recorded information will include a description of the
type of therapy, duration of use, dosing regimen, route of administration, and indication.
Modification of an effective preexisting therapy should not be made for the explicit purpose of
entering a participant into the study. Any questions or concerns with the use of concomitant
therapies should be discussed with the study sponsor and/or medical monitor.
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Status: Approved,  Date:  15 November 2022
NSAIDs or Other Analgesics
Participants may be treated with NSAIDs, including COX-2 inhibitors, during the study. The
participant’s standing dose should remain stable during the study, unless dose reduction is required
for safety reasons. The choice and doses of NSAIDs are at the discretion of the investigator. For
participants who receive corticosteroids and/or NSAIDs, prophylactic treatment such as
rebamipide, or H2-receptor blockers should be considered. Prophylactic treatment should be added
according to the investigator’s discretion.
Oral Corticosteroids
Participants may receive corticosteroids at a stable dose of ≤10 mg/day of prednisolone or
equivalent during the study. Increases in corticosteroid doses for treatment of SSc are not allowed
during the study. To treat non-SSc-related conditions such as asthma, increased doses of oral
corticosteroids of up to 20 mg of prednisone daily (or equivalent) for 2 weeks are permitted. The
dose of the corticosteroid should be tapered down to the previous level as rapidly as medically
possible.
Medications for Pulmonary Arterial Hypertension
Participants may be treated with following medications for pulmonary arterial hypertension:
endothelin receptor antagonists (eg, bosentan, ambrisentan and macitentan), phosphodiesterase 5
inhibitors (eg, sildenafil and tadalafil), and prostacyclins (eg, epoprostenol, iloprost and
treprostinil). The dose should remain stable during the study.
ACE Inhibitors, Calcium-Channel Blockers, or Protein-Pump Inhibitors
Participants receiving ACE inhibitors, calcium-channel blockers, proton-pump inhibitors, and/or
oral vasodilators have to be on a stable dose during the study, unless dose adjustments are required
for safety reasons.
Prohibited and restricted therapies
 
During the study
 
IL-23 inhibitor therapy (including but not limited to guselkumab, risankizumab,
tildrakizumab, brazikumab, mirikizumab)
 
tocilizumab
 
sirukumab, sarilumab, mavrilimumab, abatacept, belimumab
 
IL-12/23 inhibitors (ustekinumab)
 
IL-17 inhibitors (secukinumab, ixekizumab, brodalumab)
 
tyrosine kinase inhibitor (nintedanib)
 
Any live viral or live bacterial vaccination
 
Rituximab
 
Any cytotoxic agents (cyclophosphamide, chlorambucil, nitrogen mustard, or other
alkylating agents)
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Status: Approved,  Date:  15 November 2022
 
Intravenous 
immunoglobulin 
(IVIG), 
apheresis 
therapy 
(plasmapheresis 
or
leukopheresis)
 
Systemic immunosuppressive agents (including but not limited to cyclosporine A,
azathioprine, tacrolimus, sirolimus, methotrexate, sulfasalazine, leflunomide with
cholestyramine washout or mycophenolate mofetil/mycophenolic acid)
 
Intramuscular, intra-articular, intrabursal, epidural, intra-lesional or IV GCs
 
Pirfenidone
 
Systemic and topical Janus kinase inhibitors (eg, tofacitinib, upadacitinib)
 
Other biologics
 
Any investigational agents/treatments
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered.
Rescue Medication
In the event that a participant experiences worsening criteria (Criteria: increase from baseline ≥5
in mRSS), investigators will have the option to treat with protocol-allowed rescue therapy after
Week 24.
 
Oral Corticosteroid ≤20 mg/day of prednisolone or equivalent
 
Immunomodulator (Azathioprine), within the approved dose for SSc
If rescue therapy as stipulated above fails to control SSc symptoms sufficiently, the investigator
should consider discontinuing the patient from the study.
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
7.1. 
Discontinuation of Study Intervention
A participant’s study intervention must be discontinued if:
 
The participant withdraws consent to receive study intervention.
 
The investigator believes that for safety reasons or tolerability reasons (eg, AE) it is in the
best interest of the participant to discontinue study intervention.
 
The investigator or sponsor believes that there are no further benefit of continuing the study
for the participants.
 
The participant becomes pregnant or planning to become pregnant while enrolled in this study
or within 12 weeks after the last administration of study intervention.
 
Noncompliance with study intervention administration.
 
The participant initiates treatment with prohibited therapies listed in Section 6.8 unless agreed
upon with the sponsor medical monitor.
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Status: Approved,  Date:  15 November 2022
 
The participant is deemed ineligible according to the following TB screening criteria:
 
A diagnosis of active TB is made.
 
A participant has symptoms suggestive of active TB based on follow-up assessment
questions and/or physical examination or has had recent close contact with a person with
active TB and cannot or will not continue to undergo additional evaluation.
 
A participant undergoing evaluation has a chest radiograph or chest CT with evidence of
current active TB and/or a positive QuantiFERON-TB test or T-SPOT test result, unless
active TB can be ruled out and appropriate treatment for latent TB can be initiated prior
to the next study intervention administration and continued to completion (see also
Section 8.2.9). Indeterminate QuantiFERON-TB test or borderline T-SPOT results
should be handled as in Section 8.2.9. Participants with persistently indeterminate
QuantiFERON-TB test results or borderline T-SPOT may continue without treatment for
latent TB if active TB is ruled out, their chest radiograph or chest CT shows no
abnormality suggestive of TB (active or old, inactive TB) and the participant has no
additional risk factors for TB as determined by the investigator. This determination must
be promptly reported to the sponsor and recorded in the participant’s source documents
and initialed by the investigator.
 
A participant receiving treatment for latent TB discontinues this treatment prematurely
or is noncompliant with the therapy.
 
The participant has a serious adverse reaction that is related to an injection or an infusion,
including an injection-site or infusion reaction, resulting in bronchospasm with wheezing
and/or dyspnea that requires ventilatory support OR that results in symptomatic hypotension
with a decrease in systolic blood pressure >40 mm Hg.
 
The participant has a reaction resulting in myalgia and/or arthralgia with fever and/or rash
(suggestive of serum sickness and not representative of signs and symptoms of other
recognized clinical syndromes) occurring 1 to 14 days after an injection of study intervention.
These may be accompanied by other events including pruritus, facial, hand, or lip edema,
dysphagia, urticaria, sore throat, and/or headache.
 
The participant has severe liver test abnormalities that are not transient and are not explained
by other etiologies. Such abnormalities would include (see Section 10.6, Appendix 6: Liver
Safety: Suggested Actions and Follow-up Assessments):
 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥5 × ULN.
 
ALT or AST ≥3 × ULN for more than 4 weeks.
 
ALT or AST ≥3 × ULN and cannot be monitored weekly for 4 weeks.
 
ALT or AST ≥3 × ULN and TBL ≥2 × ULN or international normalized ratio [INR] >1.5
(INR not acceptable for participants on anticoagulants).
 
ALT or AST ≥3× ULN and symptoms (new or worsening) believed to be related to liver
injury (such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, or
jaundice) or hypersensitivity (such as fever, rash or eosinophilia).
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Status: Approved,  Date:  15 November 2022
 
The participant has a malignancy including squamous cell skin cancer. Consideration may be
given to allowing participants who develop ≤2 basal cell skin cancers that are adequately
treated with no evidence of residual disease to continue to receive study intervention.
Discontinuation of a participant’s study intervention must be strongly considered under
the following conditions:
 
The participant develops a serious infection, including but not limited to sepsis or pneumonia.
 
The participant develops a severe injection-site or infusion reaction.
If a participant discontinues study intervention for any reason before the end of the double-blind
phase, then the assessments should be obtained as specified in the SoA (Section 1.3). Study
intervention assigned to the participant who discontinued study intervention may not be assigned
to another participant. Additional participants will not be entered.
7.1.1. 
Liver Chemistry Stopping Criteria
Discontinuation of study intervention for abnormal liver tests is required by the investigator when
a participant meets 1 of the conditions outlined in Section 10.6, Appendix 6: Liver Safety:
Suggested Actions and Follow-up Assessments, or in the presence of abnormal liver chemistries
not meeting protocol-specified stopping rules if the investigator believes that it is in best interest
of the participant.
7.2. 
Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons:
 
Lost to follow-up
 
Withdrawal of consent
 
Death
When a participant withdraws before study completion, the reason for withdrawal is to be
documented in the eCRF and in the source document. If the reason for withdrawal from the study
is withdrawal of consent, then no additional assessments are allowed.
Withdrawal of Consent
A participant declining to return for scheduled visits does not necessarily constitute withdrawal of
consent. Alternate follow-up mechanisms that the participant agreed to when signing the consent
form apply (eg, consult with family members, contacting the participant’s other physicians,
medical records, database searches, use of locator agencies at study completion) as local
regulations permit.
7.2.1. 
Withdrawal From the Use of Research Samples
A participant who withdraws from the study will have the following options regarding the optional
research sample:
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 
The collected sample will be retained and used in accordance with the participant’s original
separate informed consent for optional research samples.
 
The participant may withdraw consent for optional research sample, in which case the sample
will be destroyed, and no further testing will take place. To initiate the sample destruction
process, the investigator must notify the sponsor study site contact of withdrawal of consent
for the optional research samples and to request sample destruction. The sponsor study site
contact will, in turn, contact the biomarker representative to execute sample destruction. If
requested, the investigator will receive written confirmation from the sponsor that the sample
has been destroyed.
Withdrawal From the Optional Research Samples While Remaining in the Main Study
The participant may withdraw consent for optional research samples while remaining in the study.
In such a case, the optional research sample will be destroyed. The sample destruction process will
proceed as described above.
7.3. 
Lost to Follow-up
To reduce the chances of a participant being deemed lost to follow-up, prior to randomization
attempts should be made to obtain contact information from each participant, eg, home, work, and
mobile telephone numbers and email addresses for both the participant as well as appropriate
family members.
A participant will be considered lost to follow-up if he or she repeatedly fails to return for
scheduled visits and is unable to be contacted by the study site. A participant cannot be deemed
lost to follow-up until all reasonable efforts made by the study site personnel to contact the
participant are deemed futile. The following actions must be taken if a participant fails to return to
the study site for a required study visit:
 
The study site personnel must attempt to contact the participant to reschedule the missed visit
as soon as possible, to counsel the participant on the importance of maintaining the assigned
visit schedule, to ascertain whether the participant wishes to or should continue in the study.
 
Before a participant is deemed lost to follow-up, the investigator or designee must make every
reasonable effort to regain contact with the participant (where possible, 3 telephone calls,
e-mails, fax, and, if necessary, a certified letter to the participant’s last known mailing address,
or local equivalent methods These contact attempts should be documented in the participant’s
medical records.
 
Should the participant continue to be unreachable, they will be considered to have withdrawn
from the study.
Should a study site close, eg, for operational, financial, or other reasons, and the investigator cannot
reach the participant to inform them, their contact information will be transferred to another study
site.
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8. 
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedule of Activities summarizes the frequency and timing of efficacy, PK, immunogenicity,
PD, biomarker, pharmacogenomic, and safety measurements applicable to this study.
If multiple assessments are scheduled for the same timepoint, it is recommended that procedures
be performed in the following sequence: ECG and vital signs (blood pressure, pulse rate,
respiratory rate, and axillary body temperature) should be performed first, and then blood draws
for PK or laboratory measurements. Urine and blood collections for PK and PD assessments should
be kept as close to the specified time as possible. Other measurements may be done earlier than
specified timepoints if needed. Actual dates and times of assessments will be recorded in the source
documentation and eCRF.
For each participant, the maximum amount of blood drawn in this study will not exceed 567  mL
through Week 112.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the
samples.
Table 3: 
Volume of Blood to be Collected from Each Participant
Type of Sample 
Volume per 
Sample (mL) 
No. of Samples 
per Participant 
Approximate
Total Volume of
Blood (mL)a
Safety (including screening and post-intervention
assessments)
  
 
 - T-spot 
10 
1 
10
 - Hematology 
2 - 3 
26 
52 - 78
 - Serum chemistry 
2.5 
26 
65
 - Serology (HIV, HBV, HCV) 
8.5 
1 
8.5
 - HBV DNA testing 
6 
8 
48
Pharmacokinetic/Immunogenicit y samples 
7.5 
25 
187.5
Pharmacodynamic/Biomarker samples 
 
 - PBMCs 
2 × 8 
4 
64
 - Serum biomarkers 
8.5 
7 
59.5
Autoantibodies 
3 
1 
3
Pharmacogenomic sampleb 
 
 - EDTA 
4 - 6 
1 
4 - 6
 - Paxgene tube 
5 
3 
15
Approximate Totalc 
 
 
516.5 – 544.5
Abbreviations: DNA=deoxyribonucleic acid; EDTA= ethylenediaminetetraacetic acid; HBV= hepatitis B virus;
HCV= hepatitis C virus; HIV= human immunodeficiency virus; PBMC= peripheral blood mononuclear cells
a. Calculated as number of samples multiplied by amount of blood per sample.
b. A blood sample will be collected only from participants who have consented to provide an optional DNA and
RNA samples for research.
c. Repeat or unscheduled samples ma y be taken for safet y reasons or technical issues with the samples.
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Screening
At the screening visit, written informed consent must be obtained from the participant for this
program by the principal investigator or designee before performing any protocol-specific
procedure. Procedures to be performed at the screening visit are outlined in the SoA (Section 1.3).
Women of childbearing potential must have a negative urine pregnancy test result at screening.
Participants must be reminded that they are required to use a highly effective method of
contraception during the study (as described in Inclusion Criteria [Section 5.1]) and must continue
taking such precautions for 12 weeks after receiving the last administration of study intervention.
The method(s) of contraception used by each participant must be documented.
Participants must undergo testing for TB (Section 8.2.9) 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 participant should be asked about past testing for TB, including
chest radiograph or chest CT results.
Participants with a negative QuantiFERON-TB test or T-SPOT result are eligible to continue with
registration procedures.
Participants with a newly identified positive QuantiFERON-TB or T-SPOT test result must
undergo an evaluation to rule out active TB and initiate appropriate treatment for latent TB.
Appropriate treatment for latent TB is defined according to local country guidelines for
immunocompromised participants.
A participant whose first QuantiFERON-TB test result is indeterminate or T-SPOT test result is
borderline should have the test repeated. If the second QuantiFERON-TB or T-SPOT test result is
also indeterminate or borderline, the participant may be enrolled without treatment for latent TB
if his/her chest radiograph or chest CT shows no abnormality suggestive of TB (active or old,
inactive TB) and the participant has no additional risk factors for TB as determined by the
investigator and Sponsor.
An assessment of all screening laboratory test results, clinical data, and concomitant medication
data will be made by the principal investigator or designee to confirm that the participant satisfies
all inclusion criteria and does not violate any exclusion criteria.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory
requisition form.
Refer to the Schedule of Activities (Section 1.3) for the timing and frequency of all sample
collections.
Study-Specific Materials
The investigator will be provided with the following supplies:
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 
Investigator Site File (includes protocol and IB)
 
IPPM and IPPI
 
Instruction for use of prefilled syringe for site staff
 
Instruction for use of prefilled syringe for subjects
 
Training guide for investigators for use of prefilled syringe
 
Subject diary for at home administration / self-administration
 
Laboratory manual
 
eCRF completion instructions
 
Participant recruitment materials (if needed)
 
Sample ICF
 
PRO questionnaire and PRO completion guidelines
 
IWRS manual
 
CT image acquisition procedure manual and CT technologist instruction form
 
Biopsy manual
 
Capillaroscopy manual and quick reference guide
 
Pulmonary function test manual
8.1. 
Efficacy Assessments
Efficacy assessments will include the following:
 
mRSS
 
ACR CRISS score
 
Pulmonary function tests (PFTs):
 
FVC and % of predicted FVC
 
DLCO (ml/min/mm Hg) and % of predicted DLCO (hemoglobin-corrected)
 
PhGA
 
Patient-Reported Outcomes (PROs):
 
PGA
 
Health Assessment Questionnaire-Disability Index (HAQ-DI)
 
Frequency Scale for the Symptoms of Gastroesophageal reflux disease (FSSG)
Questionnaire
 
Digital ulcer assessment
 
Nailfold Capillaroscopy
 
Lung HRCT (centrally read)
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8.1.1. 
Modified Rodnan Skin Score
The mRSS is a validated physical examination method for estimating skin induration. It correlates
with biopsy measures of skin thickness and reflects prognosis and visceral involvement, especially
in early disease. It is scored on 0 (normal) to 3 (severe induration) ordinal scales over 17 body
areas, with a maximum score of 51 and is used to categorize severity of SSc (Khanna 2007). It has
been extensively used as a primary and secondary outcome measure in randomized clinical trials
(Khanna 2016a; Khanna 2020). This assessment should be performed by a physician who is
experienced and trained in skin scoring. To prevent inter-observer variability, the same physician
must perform skin scoring for the same participant throughout the entire study.
8.1.2. 
American College of Rheumatology Combined Response Index in
Diffuse Cutaneous Systemic Sclerosis Score
ACR CRISS is composite response index for clinical trials in early dcSSc developed by an
international group of experts in SSc. Application of ACR CRISS algorithm in a randomized
clinical trial is a 2-step process. Firstly, evaluate if participants have met the criterion for not-
improved. If yes, these participants are assigned a probability score of 0.0.
Investigators will evaluate if the participants have met the criterion:
 
New scleroderma renal crisis
 
Decline in FVC % predicted ≥15% (relative), confirmed by another FVC test within a
month, HRCT to confirm ILD (if previous HRCT of chest did not show ILD) and FVC
<80% of predicted*
 
New onset of left ventricular failure (defined as left ventricular ejection fraction ≤45%)
requiring treatment*
 
New onset of PAH on right-sided heart catheterization requiring treatment*
* Attributable to systemic sclerosis
For the remaining participants, calculate the probability based on change in 5 measures: mRSS, %
of predicted FVC, HAQ-DI, patient’s global assessment, and physician’s global assessment, where
each measure has a probability score between 0 and 1 (Khanna 2016b). ACR CRISS sore will be
calculated by the sponsor.
8.1.3. 
Pulmonary Function Tests
The following lung function measurements will be performed locally:
 
FVC and % of predicted FVC
 
DLCO (ml/min/mm Hg) and % of predicted DLCO (hemoglobin-corrected)
Also, oxygen saturation data will be collected.
8.1.4. 
Physician Global Assessment
PhGA rated subject’s overall SSc condition will be assessed, using a 10 cm visual analogue scale
where 0  excellent and 10  extremely poor.
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8.1.5. 
Patient-reported Outcomes
The participant’s overall health and physical function would be assessed using 2 PRO instruments:
PGA and HAQ-DI. In addition, the esophageal symptoms of gastroesophageal reflux disease
(GERD) will be evaluated using the Frequency Scale for the Symptoms of GERD (FSSG)
questionnaire.
Patient Global Assessment
Participant’s overall health will be assessed using the patient-reported outcome instrument of PGA.
The PGA would rate subject’s overall health related to SSc in the past 7 days, using a 10 cm visual
analogue scale where 0  excellent and 10  extremely poor.
Health Assessment Questionnaire -Disability Index
The Stanford HAQ is a brief self-report questionnaire assessing physical function pertaining to
activities of daily living across 8 domains: dressing and grooming, arising, eating, walking,
hygiene, reach, grip, and activities. Originally developed for use in RA, it has been successfully
applied to a variety of rheumatic conditions, including idiopathic inflammatory myopathy. The
Stanford HAQ translated into Japanese with culturally appropriate modifications of the arising,
eating, and reach category questions will be used in the study (Matsuda 2003).
Frequency Scale for the Symptoms of Gastroesophageal reflux disease (FSSG)
The FSSG questionnaire is a succinct questionnaire to evaluate esophageal symptoms of GERD
which is validated based on endoscopic esophagitis. The original version of FSSG consists of the
most prevalent 7 acid-reflux related and 5 dysmotility-related symptoms of GERD with higher
scores being more indicative of underlying GERD. Each score was determined as follows:
0  never, 1  occasionally, 2  sometimes, 3  often, and 4  always.
The PRO instruments will be provided in the local language in accordance with local guidelines.
 
The PRO instruments must be available for regulators and for Institutional Review Board
(IRB)/Independent Ethics Committee (IEC) submissions, therefore the PRO instruments or
screen shots need to be attached to the protocol or provided in a companion manual with the
instruments that will be submitted with the protocol.
 
The PRO and AE data will not be reconciled with one another.
8.1.6. 
Digital Ulcer Assessments
Digital ulcers are defined as a full thickness (>3mm in maximal diameter) skin lesion with loss of
epithelium including lesions covered by eschar (Note: Pitting scars and hyperkeratotic lesions are
excluded). Healing is defined by re-epithelialization with loss of pain and exudate. The digital
ulcer assessments would be performed by the investigator designee during the study as specified
in the SoA (Section 1.3). Ulcer counts and ulcer burden would be calculated by the sponsor.
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8.1.7. 
Nailfold Capillaroscopy
Nailfold capillaroscopy is a non-invasive method to visualize the nailfold capillaries and assess
microvascular morphology. Nailfold capillary abnormalities are included in ACR/EULAR
classification criteria for SSc. Nailfold capillary abnormalities are evaluated by using nailfold
capillaroscopy. The typical changes of the nailfold capillaries during SSc include the total number
of capillaries, capillary dimension, capillary morphology, hemorrhages, blood flow velocity in
capillaries, and length of nailfold. These changes would be calculated (Smith 2020; Smith 2010;
Smith 2012). Visual media will be taken. For details, refer to the manual.
8.1.8. 
High-resolution Computed Tomography (HRCT) Assessment
Lung involvement is one of the most important cause of morbidity and mortality in patients with
SSc. Because of recent advancement of computer-based scoring, analysis of CT images is drawing
attention as a method to assess fibrotic changes in ILD. Texture-based analysis and computer
vision-based approaches can be applied to imaging data, and used to evaluate the extent of lung
fibrosis in chest CT images (Weatherley 2019). This assessment should be done at central. For
details on HRCT, refer to CT technologist instruction form.
8.2. 
Safety Assessments
Adverse events will be reported and followed by the investigator as specified in Section 8.3,
Adverse Events, Serious Adverse Events, and Other Safety Reporting, and Section 10.4, Appendix
4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other Safety
Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting.
Any clinically relevant changes occurring during the study must be recorded on the Adverse Event
section of the eCRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will be
followed by the investigator until resolution or until a clinically stable condition is reached.
The study will include the following evaluations of safety and tolerability according to the time
points provided in the Schedule of Activities.
8.2.1. 
Physical Examinations
Physical examinations will be performed as specified in the Schedule of Activities (Section 1.3).
While assessment of the participants for safety and efficacy requires some physical examination
by an investigator at all visits, a more complete, detailed physical exam will be performed at
specified visits.
Height and weight of the participants will be measured at specified visits. Participants will be
instructed to remove shoes and outdoor apparel and gear prior to these measurements.
8.2.2. 
Vital Signs
Temperature (axillary), pulse/heart rate, respiratory rate, blood pressure will be assessed.
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Through Week 112, vital signs (including temperature, pulse/heart rate, respiratory rate, and blood
pressure) will be obtained before and approximately every 30 minutes during every IV infusion,
and for 1 hour at approximately 30-minute intervals after completion of the final IV infusion. Vital
signs should be obtained before and approximately 30 minutes after the final SC injection.
8.2.3. 
Electrocardiograms
A 12-lead ECG will be performed at screening and at timepoints specified in the SoA (Section 1.3).
During the collection of ECGs, participants should be in a quiet setting without distractions (eg,
television, cell phones). Participants should rest in a supine position for at least 5 minutes before
ECG collection and should refrain from talking or moving arms or legs. If blood sampling or vital
sign measurement is scheduled for the same time point as ECG recording, the procedures should
be performed in the following order: ECG(s), vital signs, blood draw.
8.2.4. 
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry and hematology and a random urine sample for urinalysis will
be collected as noted in Section 10.2, Appendix 2: Clinical Laboratory Tests. The investigator
must review the laboratory results, document this review, and record any clinically relevant
changes occurring during the study in the AE section of the eCRF. The laboratory reports must be
filed with the source documents.
8.2.5. 
Interstitial Lung Disease Monitoring
The presence of ILD must be evaluated at screening using chest x-ray/lung HRCT and/or PFTs
(FVC and DLCO). All participants must be monitored with lung HRCT, and/or PFTs (FVC and
DLCO) as scheduled in Section 1.3 during the study.
8.2.6. 
Adverse Events Temporally Associated with Infusion
Any AE (except laboratory abnormalities) that occurs during or within 1 hour after the IV infusion
of study intervention will be carefully evaluated. Minor infusion-related AEs may be managed by
slowing the rate of the IV infusion and/or treating with antihistamines and/or acetaminophen
(paracetamol) as clinically indicated. If an IV infusion of study intervention is stopped because of
an AE that, in the opinion of the investigator, is not severe or does not result in a SAE, the infusion
may be restarted with caution.
8.2.7. 
Injection-site Reactions
An injection-site reaction is any adverse reaction at a SC study intervention injection site. Injection
sites will be evaluated for reactions and any injection-site reaction will be recorded as an AE.
8.2.8. 
Hypersensitivity Reactions
Before any SC injection or IV infusion, appropriately trained personnel and medications must be
available to treat hypersensitivity reactions, including anaphylaxis. All participants must be
observed carefully for symptoms of a hypersensitivity reaction (eg, urticaria, itching, hives). If a
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mild or moderate hypersensitivity reaction is observed, acetaminophen, nonsteroidal anti-
inflammatory drugs, and/or diphenhydramine may be administered.
In the case of a severe hypersensitivity reaction (eg, anaphylaxis), SC aqueous epinephrine,
corticosteroids, respiratory assistance, and other proper resuscitative measures are essential and
must be available at the study site where the injections or infusions are being administered.
Participants who experience serious adverse reactions related to an injection or infusion should be
discontinued from further study intervention administrations.
Participants who experience reactions following an injection or infusion that result in
bronchospasm with wheezing and/or dyspnea that requires ventilatory support, or symptomatic
hypotension with a decrease in systolic blood pressure greater than 40 mm Hg will not be permitted
to receive additional study intervention.
Participants who experience reactions suggestive of serum sickness-like reactions (resulting in
symptoms such as myalgia and/or arthralgia with fever and/or rash that are not representative of
signs and symptoms of other recognized clinical syndromes) occurring 1 to 14 days after an
injection of study intervention, should be discontinued from further study intervention
administrations. Note that these symptoms may be accompanied by other events including pruritus,
facial, hand, or lip edema, dysphagia, urticaria, sore throat, and/or headache.
8.2.9. 
Tuberculosis evaluations
8.2.9.1. 
Initial Tuberculosis Evaluation
Participants 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 participant should be asked about past testing for TB, including
chest radiograph and/or CT results. If either the QuantiFERON-TB test or T-SPOT is positive, the
participant is considered to have latent TB infection for the purposes of eligibility for this study.
Participants with a negative QuantiFERON-TB (or T-SPOT if performed) test result are eligible
to continue with screening procedures. Participants with a newly identified positive
QuantiFERON-TB (or T-SPOT if performed) test result must undergo an evaluation to rule out
active TB and initiate appropriate treatment for latent TB. Appropriate treatment for latent TB is
defined according to local country guidelines for immunocompromised patients. Otherwise, the
participant will be excluded from the study.
A participant whose first QuantiFERON-TB test result is indeterminate or T-SPOT test result is
borderline should have the test repeated. In the event that the second QuantiFERON-TB test or T-
SPOT result is also indeterminate or borderline, the participant may be enrolled without treatment
for latent TB if active TB is ruled out, their chest radiograph shows no abnormality suggestive of
TB (active or old, inactive TB) and the participant has no additional risk factors for TB as
determined by the investigator. This determination must be promptly reported to the Sponsor and
recorded in the participant’s source documents and initialed by the investigator.
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8.2.9.2. 
Ongoing Tuberculosis Evaluation
Early Detection of Active Tuberculosis
To aid in the early detection of TB reactivation or new TB infection during study participation,
participants must be evaluated for signs and symptoms of active TB at scheduled visits or by
telephone contact approximately every 8 to 12 weeks. The following series of questions is
suggested for use during the evaluation:
 
“Have you had a new cough of >14 days’ duration or a change in a chronic cough?”
 
“Have you had any of the following symptoms:
 
Persistent fever?
 
Unintentional weight loss?
 
Night sweats?”
 
“Have you had close contact with an individual with active TB?” (If there is uncertainty as to
whether a contact should be considered “close,” a physician specializing in TB should be
consulted.)
If the evaluation raises suspicion that a participant 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 participants may
present as disseminated disease or with extrapulmonary features. Participants with evidence of
active TB should be referred for appropriate treatment.
Participants 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 or T-SPOT test, and, if
possible, referral to a physician specializing in TB to determine the participant’s risk of developing
active TB and whether treatment for latent TB is warranted.
Study intervention administration should be interrupted during the investigation. A positive
QuantiFERON-TB test or T-SPOT test result should be considered detection of latent TB. If the
QuantiFERON-TB test result is indeterminate or T-SPOT result is borderline, the test should be
repeated. Participants should be encouraged to return for all subsequent scheduled study visits
according to the protocol. Participants who discontinue treatment for latent TB prematurely or who
are noncompliant with therapy must immediately discontinue further administration of study
intervention and be encouraged to return for all subsequent scheduled study visits according to the
SoA (Section 1.3).
8.2.10. 
Infections
Study intervention administration should not be given to a participant with a clinically important,
active infection. Investigators are required to evaluate participants for any signs or symptoms of
infection at scheduled visits. If a participant develops a serious infection, including but not limited
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to sepsis or pneumonia, discontinuation of study intervention (ie, no further study intervention
administrations) must be considered.
8.2.11. 
Hepatitis B Monitoring
For participants who are eligible with surface antigen (HbsAg) negative, core antibody (anti HBc)
and/or surface antibody (anti-HBs) positive, and HBV deoxy ribonucleic acid (DNA) test is
negative, HBV DNA quantitation should be monitored at least every 3 months or shorter.
8.2.12. 
Concomitant Medication Review
Concomitant medications will be reviewed at each visit.
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting
Timely, accurate, and complete reporting and analysis of safety information, including AEs, SAEs,
and PQC, from clinical studies are crucial for the protection of participants, investigators, and the
sponsor, and are mandated by regulatory agencies worldwide. The sponsor has established
Standard Operating Procedures in conformity with regulatory requirements worldwide to ensure
appropriate reporting of safety information; all clinical studies conducted by the sponsor or its
affiliates will be conducted in accordance with those procedures.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate,
or the participant’s legally acceptable representative) for the duration of the study.
For study intervention that meets the definition of a combination product, malfunctions or
deficiencies of a device constituent will be reported as PQC.
Further details on AEs, SAEs, and PQC can be found in Section 10.4, Appendix 4: Adverse Events,
Serious Adverse Events, Product Quality Complaints, and Other Safety Reporting: Definitions and
Procedures for Recording, Evaluating, Follow-up, and Reporting.
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information
All Adverse Events
All AEs and special reporting situations, whether serious or non-serious, will be reported from the
time a signed and dated ICF is obtained until completion of the participant’s last study-related
procedure, which may include contact for follow-up of safety. Serious adverse events, including
those spontaneously reported to the investigator within 12 weeks after the last dose of study
intervention, 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.
Serious Adverse Events
All SAEs, as well as PQC, occurring during the study must be reported to the appropriate sponsor
contact person by study site personnel within 24 hours of their knowledge of the event.
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Serious adverse events, including those spontaneously reported to the investigator within 12 weeks
after the last dose of study intervention, must be reported. The sponsor will evaluate any safety
information that is spontaneously reported by an investigator beyond the time frame specified in
the protocol. Possible Hy’s law case (AST or ALT ≥ 3 x ULN together with total bilirubin ≥ 2 x
ULN or INR > 1.5) is considered an important medical event and must be reported to the sponsor
in an expedited manner using the Serious Adverse Event Form, even before all other possible
causes of liver injury have been excluded.  (INR criterion is not applicable to participants receiving
anticoagulants.)
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event
Form, which must be completed and signed by a physician from the study site, and transmitted to
the sponsor within 24 hours. The initial and follow-up reports of an SAE should be made by
facsimile (fax). Telephone reporting should be the exception and the reporter should be asked to
complete the appropriate form(s) first.
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and nonleading
verbal questioning of the participant is the preferred method to inquire about AE occurrence.
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events
The investigator is obligated to perform or arrange for the conduct of supplemental measurements
and evaluations as medically indicated to elucidate the nature and causality of the AE, SAE, or
PQC as fully as possible. This may include additional laboratory tests or investigations,
histopathological examinations, or consultation with other health care professionals.
Adverse events, including pregnancy, will be followed by the investigator as specified in Section
10.4, Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and
Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and
Reporting.
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities.
The sponsor will also report to the investigator (and the head of the investigational institute where
required) all suspected unexpected serious adverse reactions (SUSARs). For individual SAEs, 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 intervention caused a serious event, they will submit a safety report in narrative format to the
investigators (and the head of the institute where required). The investigator (or sponsor where
required) must report SUSARs to the appropriate IEC/IRB that approved the protocol unless
otherwise required and documented by the IEC/IRB. A SUSAR will be reported to regulatory
authorities unblinded. Participating investigators and IEC/IRB will receive a blinded SUSAR
summary, unless otherwise specified.
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8.3.5. 
Pregnancy
All initial reports of pregnancy in female participants or partners of male participants must be
reported to the sponsor by the study site personnel within 24 hours of their knowledge of the event
using the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg,
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are
considered SAEs and must be reported using an SAE reporting form. Any participant who becomes
pregnant during the study must be promptly withdrawn from the study and discontinue further
study intervention.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the
infant will be required.
8.3.6. 
Adverse Events of Special Interest (AESI)
Any newly identified malignancy or case of active TB or ILD occurring after the first study
intervention administration(s) in participants participating in this clinical study must be reported
by the investigator to the sponsor or designee within 24 hours after being made aware of the event
for SAEs. 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.
8.4. 
Pharmacokinetics
Serum samples will be used to evaluate the PK of guselkumab according to the SoA (Section 1.3).
Additionally, serum samples should also be collected at the final visit from participants who
discontinued study intervention or were withdrawn from the study. These samples will be tested
by the sponsor or sponsors designee. Serum collected for PK may additionally be used to evaluate
safety or efficacy aspects that address concerns arising during or after the study period. Additional
blood sampling may be considered when participant experienced SAE. Genetic analyses will not
be performed on these serum samples. Participant confidentiality will be maintained.
8.4.1. 
Evaluations
At visits where only serum concentration of guselkumab will be evaluated (ie, no antibodies to
guselkumab will be evaluated), 1 venous blood sample of sufficient volume should be collected,
and each serum sample should be divided into 2 aliquots (1 for serum concentration of guselkumab,
and a back-up). At visits where serum concentration of guselkumab and antibodies to guselkumab
will be evaluated, 1 venous blood sample of sufficient volume should be collected, and each serum
sample will be divided into 3 aliquots (1 each for serum concentration of guselkumab, antibodies
to guselkumab, and a back-up).
8.4.2. 
Analytical Procedures
Pharmacokinetics
Serum samples will be analyzed to determine concentrations of guselkumab using a validated,
specific, and sensitive method by or under the supervision of the sponsor’s representative.
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8.4.3. 
Pharmacokinetic Parameters and Evaluations
Parameters
Based on the individual serum concentration-time data, using the actual dose taken and the actual
sampling times, PK parameters and exposure information of guselkumab may be derived using
population PK modeling. Details will be given in a population PK analysis plan.
Pharmacokinetic/Pharmacodynamic Evaluations
The relationship between serum concentrations of guselkumab and the efficacy measures and/or
relevant PD endpoints, including biomarkers in blood or in skin biopsies, may be explored. Details
will be given in a population PK/PD analysis plan if explored.
8.5. 
Pharmacogenomics
A pharmacogenomic blood sample will be collected from participants who consent separately to
this component of the study to allow for pharmacogenomic research, as necessary. Participant
participation in pharmacogenomic research is optional.
8.6. 
Biomarkers
An optional biomarker sub-study will obtain a biopsy sample of non-lesional (unaffected) skin
sample at Week 0, and lesional (at Week 0) skin at Week 0 and 24 from all participants who
consent. For details, refer to the manual.
Data collected from these samples will be used for exploratory research that will include, but are
not limited to, the following objectives:
 
To understand the molecular effects of guselkumab.
 
To understand SSc pathogenesis.
 
To understand why individual participants may respond differently to guselkumab.
 
To understand the impact of treatment with guselkumab on skin or systemic inflammation.
 
To develop diagnostic tests to identify SSc or SSc populations that may be responsive or
nonresponsive to treatment with guselkumab.
8.6.1. 
Pharmacodynamics
Peripheral blood mononuclear cell (PBMC) and serum samples will be collected at timepoints
specified in the SoA (Section 1.3), to assess the blood cellular and molecular biomarkers to enable
evaluation of target engagement in tissue/efficacy PD readouts.
8.7. 
Immunogenicity Assessments
Anti-guselkumab antibodies will be evaluated in serum samples collected from all participants
according to the SoA. Additionally, serum samples should also be collected at the final visit from
participants who discontinued study intervention or were withdrawn from the study. These samples
will be tested by the sponsor or sponsor’s designee.
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Serum samples will be screened for antibodies binding to guselkumab and the titer of confirmed
positive samples will be reported as applicable. Serum samples positive for anti-guselkumab
antibodies will be further characterized for Nabs to guselkumab. Other analyses may be performed
to verify the stability of anti-guselkumab antibodies and/or further characterize the
immunogenicity of guselkumab.
Samples collected for immunogenicity analyses may additionally be used to evaluate safety or
efficacy aspects that address concerns arising during or after the study period. Genetic analyses
will not be performed on these serum samples. Participant confidentiality will be maintained.
Analytical Procedures
The detection and characterization of antibodies to guselkumab will be performed using a validated
assay method by or under the supervision of the sponsor.
8.8. 
Autoantibodies
Samples will be collected at screening (see Section 1.3), to evaluate the presence of autoantibodies
(including, but not limited to anti-RNA polymerase, anti-centromere, and anti-topoisomerase).
Anti-centromere antibodies are very useful in distinguishing patients with SSc from healthy
controls and from patients with other connective tissue disease. Anti-centromere antibodies often
predict a limited skin involvement and the absence of pulmonary involvement anti-RNA-
polymerase autoantibodies occur less frequently and are also predictive of diffuse skin
involvement and systemic disease (Ho 2003).
9. 
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general
description of the statistical methods to be used to analyze the efficacy and safety data is outlined
below. Specific details will be provided in the Statistical Analysis Plan (SAP).
9.1. 
Statistical Hypotheses
This is a PoC study aimed at detecting an early efficacy signal of guselkumab in participants with
SSc, compared to placebo, to support further clinical development.
 
The null hypothesis is that the treatment difference between guselkumab and placebo for the
primary endpoint is 0.
 
The alternative hypothesis is that the treatment difference between guselkumab and placebo
for the primary endpoint is ≠0.
Due to the PoC nature of this study, a 2-sided alpha of 0.2 is allocated for testing this PoC
hypothesis. The PoC objective will be considered met if the calculated p-value for testing this PoC
hypothesis is less than 0.2.
9.2. 
Sample Size Determination
There is lack of positive placebo-controlled trials in dcSSc.
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Taking into account the following 4 Phase 2/3 placebo-controlled trials in SSc with mRSS results
reported in the ClinicalTrials.gov registry, a reasonable estimate of the standard deviation (SD) to
be used in the sample size calculation of this study has been taken as 8.0.
Standard deviations of mRSS in Referenced Phase 2/3 Placebo-controlled Trials in SSc
Trial
Treatment group 
Placebo group
N 
Estimated 
SD 
N
Estimated
SD
A Double-Blind, Randomised, Placebo-controlled Trial
Evaluating Efficacy and Safety of Oral Nintedanib
Treatment for at Least 52 Weeks in Patients With 
Systemic Sclerosis Associated Interstitial Lung Disease
(SSc-ILD) (NCT02597933)
288 
4.582 
288 
4.412
A Phase 3, Multicenter, Randomized, Double-Blind,
Placebo-Controlled, Parallel-Group Study to Assess the
Efficacy and Safety of Tocilizumab Versus Placebo in
Patients With Systemic Sclerosis (NCT02453256)
104 
8.169 
106 
8.142
A Phase 2/3, Multicenter, Randomized, Double-blind,
Placebo-controlled Study To Assess The Efficacy And
Safety Of Tocilizumab Versus Placebo In Patients With
Systemic Sclerosis (NCT01532869)
43 
8.266 
41 
8.933
A Phase 2 Study to Evaluate Subcutaneous Abatacept
vs. Placebo in Diffuse Cutaneous Systemic Sclerosis- a
Double-blind, Placebo-controlled, Randomized
Controlled Trial (NCT02161406)
44 
7.562 
44 
7.562
 
Khanna et al (2006) revealed that a 95% confidence interval (CI) of [-4.7, -1.7] in mRSS change
from baseline to 6 months was considered a clinically meaningful change. The lower bound of this
95% CI, -4.7, has been taken as the expected treatment difference in the sample size calculation of
this study, assuming guselkumab can achieve a clinically meaningful change in most of
guselkumab-treated participants.
Assuming an SD of 8 points, an 80% power at a 2-sided significance level of 0.20, with a 1:1
randomization ratio, to detect a treatment effect of -4.7 points, a total of at least 54 participants
will be required.
Allowing for up to 2 participants randomized but without post-baseline efficacy assessments,
approximately 56 (28 each) randomized participants are planned. In order to evaluate the inter-
observer and intra-observer variability of the mRSS to support Phase 3 planning, it is desirable for
each center to randomize 3 participants at least.
9.3. 
Populations for Analysis Sets
For purposes of analysis, the following populations are defined:
Population 
Description
Enrolled 
All participants who sign the ICF.
Randomized 
All participants who were randomized in the study.
Full Analysis Set 
All randomized participants who received at least 1 dose (complete or partial) of study
intervention.
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Population 
Description
Note: Efficacy and participant information analyses will be based on the randomized
treatment groups, regardless of the treatment the y actuall y received.
Safety 
All randomized participants who received at least 1 dose (complete or partial) of study
intervention.
Note: Safety will be analyzed based on the treatment they receive, regardless of the treatment
groups to which the y are assigned.
PK 
All participants who received at least 1 complete dose of guselkumab and have at least 1
observed post dose PK data.
Immunogenicity 
All participants who received at least 1 dose of guselkumab and have at least 1 observed post
dose immune response data.
9.4. 
Statistical Analyses
The statistical analysis plan will be finalized prior to each DBL and it will include a more technical
and detailed description of the statistical analyses described in this section. This section is a
summary of the planned statistical analyses of the most important endpoints including primary and
key secondary endpoints.
9.4.1. 
General Considerations
An interim analysis will be performed when all participants have completed the Week 52 visit or
discontinued earlier. The final analysis will be performed when all participants have completed the
last study visit or discontinued earlier.
Simple descriptive summary statistics, such as n, mean, SD, median, inter quantile range,
minimum, and maximum for continuous variables, and counts and percentages for discrete
variables will be used to summarize most data.
9.4.2. 
Primary Endpoint
For primary endpoint (Change from baseline in mRSS at Week 24), treatment comparison will be
performed using a Mixed-Effect Model Repeated Measure (MMRM) model. The MMRM model
includes treatment group, baseline mRSS, stratification factors, visit, treatment group by visit
interaction, and baseline mRSS by visit interaction as fixed effects. Treatment effects will be
estimated based on least-square (LS) means of the differences. The p-values for the LS mean
differences along with the 2-sided 80% CI will be presented.
Sensitivity and subgroup analyses for the primary endpoint will be performed, if appropriate. The
details of these analyses and data handling rules will be specified in the SAP.
9.4.3. 
Secondary Endpoints
All secondary efficacy endpoints will be summarized over time by treatment group. Treatment
comparisons will be performed using an MMRM model where there are repeated continuous
measurements or a logistic model where there is a dichotomous response variable. No adjustments
for multiple comparisons will be made for the secondary endpoints and all p-values will be
considered nominal. The detailed methods of analysis and the data-handling rules will be provided
in the SAP.
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9.4.4. 
Exploratory Endpoints
The detailed methods of analysis and the data-handling rules for the exploratory endpoints will be
provided in the SAP.
9.4.5. 
Safety Analyses
All safety analyses will be made on the Safety Population.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the
Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent AEs are AEs with
onset during the treatment phase or that are a consequence of a preexisting condition that has
worsened since baseline.
Adverse events, SAEs, related AEs, and AEs by severity will be summarized by treatment group.
More specification of other AESIs such as ILD will be described in the SAP.
Summaries, listings, or participant narratives may be provided, as appropriate, for those
participants who die, who discontinue intervention due to an AE, or who experience a severe or
an SAE.
Clinical Laboratory Tests
The laboratory parameters and change from baseline in selected laboratory parameters
(hematology and chemistry), and the number of participants with abnormal laboratory parameters
(hematology and chemistry) based on National Cancer Institute Common-Terminology Criteria
for Adverse Events (NCI-CTCAE) toxicity grading will be summarized by intervention group.
Electrocardiogram
Clinically relevant abnormalities will be evaluated by frequency tabulations.
Vital Signs
Descriptive statistics of temperature, pulse/heart rate, respiratory rate, and blood pressure (systolic
and diastolic) values and changes from baseline will be summarized at each scheduled time point.
The percentage of participants with values beyond clinically important limits will be summarized.
9.4.6. 
Other Analyses
Pharmacokinetic Analyses
Unless otherwise noted, PK analyses will be based on the PK Analysis Set. Detailed rules for the
analysis including exclusion from the PK analyses will be specified in the SAP.
All serum concentrations below the lowest quantifiable concentration or missing data will be
labeled as such in the concentration data presentations or SAS dataset. Concentrations below the
lower quantifiable concentration will be treated as zero in the summary statistics. All participants
and samples excluded from the analysis will be clearly documented in the clinical study report.
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Descriptive statistics will be used to summarize guselkumab serum concentrations at each
sampling time point.
If sufficient data are available, population PK analysis of serum concentration-time data of
guselkumab will be performed using nonlinear mixed effects modeling. If the population PK
analysis is conducted, details will be given in a population PK analysis plan and the results of the
analysis will be presented in a separate report.
Biomarkers Analyses
Characterization of gene expression changes in the skin during treatment would be analyzed as
determined by RNA-seq at Weeks 0 and 24. If feasible, a non-lesional (unaffected) skin sample
will be collected at Week 0; lesional (at Week 0) samples to be collected at both Weeks 0 and 24.
If feasible, characterization of the tissue immunopathological changes in the skin as determined
by immunohistochemistry (IHC)/ immunofluorescence (IF)/ in situ hybridization (ISH), as well as
histology analysis (eg, fibrosis) will be performed. Multiparameter protein profiling (eg, imagine
CyTOF) may be considered.
Immunogenicity Analyses
The incidence of anti-guselkumab antibodies will be summarized for the immunogenicity analysis
set.
A listing of participants who are positive for anti-guselkumab antibodies will be provided. The
maximum titers of anti-guselkumab antibodies will be summarized for participants who are
positive for anti-guselkumab antibodies.
The incidence of Nabs to guselkumab will be summarized for participants who are positive for
anti-guselkumab antibodies and have samples evaluable for Nabs to guselkumab.
Pharmacodynamic Analyses
Serum will be collected from all subjects to assess PD markers associated with guselkumab as well
as markers related to SSc. Measurements may include but are not limited to serum levels of IL-17A,
IL-17F, IL-22, beta defensin-2 (BD-2), and SAA. The samples will be collected at Weeks 0, 4, 12,
16, 24, 28, and 48 and analyzed by immunoassays. Broader proteomic profiling (eg, via Olink
method) for biomarker discovery may be performed. Additionally, serum samples should also be
collected at the final visit from participants who discontinued study intervention or were
withdrawn from the study.
Blood samples for the isolation of PBMCs will also be collected for subsequent
immunophenotyping analyses by multiparameter flow cytometry or mass cytometry (CyTOF)
analysis to measure immune cell populations before and during treatment. The samples will be
collected at Weeks 0, 4, 24, and 48. Gene expression analysis may also be performed; this may
include single cell RNA-seq profiling. Additionally, serum samples for isolation of PBMCs should
also be collected at the final visit from participants who discontinued study intervention or were
withdrawn from the study
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Results of pharmacodynamic/biomarker analyses will be presented in a separate report.
Pharmacokinetic/Pharmacodynamic Analyses
The relationship between serum concentrations of guselkumab and the efficacy measures and/or
relevant PD endpoints, including biomarkers in blood or in skin biopsies, may be explored
graphically when appropriate. If any visual trend is observed, additional analysis may be conducted
if deemed necessary.
Pharmacogenomic Analyses
Genetic analysis may help to identify population subgroups that respond differently to a drug. A
single DNA sample at Week 0 as specified in the SoA (Section 1.3) will be used to explore genetic
factors that may influence molecular effects, clinical efficacy, or tolerability of guselkumab and to
identify genetic factors associated with SSc. A locus of interest is the IL12RB1 gene; a reported
SSc risk allele has been identified in this gene and there is potential association with expression of
the gene product (encoding a receptor for IL-23). Analysis applied to DNA samples may focus on
genotyping, using molecular arrays to scan polymorphisms across the genome. Participation in the
DNA sampling is optional.
Results will be presented in a separate report.
Interim Analysis
An interim analysis will be performed when all participants have completed EOS of the main study.
All sponsor personnel will be unblinded at the analyses for internal decision-making and/or
interactions with health authorities.
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. 
Appendix 1: Abbreviations and Definitions
ACR 
American College of Rheumatology
ACR CRISS 
American College of Rheumatology Combined Response Index in diffuse cutaneous systemic
sclerosis
AE 
adverse event
AESI 
adverse event of special interest
ALT 
alanine aminotransferase
AST 
aspartate aminotransferase
BCG 
Bacille Calmette-Guérin
CD 
Crohn’s disease
CI 
confidence interval
COVID-19 
coronavirus disease 2019
CRP 
C-reactive protein
CT 
computed tomography 
DBL 
database lock
dcSSc 
diffuse cutaneous systemic sclerosis
DLCO 
diffusin  g capacit y of the lun  g for carbon monoxide
DNA 
deoxyribonucleic acid
ECG 
electrocardiogram
eCRF 
electronic case report form
eDC 
electronic data capture
EULAR 
European League Against Rheumatism
FOIA 
Freedom of Information Act
FSH 
follicle stimulatin  g hormone
FSSG 
Frequenc y Scale for the Symptoms of Gastroesophageal reflux disease
FVC 
forced vital capacity 
GCA 
giant cell arteritis
GCP 
Good Clinical Practice
GERD 
Gastroesophageal reflux disease
HAQ-DI 
Health Assessment Questionnaire-Disabilit y Index
HbsAg 
hepatitis B surface antigen
HBV 
hepatitis B virus
HIV 
human immunodeficienc y virus
HRCT 
high resolution computed tomography 
HS 
hidradenitis suppurativa
HSCT 
hematopoietic stem cell transplant
IB 
investigator’s brochure
ICF 
informed consent form
ICH 
International Council for Harmonisation
IEC 
Independent Ethics Committee
IGRA 
interferon gamma release assays
INR 
international normalized ratio
IL 
interleukin
IPPI 
Investigational Product Procedure Instructions
ILD 
interstitial lun  g disease
IPPM 
Investigational Product Procedures Manual
IRB 
Institutional Review Board
IV 
intravenous
IVIG 
intravenous immunoglobulin
IWRS 
interactive web response system
Q4W 
ever y 4 weeks
LC-MS/MS 
liquid chromatography/mass spectrometry/mass spectrometry
lcSSc 
limited cutaneous systemic sclerosis
LN 
lupus nephritis
LTE 
long-term extension
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mAb 
monoclonal antibody 
MedDRA 
Medical Dictionar y for Regulator y Activities
MMRM 
mixed-effect model repeated measure
mRSS 
modified Rodnan skin score
NOAEL 
no observed adverse event level
PBMC 
peripheral blood mononuclear cell
PD 
pharmacodynamic(s)
PFS 
prefilled syringe
PFS-U 
UltraSafe Plus™ passive needle safet y device
PFT 
pulmonar y function test
PGA 
patient global assessment
PhGA 
physician global assessment
PK 
pharmacokinetic(s)
PQC 
product qualit y complaint
PRO 
patient-reported outcome(s) (paper or electronic as appropriate for this study)
PsA 
psoriatic arthritis
PsO 
plaque psoriasis
Q4W 
ever y 4 weeks
RA 
rheumatoid arthritis
RNA 
ribonucleic acid
SAP 
statistical analysis plan
SAE 
serious adverse event
SSc 
systemic sclerosis
SC 
subcutaneous
SD 
standard deviation
SoA 
Schedule of Activities
SUSAR 
suspected unexpected serious adverse reaction
TB 
tuberculosis
UC 
ulcerative colitis
ULN 
upper limit normal
US 
United States
Definitions of Terms
Electronic source 
system 
Contains data traditionally maintained in a hospital or clinic record to document medical
care or data recorded in a CRF as determined by the protocol. Data in this system may be
considered source documentation.
PRO 
Reports directl y from the participant without interpretation b y clinician or anyone else
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10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
10.3.1. 
Regulatory and Ethical Considerations
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the
protocol, current International Council for Harmonisation (ICH) guidelines on Good Clinical
Practice (GCP), and applicable regulatory and country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing,
conducting, recording, and reporting studies that involve the participation of human participants.
Compliance with this standard provides public assurance that the rights, safety, and well-being of
study participants are protected, consistent with the principles that originated in the Declaration of
Helsinki, and that the study data are credible.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by
the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by the
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or
when the relevant competent authority has raised any grounds for non-acceptance, except when
necessary to eliminate immediate hazards to the participants, in which case the amendment must
be promptly submitted to the IEC/IRB and relevant competent authority. Documentation of
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the
change(s) involve only logistic or administrative aspects of the study, the IEC/IRB (where
required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable,
the investigator or other physician in attendance will contact the appropriate sponsor representative
listed in the Protocol Supplementary Information, 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 CRF and source
documents will reflect any departure from the protocol, and the source documents will describe
this departure and the circumstances requiring it.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities
in each respective country, if applicable. A study may not be initiated until all local regulatory
requirements are met.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study intervention
to the study site:
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 
Protocol and amendment(s), if any, signed and dated by the principal investigator
 
A copy of the dated and signed (or sealed, where appropriate per local regulations), written
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if
applicable, participant compensation programs. This approval must clearly identify the
specific protocol by title and number and must be signed (or sealed, where appropriate per
local regulations) by the chairman or authorized designee.
 
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their
function, with a statement that it is organized and operates according to GCP and the
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a
member of the study site personnel is a member of the IEC/IRB, documentation must be
obtained to state that this person did not participate in the deliberations or in the vote/opinion
of the study.
 
Regulatory authority approval or notification, if applicable
 
Signed and dated statement of investigator (eg, Form FDA 1572), if applicable
 
Documentation of investigator qualifications (eg, curriculum vitae)
 
Completed investigator financial disclosure form from the principal investigator, where
required
 
Signed and dated clinical trial agreement, which includes the financial agreement
 
Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first
participant:
 
Completed investigator financial disclosure forms from all subinvestigators
 
Documentation of subinvestigator qualifications (eg, curriculum vitae)
 
Name and address of any local laboratory conducting tests for the study, and a dated copy of
current laboratory normal ranges for these tests, if applicable
 
Local laboratory documentation demonstrating competence and test reliability
(eg, accreditation/license), if applicable
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB
with current and complete copies of the following documents (as required by local regulations):
 
Final protocol and, if applicable, amendments
 
Sponsor-approved ICF (and any other written materials to be provided to the participants)
 
IB (or equivalent information) and amendments/addenda
 
Sponsor-approved participant recruiting materials
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 
Information on compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 
Investigator's curriculum vitae or equivalent information (unless not required, as documented
by the IEC/IRB)
 
Information regarding funding, name of the sponsor, institutional affiliations, other potential
conflicts of interest, and incentives for participants
 
Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol,
amendments (if any, excluding the ones that are purely administrative, with no consequences for
participants, data or study conduct, unless required locally), the ICF, applicable recruiting materials,
and participant compensation programs, and the sponsor has received a copy of this approval. This
approval letter must be dated and must clearly identify the IEC/IRB and the documents being
approved.
Approval for the collection of optional samples for research and for the corresponding ICF must
be obtained from the IEC/IRB. Approval for the protocol can be obtained independent of this
optional research component.
During the study the investigator (or sponsor where required) will send the following documents
and updates to the IEC/IRB for their review and approval, where appropriate:
 
Protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct)
 
Revision(s) to ICF and any other written materials to be provided to participants
 
If applicable, new or revised participant recruiting materials approved by the sponsor
 
Revisions to compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 
New edition(s) of the IB and amendments/addenda
 
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at
least annually)
 
Reports of AEs that are serious, unlisted/unexpected, and associated with the study
intervention
 
New information that may adversely affect the safety of the participants or the conduct of the
study
 
Deviations from or changes to the protocol to eliminate immediate hazards to the participants
 
Report of deaths of participants under the investigator's care
 
Notification if a new investigator is responsible for the study at the site
 
Development Safety Update Report and Line Listings, where applicable
 
Any other requirements of the IEC/IRB
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For all protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct), the amendment and applicable ICF revisions
must be submitted promptly to the IEC/IRB for review and approval before implementation of the
change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about
the study completion (if applicable, the notification will be submitted through the head of
investigational institution).
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
10.3.2. 
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial
information in accordance with local regulations to allow the sponsor to submit complete and
accurate financial certification or disclosure statements to the appropriate regulatory authorities.
Investigators are responsible for providing information on financial interests during the course of
the study and for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) for details on financial disclosure.
10.3.3. 
Informed Consent Process
Each participant must give written consent according to local requirements after the nature of the
study has been fully explained. The ICF(s) must be signed before performance of any study-related
activity. The ICF(s) that is/are used must be approved by both the sponsor and by the reviewing
IEC/IRB and be in a language that the participant can read and understand. The informed consent
should be in accordance with principles that originated in the Declaration of Helsinki, current ICH
and GCP guidelines, applicable regulatory requirements, and sponsor policy.
Informed consent may be obtained remotely. Refer to the Monitoring Guideline.
Before enrollment in the study, the investigator or an authorized member of the study site personnel
must explain to potential participants the aims, methods, reasonably anticipated benefits, and
potential hazards of the study, and any discomfort participation in the study may entail. Participants
will be informed that their participation is voluntary and that they may withdraw consent to
participate at any time. They will be informed that choosing not to participate will not affect the
care the participant will receive. Finally, they will be told that the investigator will maintain a
participant identification register for the purposes of long-term follow-up if needed and that their
records may be accessed by health authorities and authorized sponsor personnel without violating
the confidentiality of the participant, to the extent permitted by the applicable law(s) or regulations.
By signing the ICF the participant is authorizing such access. It also denotes that the participant
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agrees to allow his or her study physician to recontact the participant for the purpose of obtaining
consent for additional safety evaluations, if needed.
The participant will be given sufficient time to read the ICF and the opportunity to ask questions.
After this explanation and before entry into the study, consent should be appropriately recorded by
means of the participant's personally dated signature. After having obtained the consent, a copy of
the ICF must be given to the participant.
Participants who are rescreened are required to sign a new ICF.
Participants will be asked for consent to provide optional samples for research. After informed
consent for the study is appropriately obtained, the participant will be asked to sign and personally
date a separate ICF indicating agreement to participate in the optional research component. Refusal
to participate in the optional research will not result in ineligibility for the study. A copy of this
signed ICF will be given to the participant.
If the participant is unable to read or write, an impartial witness should be present for the entire
informed consent process (which includes reading and explaining all written information) and
should personally date and sign the ICF after the oral consent of the participant is obtained.
10.3.4. 
Data Protection
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality
and compliance with applicable data privacy protection laws and regulations. Appropriate
technical and organizational measures to protect the personal data against unauthorized disclosures
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place.
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity
of participants confidential.
The informed consent obtained from the participant includes explicit consent for the processing of
personal data and for the investigator/institution to allow direct access to his or her original medical
records (source data/documents) for study-related monitoring, audit, IEC/IRB review, and
regulatory inspection. This consent also addresses the transfer of the data to other entities and to
other countries.
The participant has the right to request through the investigator access to his or her personal data
and the right to request rectification of any data that are not correct or complete. Reasonable steps
will be taken to respond to such a request, taking into consideration the nature of the request, the
conditions of the study, and the applicable laws and regulations.
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Exploratory research is not conducted under standards appropriate for the return of data to
participants. In addition, the sponsor cannot make decisions as to the significance of any findings
resulting from exploratory research. Therefore, exploratory research data will not be returned to
participants or investigators, unless required by law or local regulations. Privacy and
confidentiality of data generated in the future on stored samples will be protected by the same
standards applicable to all other clinical data.
10.3.5. 
Publication Policy/Dissemination of Clinical Study Data
All information, including but not limited to information regarding guselkumab or the sponsor's
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior
clinical data, formulation information) supplied by the sponsor to the investigator and not
previously published, and any data, including pharmacogenomic or exploratory biomarker
research data, generated as a result of this study, are considered confidential and remain the sole
property of the sponsor. The investigator agrees to maintain this information in confidence and use
this information only to accomplish this study and will not use it for other purposes without the
sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the
sponsor in connection with the continued development of guselkumab, 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
pharmacogenomic or exploratory biomarker analyses performed after the clinical study report has
been issued will be reported in a separate report and will not require a revision of the clinical study
report.
Study participant identifiers will not be used in publication of results. Any work created in
connection with performance of the study and contained in the data that can benefit from copyright
protection (except any publication by the investigator as provided for below) shall be the property
of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary (multicenter)
data and information without approval from the investigator. The investigator has the right to
publish study site-specific data after the primary data are published. If an investigator wishes to
publish information from the study, a copy of the manuscript must be provided to the sponsor for
review at least 60 days before submission for publication or presentation. Expedited reviews will
be arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in
writing, the investigator will withhold such publication for up to an additional 60 days to allow for
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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 sub-study approaches, secondary results generally should not
be published before the primary endpoints of a study have been published. Similarly, investigators
will recognize the integrity of a multicenter study by not submitting for publication data derived
from the individual study site until the combined results from the completed study have been
submitted for publication, within 18 months after the study end date, or the sponsor confirms there
will be no multicenter study publication. Authorship of publications resulting from this study will
be based on the guidelines on authorship, such as those described in the ICMJE Recommendations
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which
state that the named authors must have made a significant contribution to the conception or design
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the
work or revised it critically for important intellectual content; and given final approval of the
version to be published; and agreed to be accountable for all aspects of the work in ensuring that
questions related to the accuracy or integrity of any part of the work are appropriately investigated
and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required
by law. The disclosure of the final study results will be performed after the end of study in order
to ensure the statistical analyses are relevant.
10.3.6. 
Data Quality Assurance
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified
investigators and appropriate study sites, review of protocol procedures with the investigator and
study site personnel before the study periodic monitoring visits by the sponsor, and direct
transmission of clinical laboratory data from a central laboratory into the sponsor's data base.
Written instructions will be provided for collection, handling, storage, and shipment of samples.
Guidelines for CRF completion will be provided and reviewed with study site personnel before
the start of the study.
The sponsor will review CRF for accuracy and completeness during on-site monitoring visits and
after transmission to the sponsor; any discrepancies will be resolved with the investigator or
designee, as appropriate. After upload of the data into the study database they will be verified for
accuracy and consistency with the data sources.
10.3.7. 
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each participant in electronic
format. All data relating to the study must be recorded in CRF. All CRF entries, corrections, and
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alterations must be made by the investigator or authorized study site personnel. The investigator
must verify that all data entries in the CRF are accurate and correct.
The study data will be transcribed by study site personnel from the source documents onto an
electronic CRF, 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 CRF. Any
such worksheets will become part of the participant's source documents. Data must be entered into
CRF in English. The CRF must be completed as soon as possible after a participant visit and the
forms should be available for review at the next scheduled monitoring visit.
If necessary, queries will be generated in the electronic data capture (eDC) tool. If corrections to
a CRF are needed after the initial entry into the CRF, this can be done in either of the following
ways:
 Investigator and study site personnel can make corrections in the eDC tool at their own
initiative or as a response to an auto query (generated by the eDC tool).
 Sponsor or sponsor delegate can generate a query for resolution by the investigator and study
site personnel.
10.3.8. 
Source Documents
At a minimum, source documents consistent in the type and level of detail with that commonly
recorded at the study site as a basis for standard medical care must be available for the following:
participant identification, eligibility, and study identification; study discussion and date of signed
informed consent; dates of visits; results of safety and efficacy parameters as required by the
protocol; record of all AEs and follow-up of AEs; concomitant medication; intervention
receipt/dispensing/return records; study intervention administration information; and date of study
completion and reason for early discontinuation of study intervention or withdrawal from the study,
if applicable.
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be
reviewed with the investigator before the study and will be described in the monitoring guidelines
(or other equivalent document).
The minimum source documentation requirements for Section 5.1, Inclusion Criteria and
Section 5.2, Exclusion Criteria that specify a need for documented medical history are as follows:
 Referral letter from treating physician or
 Complete history of medical notes at the site
 Discharge summaries
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Inclusion and exclusion criteria not requiring documented medical history must be verified at a
minimum by participant interview or other protocol-required assessment (eg, physical examination,
laboratory assessment) and documented in the source documents.
An eSource system may be utilized, which contains data traditionally maintained in a hospital or
clinic record to document medical care (eg, electronic source documents) as well as the clinical
study-specific data fields as determined by the protocol. This data is electronically extracted for
use by the sponsor. If eSource is utilized, references made to the eCRF in the protocol include the
eSource system but information collected through eSource may not be limited to that found in the
eCRF.
10.3.9. 
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
CRF are known to the sponsor and study site personnel and are accessible for verification by the
sponsor study site contact. If electronic records are maintained at the study site, the method of
verification must be discussed with the study site personnel.
Direct access to source 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.
10.3.10. 
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. Participant privacy must, however, be
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respected. The investigator and study site personnel are responsible for being present and available
for consultation during routinely scheduled study site audit visits conducted by the sponsor or its
designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part
of a national GCP compliance program or to review the results of this study in support of a
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
10.3.11. 
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRF and
all source documents that support the data collected from each participant, as well as all study
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical
Trial, and all study documents as specified by the applicable regulatory requirement(s). The
investigator/institution will take measures to prevent accidental or premature destruction of these
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing
application in an ICH region and until there are no pending or contemplated marketing applications
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical
development of the investigational product. These documents will be retained for a longer period
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the
responsibility of the sponsor to inform the investigator/institution as to when these documents no
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the
responsibility of keeping the study records, custody must be transferred to a person who will accept
the responsibility. The sponsor must be notified in writing of the name and address of the new
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any
documentation relating to this study, the investigator/institution must permit access to such reports.
10.3.12. 
Study and Site Start and Closure
First Act of Recruitment
The first site open is considered the first act of recruitment and it becomes the study start date.
Study/Site Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been collected
and a study site closure visit has been performed.
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The investigator may initiate study site closure at any time, provided there is reasonable cause and
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not
limited to:
 Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or
local health authorities, the sponsor's procedures, or GCP guidelines
 Inadequate recruitment of participants by the investigator
 Discontinuation of further study intervention development
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10.4. 
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality
Complaints, and Other Safety Reporting: Definitions and Procedures for
Recording, Evaluating, Follow-up, and Reporting
10.4.1. 
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a
pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have
a causal relationship with the intervention. An AE can therefore be any unfavorable and unintended
sign (including an abnormal finding), symptom, or disease temporally associated with the use of a
medicinal (investigational or non-investigational) product, whether or not related to that medicinal
(investigational or non-investigational) product. (Definition per ICH)
This includes any occurrence that is new in onset or aggravated in severity or frequency from the
baseline condition, or abnormal results of diagnostic procedures, including laboratory test
abnormalities.
Note: The sponsor collects AEs starting with the signing of the ICF (refer to All Adverse Events
under Section 8.3.1, Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information, for time of last AE recording).
Serious Adverse Event
A SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for Human
Use is any untoward medical occurrence that at any dose:
 
Results in death
 
Is life-threatening
(The participant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.)
 
Requires inpatient hospitalization or prolongation of existing hospitalization
 
Results in persistent or significant disability/incapacity
 
Is a congenital anomaly/birth defect
 
Is a suspected transmission of any infectious agent via a medicinal product
 
Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is
also appropriate in other situations, such as important medical events that may not be immediately
life-threatening or result in death or hospitalization but may jeopardize the participant or may
require intervention to prevent one of the other outcomes listed in the definition above. These
should usually be considered serious.
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If a serious and unexpected AE occurs for which there is evidence suggesting a causal relationship
between the study intervention and the event (eg, death from anaphylaxis), the event must be
reported as a serious and unexpected suspected adverse reaction even if it is a component of the
study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable product
reference safety information. For guselkumab, the expectedness of an AE will be determined by
whether or not it is listed in the IB.
10.4.2. 
Attribution Definitions
Assessment of Causality
The causal relationship to study intervention is determined by the investigator. The following
selection should be used to assess all AEs.
Related
There is a reasonable causal relationship between study intervention administration and the AE.
Not Related
There is not a reasonable causal relationship between study intervention administration and the
AE.
The term "reasonable causal relationship" means there is evidence to support a causal relationship.
10.4.3. 
Severity Criteria
An assessment of severity grade will be made using the following general categorical descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation.
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly
experienced by the participant (eg, laboratory abnormalities).
10.4.4. 
Special Reporting Situations
Safety events of interest on a sponsor study intervention in an interventional study that may require
expedited reporting or safety evaluation include, but are not limited to:
 
Overdose of a sponsor study intervention
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 
Suspected abuse/misuse of a sponsor study intervention
 
Accidental or occupational exposure to a sponsor study intervention
 
Unexpected therapeutic or clinical benefit from use of a sponsor study intervention
 
Medication error, intercepted medication error, or potential medication error involving a
Johnson & Johnson medicinal product (with or without patient exposure to the Johnson &
Johnson medicinal product, eg, product name confusion, product label confusion, intercepted
prescribing or dispensing errors)
 
Exposure to a sponsor study intervention from breastfeeding
Special reporting situations should be recorded in the CRF. Any special reporting situation that
meets the criteria of an SAE should be recorded on the SAE page of the CRF.
10.4.5. 
Procedures
All Adverse Events
All AEs, regardless of seriousness, severity, or presumed relationship to study intervention, must
be recorded using medical terminology in the source document and the CRF. Whenever possible,
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough,
runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory
infection"). Investigators must record in the CRF their opinion concerning the relationship of the
AE to study therapy. All measures required for AE management must be recorded in the source
document and reported according to sponsor instructions.
For all studies with an outpatient phase, including open-label studies, the participant must be
provided with a "wallet (study) card" and instructed to carry this card with them for the duration
of the study indicating the following:
 
Study number
 
Statement, in the local language(s), that the participant is participating in a clinical study
 
Investigator's name and 24-hour contact telephone number
 
Local sponsor's name and 24-hour contact telephone number (for medical personnel only)
 
Site number
 
Participant number
 
Any other information that is required to do an emergency breaking of the blind
Serious Adverse Events
All SAEs that have not resolved by the end of the study, or that have not resolved upon the
participant's discontinuation from the study, must be followed until any of the following occurs:
 
The event resolves
 
The event stabilizes
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 
The event returns to baseline, if a baseline value/status is available
 
The event can be attributed to agents other than the study intervention or to factors unrelated
to study conduct
 
It becomes unlikely that any additional information can be obtained (participant or health care
practitioner refusal to provide additional information, lost to follow-up after demonstration of
due diligence with follow-up efforts)
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during
participation in the study must be reported as an SAE, except hospitalizations for the following:
 
Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as pending
placement in long-term care facility)
 
Surgery or procedure planned before entry into the study (must be documented in the eCRF).
Note: Hospitalizations that were planned before the signing of the ICF, and where the
underlying condition for which the hospitalization was planned has not worsened, will not be
considered SAEs. Any AE that results in a prolongation of the originally planned
hospitalization is to be reported as a new SAE.
The cause of death of a participant in a study within 12 weeks of the last dose of study intervention,
whether or not the event is expected or associated with the study intervention, is considered an
SAE.
Information regarding SAEs will be transmitted to the sponsor using an SAE reporting form, which
must be completed and signed by a physician from the study site, and transmitted in a secure
manner to the sponsor within 24 hours. The initial and follow-up reports of an SAE should be
made by facsimile (fax). Telephone reporting should be the exception and the reporter should be
asked to complete the appropriate form(s) first.
10.4.6. 
Product Quality Complaint Handling
Definition
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, reliability, or performance of a distributed product, including its labeling, drug delivery
system, or package integrity. A PQC may have an impact on the safety and efficacy of the product.
In addition, it includes any technical complaints, defined as any complaint that indicates a potential
quality issue during manufacturing, packaging, release testing, stability monitoring, dose
preparation, storage or distribution of the product or the drug delivery system.
This definition includes any PQC related to a device constituent in a combination product,
including those used in the administration of the study intervention or the comparator. A device
deficiency is an inadequacy of a device with respect to its identity, quality, durability, reliability,
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safety, or performance. Device deficiencies include malfunctions, use errors, and inadequate
labeling.
Procedures
All initial PQCs must be reported to the sponsor by the study site personnel within 24 hours after
being made aware of the event.
A sample of the suspected product should be maintained under the correct storage conditions until
a shipment request is received from the sponsor.
10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding safety issues, PQC, or questions regarding the study are listed in the Protocol
Supplementary Information, which will be provided as a separate document.
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10.5. 
Appendix 5: Contraceptive and Barrier Guidance
Participants must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria.
Pregnancy information will be collected and reported as noted in Section 8.3.5, Pregnancy and
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and
Reporting.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless
permanently sterile (see below).
Woman Not of Childbearing Potential
 
premenarchal
A premenarchal state is one in which menarche has not yet occurred.
 
postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical
cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the
postmenopausal range may be used to confirm a postmenopausal state in women not using
hormonal contraception or hormonal replacement therapy (HRT), however in the absence of
12 months 
of 
amenorrhea, 
a 
single 
FSH 
measurement 
is 
insufficient.
If there is a question about menopausal status in women on HRT, the woman will be required
to use one of the non-estrogen-containing hormonal highly effective contraceptive methods if
she wishes to continue HRT during the study.
 
permanently sterile (for the purpose of this study)
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral
oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually
active becomes active), a woman must begin a highly effective method of contraception, as
described throughout the inclusion criteria.
Contraceptive (birth control) use by men or women should be consistent with local regulations
regarding the acceptable methods of contraception for those participating in clinical studies.
Typical use failure rates may differ from those when used consistently and correctly.
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Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
USER INDEPENDENT
Highly Effective Methods That Are User Independent Failure rate of <1% per year when used
consistently and correctly.
 Intrauterine device (IUD)
 Intrauterine hormone-releasing system (IUS)
 Bilateral tubal occlusion
 Azoospermic partner (vasectomized or due to medical cause)
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the
sole sexual partner of the woman of childbearing potential and the absence of sperm has been
confirmed. If not, additional highly effective method of contraception should be used.
Spermatogenesis cycle is approximately 74 days.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used
consistently and correctly.
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with
inhibition of ovulationb
 oral
 Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from
heterosexual intercourse during the entire period of risk associated with the study intervention. The
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the
preferred and usual lifestyle of the participant.)
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY (not
considered to be highly effective - failure rate of 1% per year)
 Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary
mode of action.
 Male condom with or without spermicide
 Periodic abstinence (calendar, symptothermal, post-ovulation methods)
 Withdrawal (coitus-interruptus)
 Lactational amenorrhea method (LAM)
a) Typical use failure rates may differ from those when used consistently and correctly.
b) Hormonal contraception may be susceptible to interaction with the study intervention, which may
reduce the efficacy of the contraceptive method. In addition, consider if the hormonal contraception
may interact with the study intervention.
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10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments
A. STOPPING ALGORITHM
Study intervention will be discontinued for a participant if liver chemistry stopping criteria are met.
Phase 2 Liver Chemistry Stopping Criteria and Increased Monitoring Algorithm
Abbreviations: ALT = alanine transaminase; AST = aspartate transaminase, INR = international normalized ratio;
SAE = serious adverse event; ULN = upper limit of normal, Tbili = Total bilirubin.
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B. FOLLOW-UP ASSESSMENTS
Phase 2 liver chemistry stopping criteria are designed to assure participant safety and to evaluate
liver event etiology.
Phase 2 Liver Chemistry Stopping Criteria and Follow-up Assessments
Liver Chemistry Stopping Criteria
ALT or AST- 
absolute
ALT or AST 5xULN
ALT or AST 
Increase
ALT or AST 3xULN persists for 4 weeks
Bilirubin1,2 
ALT or AST 3xULN and total bilirubin 2xULN (>35% direct bilirubin)
INR2 
ALT or AST 3xULN and international normalized ratio (INR) >1.5
Cannot Monitor ALT or AST3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3 
ALT or AST 3xULN associated with symptoms (new or worsening)
believed to be related to liver injury or hypersensitivity
Suggested Actions, Monitoring, and Follow-up Assessments
Actions 
Follow-up Assessments
 Immediately discontinue study intervention
 Report the event to the sponsor within
24 hours
 Complete the liver event/expedited reporting
form, and complete an SAE CRF if the
event also met the criteria for an SAE2
 Perform follow-up assessments as described
in the Follow-up Assessment column. 
 Monitor the participant until liver chemistry
test abnormalities resolve, stabilize, or
return to baseline
MONITORING:
If ALT or AST 3xULN AND total bilirubin
2xULN or INR >1.5:
 Repeat liver chemistry tests (include ALT,
aspartate transaminase [AST], alkaline
phosphatase, total bilirubin, and INR) and
perform liver event follow-up assessments
within 24 hours
 Monitor participant twice weekly until liver
chemistry test abnormalities resolve,
stabilize, or return to baseline
 A hepatology consultation is recommended
If ALT or AST3xULN AND total bilirubin
<2xULN and INR 1.5:
 Viral hepatitis serology4
 Obtain blood sample for pharmacokinetic
(PK) analysis approximately 60 minutes
after the most recent dose5
 Obtain serum creatine phosphokinase
(CPK), lactate dehydrogenase (LDH),
gamma-glutamyltransferase (GGT),
glutamate dehydrogenase (GLDH), and
serum albumin
 Fractionate bilirubin, if total bilirubin
2xULN
 Obtain complete blood count with
differential to assess eosinophilia
 Record the appearance or worsening of
clinical symptoms of liver injury, or
hypersensitivity, on the liver
event/expedited reporting form
 Record use of concomitant medications
(including acetaminophen, herbal
remedies, and other over-the-counter
medications) on the concomitant
medications CRF
 Record alcohol use on the liver event
alcohol intake form
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 Repeat liver chemistry tests (include ALT,
AST, alkaline phosphatase, total bilirubin
and INR) and perform liver chemistry
follow-up assessments within 24 to 72
hours
 Monitor participants weekly until liver
chemistry abnormalities resolve, stabilize, or
return to baseline
 Do not restart/rechallenge participant with
study intervention unless allowed per
protocol and sponsor approval is granted
If ALT or AST3xULN AND total
bilirubin 2xULN or INR >1.5 obtain the
following in addition to the assessments
listed above:
 Anti-nuclear antibody, anti-smooth
muscle antibody, Type 1 anti-liver kidney
microsomal antibodies, and quantitative
total immunoglobulin G (IgG) or gamma
globulins
 Serum acetaminophen adduct assay,
when available, to assess potential
acetaminophen contribution to liver
injury in participants with definite or
likely acetaminophen use in the
preceding week
 Liver imaging (ultrasound, magnetic
resonance, or computerized tomography)
to evaluate liver disease; complete liver
imaging form
 Liver biopsy may be considered and
discussed with local specialist if
available, for instance:
 In participants when serology raises
the possibility of autoimmune
hepatitis (AIH)
 In participants when suspected
drug-induced liver injury (DILI)
progresses or fails to resolve on
withdrawal of study intervention
 In participants with acute or chronic
atypical presentation
 If liver biopsy conducted complete liver
biopsy form
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not
immediately available, discontinue study intervention if ALT or AST 3xULN and total bilirubin 2xULN.
Additionally, if serum bilirubin fractionation testing is unavailable, record the absence/presence of detectable
urinary bilirubin on dipstick which is indicative of direct bilirubin elevations suggesting liver injury.
2. All events of ALT or AST 3xULN and total bilirubin 2xULN (>35% direct bilirubin) or ALT or AST
3xULN and INR >1.5 may indicate severe liver injury (possible ‘Hy’s Law’) and must be reported to
sponsor in an expedited manner and as an SAE if SAE criteria met (excluding studies of hepatic
impairment or cirrhosis). The INR stated threshold value will not apply to participants receiving
anticoagulants.
3. New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper
quadrant pain or tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia).
4. Includes HBsAg (HBV surface antigen), anti-HBs (HBV surface antibody), and anti-HBc total (HBV core
antibody total). For participants who are eligible with negative HBsAg, and positive core antibody (anti-HBc)
and/or surface antibody (anti-HBs), and negative HBV DNA test, HBV DNA quantitation should be monitored
at least every 3 months or shorter.
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5. PK sample may not be required for participants known to be receiving placebo or non-comparator interventions.
Record the date/time of the PK blood sample draw and the date/time of the last dose of study intervention prior
to the blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the participant’s best
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in
the Investigational Product Procedures Manual (IPPM) and Investigational Product Procedure Instructions (IPPI).
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10.8. 
Appendix 8: Study Conduct During a Natural Disaster
GUIDANCE ON STUDY CONDUCT DURING 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 participants and
study site personnel; travel restrictions/limited access to public places, including hospitals; study
site personnel being reassigned to critical tasks.
In alignment with recent health authority guidance, the sponsor is providing options for study
related participant management in the event of disruption to the conduct of the study. This guidance
does not supersede any local or government requirements or the clinical judgement of the
investigator to protect the health and well-being of participants and site staff. If, at any time, a
participant’s safety is considered to be at risk, study intervention will be discontinued, and study
follow-up will be conducted.
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each
contact, participants will be interviewed to collect safety data. Key efficacy endpoint assessments
should be performed if required and as feasible. Participants will also be questioned regarding
general health status to fulfill any physical examination requirement.
Every effort should be made to adhere to protocol-specified assessments for participants on study
intervention, including follow-up. Modifications to protocol-required assessments may be
permitted via COVID-19 Appendix after consultation with the participant, investigator, and the
sponsor. Missed assessments/visits will be captured in the clinical trial management system for
protocol deviations. Discontinuations of study interventions and withdrawal from the study should
be documented with the prefix “COVID-19-related” in the eCRF.
The sponsor will continue to monitor the conduct and progress of the clinical study, and any
changes will be communicated to the sites and to the health authorities according to local guidance.
If a participant has tested positive for COVID-19, the investigator should contact the sponsor’s
responsible medical officer to discuss plans for study intervention and follow-up. Modifications
made to the study conduct as a result of the COVID-19 pandemic should be summarized in the
clinical study report.
ADDITIONAL ELEMENTS, WHERE APPLICABLE:
 
Certain protocol-mandated visits to the study site may not be possible during the COVID-19
outbreak. Therefore, temporary measures may be implemented if considered appropriate by
the sponsor and investigator to maintain continuity of participant care and study integrity.
Certain measures, such as those listed below, may be necessary and should be instituted in
accordance with applicable (including local) laws, regulations, guidelines, and procedures:
 
remote (eg, by phone/telemedicine) or in-person, off-site (eg, in-home) interactions
between site staff (or designees) and participants for study procedures eg, those related
to safety monitoring/efficacy evaluation/study intervention storage and administration
(including training where pertinent)
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procurement of study intervention by participants (or designee) or shipment of study
intervention from the study site directly to participants for at home administration
(including the potential for self-administration of study intervention)
 
laboratory assessments using a suitably accredited local laboratory; for selected measures 
(eg, urine pregnancy), home testing may be employed
 
other procedures, eg, imaging, may be conducted at an appropriate facility
 
Missed assessments/visits will be captured in the clinical trial management system for
protocol deviations. Discontinuations of study interventions and withdrawal from the study
should be documented with the prefix “COVID-19-related” in the case report form (CRF).
 
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 Statistical Analysis Plan(s) (SAPs).
 
Exclusion: a potential participant with the following features will be excluded from
participating in the study protocol:
 
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
o 
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, eg, 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 participant is excluded due to recent COVID-19-related features, the reason for
screen failure should be documented in the case report form under the exclusion criterion
of having a condition for which participation would not be in the participant’s interest or
could confound study assessments.
2. The field of COVID-related testing (for presence of, and immunity to, the SARS-CoV-2
virus) is rapidly evolving. Additional testing may be performed as part of screening
and/or during the study if deemed necessary by the investigator and in accordance with
current regulations/guidance from authorities / 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.
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10.9. 
Appendix 9: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located directly
before the Table of Contents (TOC).
Amendment 4 (25 August 2022)
Overall Rationale for the Amendment: To clarify the analysis timepoint, and to add exploratory
endpoints.
The changes to the protocol are described in the table below. For select changes, additions to the text are
indicated by underline; deletion of text is shown in strikethrough.
Section Number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
3 OBJECTIVES AND 
END POINTS 
Endpoints for the long-term efficacy of guselkumab in 
participant with SSc was added and modified: 
• Change from baseline and Week 52 in mRSS at
Week 76 and Week 104
• The proportion of participants who experience
worsening of mRSS at Week 76 and Week 104
• The proportion of participants achieving a score of
0.6 in American College of Rheumatology Combined
Response Index in dcSSc (ACR CRISS) at Week 76
and Week 104
• Change from baseline in forced vital capacity
(FVC) and percent predicted FVC at Week 76 and
Week 104
• The proportion of participants who experience
worsening of FVC at Week 76 and Week 104
• Change from baseline in the measured absolute
diffusing capacity of the lung for carbon monoxide
(DLCO) and the derived percent predicted DLCO at
Week 76 and Week 104
• Change from baseline in Health Assessment
Questionnaire-Disability Index (HAQ-DI) score at
Week 76 and Week 104
• Change from baseline in digital ulcer counts at
Week 76 and Week 104
• Change from baseline in fibrotic change assessed
with high-resolution computed tomography (HRCT) at
Week 76 and Week 104 in participants with baseline
fibrosis/fibrotic changes
• The proportion of participants who experience
worsening of fibrotic change assessed with HRCT at
Week 76 and Week 104
• Change from baseline in Frequency Scale for the
Symptoms of Gastroesophageal reflux disease (FSSG)
score at Week 76 and Week 104
 
Endpoints for the safety and tolerability of guselkumab
in participants with SSc was modified:
• Number and proportion of participants with
treatment-emergent adverse events (AEs) and serious
adverse events (SAEs) or adverse events of special
interest (AESI) from baseline through Week 24, Week
52 and Week76 and Week 104
To add exploratory
endpoints for LTE.
1.1 Synopsis 
Endpoints for to additional efficac y of guselkumab in 
For Clarification
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Section Number 
and Name
Description of Change 
Brief Rationale
3 OBJECTIVES AND 
END POINTS 
participants with SSc was modified:
• Change from baseline in digital ulcer counts at
Week 24 and Week 52 in participants with digital
ulcers at baseline
1.3 Schedule of Activities 
(SoA) Table 1 
The following text was modified: 
Autoantibodies (including, but not limited to anti-RNA
polymerase, anti-centromere, and anti-topoisomerase)j
For clarification.
7.1 Discontinuation of 
Study intervention 
The following text was modified: 
• The participant initiates treatment with prohibited
therapies listed in Section 6.8 unless agreed upon with
the sponsor medical monitor.
For clarification.
8.8 Autoantibodies 
The following text was modified: 
Samples will be collected at screening (see Section 1.3),
to evaluate the presence of autoantibodies (including,
but not limited to anti-RNA polymerase, anti-
centromere, and anti-topoisomerase).
For clarification.
9.4.1 General 
Considerations 
The following text was added: 
The primary analysis will be performed when all 
participants have completed the Week 24 visit or 
discontinued earlier. The final analysis will be
performed when all participants have completed the last
study visit or discontinued earlier. Other analysis
timepoints are described in Section 9.4.6.
To clarify the timing of
primary analysis and
final analysis.
9.4.6 Other Analysis 
Interim Analysis 
The following text was modified:  
No interim analysis is planned. The primary analysis 
will be performed when all participants have completed 
Week 24 or discontinued earlier. Internal Decision
committee (IDC) will determine whether the LTE can
continue or not based on the primary analysis results. In
addition, selected sponsor personnel will be unblinded
at the primary analysis for internal decision-making.
Details of the unblinding will be specified in SAP.
If LTE continues, an interim analysis will be performed
when all participants have completed Week 52 or
discontinued earlier. All sponsor personnel will be
unblinded at the analyses for internal decision-making
and/or interactions with health authorities.
To clarify the analysis
timepoints during the
study.
Amendment 3 (30 September 2021)
Overall Rationale for the Amendment: To add long-term extension (LTE) and Self-administration of
study intervention.
The changes to the protocol are described in the table below. For select changes, additions to the text are
indicated by underline; deletion of text is shown in strikethrough.
Section Number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis
OBJECTIVES AND
ENDPOINTS
 
3 OBJECTIVES AND
ENDPOINTS
The following text was modified:
Secondary Endpoint:
• Number and proportion of participants with
treatment-emergent adverse events (AEs) and serious
adverse events (SAEs) or adverse events of special
interest (AESI) from baseline through Wee k 24,
LTE was added to
evaluate the long- term
safety of guselkumab in
systemic sclerosis
participants. In addition,
efficac y will be
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Section Number 
and Name
Description of Change 
Brief Rationale
Week 52 and Week 52 104. 
 
Additional Exploratory Objectives and Endpoints were
added:
Objectives:
To evaluate the long-term efficacy of guselkumab in
participant with SSc
Endpoints:
• Change from baseline in mRSS at Week 104
• The proportion of participants who experience
worsening of mRSS at Week 104
• The proportion of participants achieving a score of
0.6 in American College of Rheumatology Combined
Response Index in dcSSc (ACR CRISS) at Week 104
• Change from baseline in forced vital capacity
(FVC) and percent predicted FVC at Week 104
• Change from baseline in the measured absolute
diffusing capacity of the lung for carbon monoxide
(DLCO) and the derived percent predicted DLCO at
Week 104
evaluated for
exploratory purpose.
1.1 Synopsis 
OVERALL DESIGN 
 
4.1 Overall Design 
The following text was modified:
The main study will be conducted in 3 phases: a
maximum 6-week screening phase, a 52-week double
blind intervention phase, and a safety follow-up phase
with a post-intervention follow-up visit at 12 weeks
after the participant’s last dose of study intervention to
collect any AEs since the last study visit.
The duration of individual participation will be
approximately 66 weeks. Two planned database locks
(DBLs) will occur when all participants complete the
Week 24 visit and Week 60 visit (safety follow up).
Participants who complete the main study (Week 0
through 52: ie, after the Week 48 evaluation, prior to
Week 52 evaluation) and who, in the opinion of the
investigator, may benefit from continued treatment, will
participate in the LTE by signing the ICF before or at
Week 52. The duration of individual participation will
be approximately 66 weeks without LTE and 118
weeks with LTE.
Three planned database locks (DBLs) will occur: when
all participants complete the Week 24 visit (hereinafter
referred to as “Week 24 DBL”), EOS of the main study
(Week 52 visit for participants who entered LTE or
Week 60 visit for participants who did not enter LTE,
hereinafter referred to as “Week 52 DBL”), and EOS of
LTE (Week 112 visit, hereinafter referred to as “Final
DBL”). Of note: if the LTE is terminated as per the
IDC’s (Internal Decision Committee) recommendation
(Section 9.5), there will be 2 DBLs (Week 24 and Week
52 DBLs) only and the LTE data collected for the
participants who already entered LTE at the time of
Week 24 DBL will be analyzed at Week 52 DBL, along
with the data through Week 52 or 60 visit.
1.1 Synopsis 
INTERVENTION 
The following text was added:
Durin  g the LTE, all participants will receive
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Section Number 
and Name
Description of Change 
Brief Rationale
GROUPS AND 
DURATION 
guselkumab treatment in LTE as below depending on
the arms they were in the main study:
• Group/Arm A (guselkumab arm from the main
study): Guselkumab 200 mg SC and placebo IV at LTE
Weeks 52, 56, and 60 followed by guselkumab 200 mg
SC Q4W from LTE Week 64 until Week 100.
• Group/Arm B (placebo arm from the main study):
Placebo SC and guselkumab 400 mg IV at LTE Weeks
52, 56, and 60 followed by guselkumab 200 mg SC
Q4W from LTE Week 64 until Week 100.
 
The following text was modified:
The duration of individual participation will be
approximately 66 weeks without LTE and 118 weeks
with LTE.
1.2 Schema 
Figure 1 was modified.
Figure 2: Schematic Overview of LTE was added.
1.3 Schedule of Activities, 
Table 1 
The following text was added/modified:
-Title:
Schedule of Activities (SoA) of Screening and Double-
Blind Study Intervention (Main Study)
-Footnotes:
n. For participants who will NOT enter LTE, refer to
Week 52 in Table 1. For participants who will enter
LTE, refer to Week 52 and the subsequent visits in
Table 2.
o. Only participants who will NOT enter LTE should
perform the safety follow up visit at Week 60.
p. ICF for participation of LTE should be obtained at
the latest at Week 52.
 
ICF for participation of LTE was added at Week 48
 
Following was added in Abbreviations:
LTE= long-term extension
1.3 Schedule of Activities, 
Table 2 
Schedule of activities table (Table 2) was added for
Long-Term Extension for Eligible Participants Who
Have Completed the Main Study (LTE).
 
4.1 Overall Design 
The following text was added:
For the main study, participants will be randomly
assigned in a 1:1 ratio, based on randomization strata of
presence of ILD (yes, no), baseline mRSS (low [≥10 to
≤15] or high [≥16 to ≤22]), and baseline anti
topoisomerase I antibody status (positive, negative), to
1 of the following treatment groups:
 
The detail is provided in Section 4.1.1 Long-term
Extension. During the LTE, Self-Administration will be
allowed for participants who complete training. Refer to
Section 4.1.2 Self-Administration of Study
Intervention.
4.1.1 Long-term Extension 
New section was added:
The objective of LTE is to evaluate the long-term safety
and efficac y of guselkumab in SSc patients. The LTE
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Status: Approved,  Date:  15 November 2022
Section Number 
and Name
Description of Change 
Brief Rationale
begins with the completion of the assessments at the
Week 52, and LTE continues through LTE Week 104.
The LTE includes a safety follow-up phase with a post-
intervention follow-up visit at LTE Week 112 (12
weeks after the participant’s last dose of study
intervention).
Participants who complete the main study and who, in
the opinion of the investigator, may benefit from
continued treatment, will participate in the LTE by
signing the ICF before or at Week 52, will receive
guselkumab treatment in LTE as below depending on
the arms they were in the main study (Week 0 through
52).
• Group/Arm A (guselkumab arm from the main
study): Guselkumab 200 mg SC and placebo IV at LTE
Weeks 52, 56, and 60 followed by guselkumab 200 mg
SC Q4W from LTE Week 64 until Week 100.
• Group/Arm B (placebo arm from the main study):
Placebo SC and guselkumab 400 mg IV at LTE Weeks
52, 56, and 60 followed by guselkumab 200 mg SC
Q4W from LTE Week 64 until Week 100.
During the LTE, all protocol-allowed concomitant
medications and rescue medications may be
administered at the discretion of the investigator.
Prohibited medications listed in Section 6.1 continue to
be prohibited in the LTE.
All study evaluations to be performed during the LTE
are listed in the Section 1.3 Schedule of Activities
(SoA).
The study blind will be maintained until the Week 52
DBL and participants will continue to receive study
intervention in a blinded manner at all visits until that
time.
The Final DBL will occur when all participants
complete the LTE (EOS for LTE period).
An internal decision committee (IDC) will be
established to determine whether the LTE can continue
or not based on the data from Week 24 DBL, as a risk
mitigation if few benefits of guselkumab has been
observed (Section 9.5). The decision will be informed
to investigators by sponsor’s study site monitor, only if
LTE is terminated. Investigators must inform all
participants to take the following actions;
• Participants who have already entered LTE will
discontinue study intervention, and perform Early
termination visit and safety follow-up visit (Week 112)
as per Section 1.3.
• Participants who are still in the main study will
continue study intervention until Week 52, and follow-
up visit (Week 60) to complete the study as per Section
1.3, unless there is any safety concern.
• If the termination decision is made for safety
concern, then all participants will be discontinued from
both LTE and main study.
At selected visits durin  g the LTE, at the discretion of
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Section Number 
and Name
Description of Change 
Brief Rationale
the investigator and participant, and after appropriate
and documented training, participants will self-
administer study intervention. Details are provided in
Section 4.1.2 Self-Administration of Study
Intervention.
A diagram of the study design is provided in Section
1.2. Schema.
4.2.1 Study-specific 
Ethical Design 
Considerations 
The following text was modified:
The total blood volume to be collected (up to 413 mL
per participant through Week 52, and up to 567 mL per
participant through Week 112) is considered to be an
acceptable amount of blood to be collected over this
time period from the population in this study based
upon the standard of the blood donation rule by the
Japanese Red Cross Society.
4.4 End of Study 
Definition 
Study Completion 
Definition 
 
The following text was modified:
A participant who will not enter LTE will be considered
to have completed the main study if he or she has
completed all the assessments at Week 52 of the
double-blind phase and completed the final safety
follow-up visit (EOS).
A participant who will enter LTE will be considered to
have completed the main study if he or she has
completed all the assessments at Week 52 of the
double-blind phase, and the participant will be
considered to have completed the LTE study if he or
she has completed all the assessments at LTE Week
104 and completed the final safety follow-up visit
(LTE-EOS).
Participants who prematurely discontinue study
intervention for any reason before completion of the
double-blind phase and LTE can be considered to have
completed the study if they have completed all the
assessments at early termination visit and completed the
final safet y follow-up visit.
6.1 Study Intervention(s) 
Administered 
The following text was added:
During the LTE, participants will receive guselkumab
treatment in LTE as below depending on the arms they
were in the main study:
• Group/Arm A (guselkumab arm from the main
study) : Guselkumab 200 mg SC and placebo IV at LTE
Weeks 52, 56, and 60 followed by guselkumab 200 mg
SC Q4W from LTE Week 64 until Week 100.
• Group/Arm B (placebo arm from the main study):
Placebo SC and guselkumab 400 mg IV at LTE Weeks
52, 56, and 60 followed by guselkumab 200 mg SC
Q4W from LTE Week 64 until Week 100.
After Week 68 participants who have been
appropriately trained in the self-administration of study
intervention may self-administer study intervention. At-
home administration is allowed for selected visits. More
details are provided in Section 4.1.2 Self-
Administration of Stud y Intervention.
6.3 Measures to Minimize 
Bias: Randomization and 
The following text was modified:
Under normal circumstances, the blind should not be
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Section Number 
and Name
Description of Change 
Brief Rationale
Blinding 
Blinding 
broken until all participants have completed the study
and the Week 60 database is finalized.the Week 52
DBL. However, selected sponsor personnel will be
unblinded for analysis after the Week 24 DBL has
occurred. All site personnel and participants will remain
blinded to the treatment assignments until the last
participant completes Week 60 evaluations and the
database has been locked.Week 52 DBL. An unblinding
plan will be developed and finalized prior to any
unblinding to designate sponsor personnel who will
have access to the unblinded data during the period
from the Week 24 DBL to the Week 6052 DBL.
An internal decision committee (IDC) will be
established to determine whether the LTE can continue
or not with the data from Week 24 DBL and the IDC
member will be unblinded to all Week 24 data to
facilitate the decision makin  g (Section 9.5).
6.6 Continued Access to 
Study Intervention After 
the End of the Study 
The following text was modified:
This protocol is designed to provide participants with
up to approximately 52104 weeks of treatment,
including LTE.
 
8 STUDY 
ASSESSMENTS AND 
PROCEDURES 
Overview 
The following text was modified:
For each participant, the maximum amount of blood
drawn from each participant in this study will not
exceed 413 567 mL through Week 112.
 
Table 3: Volume of Blood to be Collected from Each
Participant was updated as per Table 1 and 2.
8.2.2 Vital Signs 
The following text was modified:
Through Week 52 112, vital signs (including
temperature, pulse/heart rate, respiratory rate, and blood
pressure) will be obtained before and approximately
every 30 minutes during every IV infusion, and for 1
hour at approximately 30-minute intervals after
completion of the final IV infusion.
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Status: Approved,  Date:  15 November 2022
Section Number 
and Name
Description of Change 
Brief Rationale
9.5 Internal Decision 
Committee 
New section was added: 
An Internal Decision Committee (IDC), composed of 
sponsor management representatives from Clinical 
Science TA, Clinical Science Physician, Safety 
Physician and Biostatistics who are not associated with 
study conduct, will be responsible for deciding whether 
to continue the LTE until its planned end based on the
overall benefit-risk profile as obtained at the Week 24
DBL. The IDC will have access to all unblinded safety
and efficacy summary tables/figures and listings
produced for Week 24 DBL. Only if it is judged by IDC
that the benefit of continuing guselkumab until the end
of LTE outweighs its risk, the LTE will continue until
LTE Week 112 as planned (Section 4.1.1). Otherwise,
the LTE will be terminated and the decision will be
communicated to investigators immediately.
The membership of this IDC, the analyses to be
performed at Week 24 DBL, the prespecified decision
criteria, and the decision communication flow chart will
be provided in SAP in greater details.
To determine Go or No-
Go of LTE.  The No-Go
criteria will be
prespecified in the SAP,
ahead of the Week 24
DBL.
4.1.2 Self-Administration 
of Study Intervention 
New section was added: 
From the LTE, all participants who are willing to 
perform self-study intervention administration can 
receive training on how to self-administer study 
intervention at the investigative site. Three times 
trainings are required, and participants can start the 
training at any time after Week 56. 
At-home administration can begin from the selected
visit according to regional/local regulations and
instruction at the discretion of the investigator and
participant, and upon completion of training.
Participants who are eligible for self-intervention
administration will be supplied with study intervention
for at-home administration at Week 80 and will have
the first at-home administration at Week 84. At-home
administration can only be performed for the following
visits (if applicable): LTE Weeks 84, 92, and 100.
Participants will record all at-home study intervention
administrations on a diary card. Participants will also be
instructed to contact the investigator promptly in the
event of any signs of an allergic reaction, infection, or
bleeding. Finally, participants will continue to have
study visits and assessments at the investigative sites
through LTE, as outlined in Section 1.3.
Participants who are unable or unwilling to have
injections administered away from the site will be
required to return to the site for administration of study
intervention.
Self-administration
(including at home
administration) was
added as an option in
LTE to obtain the data
of self-administration
with guselkumab.
6.2 Preparation/ 
Handling/Storage/ 
Accountability 
Preparation/Handling/Stor 
age 
The following text was added:
Study personnel will instruct participants on how to
transport, store, and administer study intervention for
at-home use during the LTE as indicated for this
protocol.
6.2 Preparation/ 
Handling/Storage/ 
The following text was added:
Participants who will be self-administerin  g study
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Status: Approved,  Date:  15 November 2022
Section Number 
and Name
Description of Change 
Brief Rationale
Accountability 
Accountability 
 
intervention at home will receive detailed instructions
for study intervention storage and disposal of used
syringes and handling of unused study material. These
participants will receive a sharps container to dispose of
used syringed and will be instructed to return the sharps
container and/or unused cartons with syringes.
Participants who self-administer at home will record
study intervention administrations with time and date
information on a diar y card.
8 STUDY 
ASSESSMENTS AND 
PROCEDURES 
Study-specific Materials 
The following supplies were added:
• Instruction for use of prefilled syringe for site staff
• Instruction for use of prefilled syringe for subjects
• Subject diary for at home administration / self-
administration
1.1 Synopsis 
OBJECTIVES AND 
ENDPOINTS 
 
3 OBJECTIVES AND
ENDPOINTS 
The following text were modified: 
Secondary Objectives:
To evaluate the additional efficacy of guselkumab in
participants with SSc
 
Exploratory Objectives:
To evaluate the other efficacy of guselkumab in
participants with SSc
To evaluate the effect of guselkumab vs placebo on the
pharmacodynamic (PD) and SSc disease biomarkers
gain insights into SSc disease biology and the role of
the IL 23 pathway in SSc
Exploratory Endpoints:
• Change from Bbaseline levels of and treatment
changes in levels of skin (optional) and blood cellular
and molecular circulating (blood cellular based)
biomarkers over time to enable:
For clarification.
1.1 Synopsis 
IMMUNOGENICITY 
EVALUATIONS 
The following text was added: 
Autoantibodies
Samples will be collected at screening to evaluate the
presence of autoantibodies (including, but not limited to
anti-ribonucleic acid [RNA] polymerase, anti-
centromere, and anti-topoisomerase).
For clarification.
1.3 Schedule of Activities, 
Table 1 
The following footnotes were modified: 
h. Screening should occur within 6 weeks prior to W0
visit. The study visit week are indicated and calculated
based on the day of randomization/first administration
of the study intervention (W0 visit). Visit window
should be ±7 days for each visit. (Visit window for W0
visit should be -7 days).
i. Pulmonary function tests include forced vital
capacity (FVC) and diffusing capacity of the lung for
carbon monoxide (DLCO). If decline in FVC%
predicted FVC ≥ 15 % (relative) is seen, another FVC
test needs to be performed within a month.
For clarification.
5.2 Exclusion Criteria 
The following text was modified: 
Prior/Concomitant Therapy 22: 
• Has received therapy within 12 weeks, or 5 half- 
lives (whichever is longer): 
Systemic and topical Janus kinase inhibitor (eg,
tofacitinib, upadacitinib)
For clarification to be
consistent with inclusion
criteria and prohibited
medications.
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Status: Approved,  Date:  15 November 2022
Section Number 
and Name
Description of Change 
Brief Rationale
 
Prior/Concomitant Therapy 23:
• Within 6 weeks of first study intervention:
Systemic immunosuppressive agents (including but not
limited to cyclosporine A, azathioprine, tacrolimus,
sirolimus, sulfasalazine, leflunomide with
cholestyramine washout or mycophenolate
mofetil/mycophenolic acid)
6.8 Concomitant Therapy 
Prohibited and restricted 
therapies 
The following text was modified: 
• Systemic immunosuppressive agents (including but 
not limited to cyclosporine A, azathioprine, 
tacrolimus, sirolimus, methotrexate, sulfasalazine,
leflunomide with cholestyramine washout or
mycophenolate mofetil/mycophenolic acid)
• Systemic and topical Janus kinase inhibitors (eg,
tofacitinib, upadacitinib)
For clarification to be
consistent with inclusion
and exclusion criteria.
8.1.2 American College of 
Rheumatology Combined 
Response Index in Diffuse 
Cutaneous Systemic 
Sclerosis Score 
The following text was modified: 
For the remaining participants, calculate the probability
based on change in 5 measures: mRSS, % of predicted
FVC %,, HAQ-DI, patient’s global assessment, and
physician’s global assessment, where each measure has
a probability score between 0 and 1 (Khanna 2016b).
ACR CRISS sore will be calculated b y the sponsor.
For clarification.
8.1.5 Patient-reported 
Outcomes 
Health Assessment 
Questionnaire -Disability 
Index 
The following text was modified: 
The Stanford HAQ translated into Japanese (original 
HAQ) and a Japanese version of the HAQ (J HAQ)
with culturally appropriate modifications of the arising,
eating, and reach category questions will be used in the
study. The J HAQ includes 20 original and 3 modified
questions. The HAQ disability index (HAQ DI) score
will be calculated in 2 ways. First, the 20 original
questions are used to calculate the original HAQ score.
Then the 17 original and 3 modified questions are used
to calculate a J HAQ score (Matsuda 2003).
Corrected factually
inaccurate description
 
8.6 Biomarkers 
The following text was added: 
Data collected from these samples will be used for
exploratory research that will include, but are not
limited to, the following objectives:
• To understand the molecular effects of guselkumab.
• To understand SSc pathogenesis.
• To understand why individual participants may
respond differently to guselkumab.
• To understand the impact of treatment with
guselkumab on skin or systemic inflammation.
• To develop diagnostic tests to identify SSc or SSc
populations that may be responsive or nonresponsive to
treatment with guselkumab.
For clarification.
Amendment 2 (20 May 2021)
Overall Rationale for the Amendment: To modify assessments on Schedule of Activities.
The changes to the protocol are described in the table below. The deletion of text is shown in strikethrough.
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CNTO1959  (guselkumab)  
Clinical Protocol CNTO1959SSC2001 Amendment 5
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
114
Status: Approved,  Date:  15 November 2022
Section Number 
and Name
Description of Change 
Brief Rationale
1.3 Schedule of 
Activities, Table 1 
Of the following timing of efficacy assessments, 
Weeks 8, 16, 32 and 40 were deleted, and Week 12 
and 36 were added. 
• Physician’s global assessment 
• Patient’s global assessment 
• HAQ-DI 
• FSSG
Changed in line with the timing of
ACR CRISS at Week 12 because
these assessments are required for
ACR CRISS. Subsequently, the
assessment interval was set to
every 12 weeks.
1.3 Schedule of 
Activities, Table 1 
Timing of mRSS assessment was changed to every 
4 weeks. 
Increased the frequency of primary
endpoint assessment.
1.3 Schedule of 
Activities, Table 1 
The following safety assessments were added to the 
Early Termination Visit (ET).
•Weight
•12-lead ECG
Absent by mistake.
1.3 Schedule of 
Activities, Table 1 
Separate blood sample collection for 
Pharmacogenomics into Blood sample collection
for DNA (EDTA tube) and Blood sample
collection for RNA (PAXgene tube) according to
the collection timing.
And following footnote was modified.
d. 
The pharmacogenomic sample should be
collected at the specified time points (EDTA
tube sample for DNA at Week 0 and Paxgene
tube samples for RNA at Week 0, 4, and 24),
but it may be collected at a later time point
without constitutin  g a protocol deviation.
For clarification.
Amendment 1 (25 March 2021)
Overall Rationale for the Amendment: To add rescue therapy and modify endpoints.
The changes to the protocol are described in the table below. For select changes, additions to the text are
indicated by underline; deletion of text is shown in strikethrough.
Section Number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis, 
SAFETY 
EVALUATIONS  
The following text was deleted: 
Safety evaluations conducted at each study visit
will include the assessment of AEs (at the visit and
those occurring between evaluation visits), ILD
monitoring (assessed by centrally read HRCT), TB
evaluation and other infection assessments, clinical
laboratory blood tests (hematology and serum
chemistry including C-reactive protein), pregnancy
testing, suicidal ideation and behavior risk
monitoring, physical examinations, ECG
measurements, vital signs (as defined in the
Schedule of Activities), concomitant medication
review, and observations for injection-site
reactions, hypersensitivity reactions, and AEs
temporall y associated with an infusion.
Added by mistake
1.1 Synopsis, 
OBJECTIVES AND 
ENDPOINTS,  
3 Objectives and 
Endpoints 
The following text was modified: 
Secondary Endpoint:  
• Change from baseline in forced vital capacity 
(FVC) and percent predicted FVCforced vital
capacity (FVC) at Week 24 and Week 52 
• Change from baseline in the measured absolute 
Major secondary endpoint and
exploratory endpoint were
modified.
 
Endpoint of DLCO was moved to
secondar y endpoint from
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Section Number 
and Name
Description of Change 
Brief Rationale
diffusing capacity of the lung for carbon monoxide 
(DLCO) and the derived percent predicted DLCO 
at Week 24 and Week 52 
Exploratory Endpoint:
• The proportion of participants who experience
worsening of percent predicted  FVC at Week 24
and Week 52
 
The following text was deleted:
Exploratory Endpoint:
• Change from baseline in the measured absolute
diffusing capacity of the lung for carbon monoxide
(DLCO) and the derived percent predicted DLCO
at Week 24 and Week 52
exploratory endpoint to evaluate
pulmonary test as secondary (FVC
and DLCO).
1.1 Synopsis,
OVERALL
DESIGN
4.1 Overall Design
The following text was added:
Two planned database locks (DBLs) will occur
when all participants complete the Week 24 visit
and Week 60 visit (safet y follow-up).
DBL timepoints were added for
clarification.
1.1 Synopsis,
OVERALL
DESIGN,
4.1 Overall Design,
8.1 Efficacy
Assessments,
8.1.3 Pulmonary
Function Tests
The following text was modified:
DLCO unit was changed from mmol/min/kPa to
ml/min/mm Hg.
 
DLCO (ml/min/mm Hg)
DLCO unit was changed for
clarification.
1.3 Schedule of
Activities, Table 1
ACR CRISS timepoints were added at screening,
week 12, 24, 52, and earl y termination visits.
Clarification on when and how
ACR CRISS score will be
calculated was updated.
8.1.2 American
College of
Rheumatology
Combined Response
Index in Diffuse
Cutaneous Systemic
Sclerosis Score
The following text was modified:
Application of ACR CRISS algorithm in a
randomized clinical trial is a 2-step process. Firstly,
evaluate if participants have met the criterion for
not-improved. If yes, these participants are
assigned a probability score of 0.0.
Investigators will evaluate if the participants have
met the criterion:
• New scleroderma renal crisis
• Decline in FVC % predicted ≥15% (relative),
confirmed by another FVC test within a month,
HRCT to confirm ILD (if previous HRCT of chest
did not show ILD) and FVC <80% of predicted*
• New onset of left ventricular failure (defined as
left ventricular ejection fraction ≤45%) requiring
treatment*
• New onset of PAH on right-sided heart
catheterization requiring treatment*
* Attributable to systemic sclerosis
 
For the remaining participants, calculate the
probability based on change in 5 measures: mRSS,
FVC %, HAQ-DI, patient’s global assessment, and
physician’s global assessment, where each measure
has a probability score between 0 and 1 (Khanna
2016b). ACR CRISS sore will be calculated b y the
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Section Number 
and Name
Description of Change 
Brief Rationale
sponsor.
1.3 Schedule of 
Activities, Table 1 
Pulmonary function test was deleted from Week 36 
and added for early termination visit. 
 
Weight was added at Week 12, 24 and 52.
Data timepoints were
added/deleted to appropriate
timing.
 
8.2.1 Physical 
Examinations  
The following text was modified:
Height and weight of the participants will be
measured at specified visits screening.
5.1 Inclusion 
Criteria 12 
The following text was modified: 
f. Aspartate aminotransferase (AST) ≤3 2 × ULN 
g. Alanine aminotransferase (ALT) ≤3 2 × ULN 
 
*For ALT/AST values >2 upper limit of normal
(ULN) participants can only be included if bilirubin
is normal.
Inclusion criteria was updated to
include appropriate population of
participants, and to be consistent
with the other Guselkumab trials.
5.4 Screen Failures 
The following text was added: 
Rescreening 
Individuals who do not meet the criteria for
participation in this study (screen failure) may be
rescreened 1 time.
Rescreening criteria was added for
clarification.
6.3 Measures to 
Minimize Bias: 
Randomization and 
Blinding  
The following text was modified:  
Under normal circumstances, the blind should not 
be broken until all participants have completed the 
study and the Week 60 database is finalized.
However, selected sponsor personnel will be
unblinded for analysis after the Week 24 DBL has
occurred. All site personnel and participants will
remain blinded to the treatment assignments until
the last participant completes Week 60 evaluations
and the database has been locked. An unblinding
plan will be developed and finalized prior to any
unblinding to designate sponsor personnel who will
have access to the unblinded data during the period
from the Week 24 DBL to the Week 60 DBL.
Text for unblind/blind status for
analysis after Week 24 DBL was
added for clarification.
6.8 Concomitant 
Therapy  
The following text was added:  
Rescue Medication 
In the event that a participant experiences 
worsening criteria (Criteria: increase from baseline
≥5 in mRSS), investigators will have the option to
treat with protocol-allowed rescue therapy after
Week 24.
 
- 
Oral Corticosteroid ≤20 mg/day of
prednisolone or equivalent
- 
Immunomodulator (Azathioprine), within the
approved dose for SSc
 
If rescue therapy as stipulated above fails to control
SSc symptoms sufficiently, the investigator should
consider discontinuin  g the patient from the study.
Rescue therapy was added for
participants who may need it
medically.
7.1 Discontinuation 
of Study 
Intervention 
The following text was modified: 
 The investigator or sponsor believes that there 
are no further benefit of continuing the study 
for the participants.
Discontinuation of study
intervention was updated for
clarification.
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Section Number 
and Name
Description of Change 
Brief Rationale
 The participant has severe liver test
abnormalities that are not transient and are not
explained by other etiologies. Such
abnormalities would include (see Section
10.6, Appendix 6: Liver Safety: Suggested
Actions and Follow-up Assessments):
- Alanine aminotransferase (ALT) or
aspartate aminotransferase (AST) ≥5 ×
ULN.
- ALT or AST ≥3 × ULN for more than 4
weeks.
- ALT or AST ≥3 × ULN and cannot be
monitored weekly for 4 weeks.
- ALT or AST ≥3 × ULN and TBL ≥2 × ULN
or international normalized ratio [INR]
>1.5(INR not acceptable for participants
on anticoagulants).ALT or AST > ≥3×
ULN and symptoms (new or worsening)
believed to be related to liver injury
(such as fatigue, nausea, vomiting, right
upper quadrant pain or tenderness, or
jaundice) or hypersensitivity (such as
fever, rash or eosinophilia).
8 Study Assessments
and Procedures 
The following text was modified:
Following study specific materials were updated: 
• Participant recruitment materials (if needed)
• CT image acquisition procedure manual and CT
technologist instruction form Imaging manual
• Capillaroscopy manual and quick reference
guide
• Pulmonar y function test manual
Study Specific Manuals were
updated.
8.1.3 Pulmonary
Function Tests
The following text was added: 
Also, oxygen saturation data will be collected.
Collection of oxygen saturation
was added for clarification
8.1.4 Physician
Global Assessment 
The following text was modified:
PhGA rated subject’s overall health related to SSc
condition will be assessed in the past 7 days, using
a 10 cm visual analogue scale where 0 = excellent
and 10 = extremel y poor.
Updated to match the evaluation.
8.1.6 Digital Ulcer
Assessments 
The following text was modified:
Ulcer counts and ulcer burden would be calculated
b y the sponsor.
For Clarification.
8.1.7 Nailfold
Capillaroscopy 
The following text was modified:
The typical changes of the nailfold capillaries
during SSc include the total number of capillaries,
capillary dimension, capillary morphology,
hemorrhages, blood flow velocity in capillaries,
and length of nailfold. These changes would be
calculated. Visual media will be taken. (Smith
2020; Smith 2010; Smith 2012).  For details, refer
to the manual. presence of enlarged or giant
capillaries, hemorrhages, loss of capillaries,
disorganization of the microvascular array, and
capillary ramifications. Reliability of semi
qualitative rating of nailfold capillaroscopy has
been investigated in a previous stud y and the scores
Updated to match the evaluation.
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Section Number 
and Name
Description of Change 
Brief Rationale
have value in predicting the occurrence of organ
involvement and mortality in SSc (Smith 2020;
Smith 2010; Smith 2012).
8.1.8 High- 
resolution Computed 
Tomography 
(HRCT) Assessment 
The following text was modified: 
Texture-based analysis and computer vision-based
approaches can be applied to imaging data, and
used to evaluate the extent of lung fibrosis in chest
CT images (Weatherley 2019). This assessment
should be done at central. For details on HRCT,
refer to CT technologist instruction form.
Quantitative lung fibrosis (QLF) scoring is an
objective quantitative tool to evaluate the extent of
lung fibrosis in chest CT images (Kim 2010). It has
shown consistent treatment efficacy results with
other outcome measures in clinical trial of SSc
related ILD (Kim 2011).
Updated to match the evaluation.
8.3.1 Time Period 
and Frequency for 
Collecting Adverse 
Event and Serious 
Adverse Event 
Information 
The text below was added: 
Possible Hy’s law case (AST or ALT ≥ 3 x ULN 
together with total bilirubin ≥ 2 x ULN or INR > 
1.5) is considered an important medical event and
must be reported to the sponsor in an expedited
manner using the Serious Adverse Event Form,
even before all other possible causes of liver injury
have been excluded.  (INR criterion is not
applicable to participants receivin  g anticoagulants.)
Added in order to obtain
information on possible Hy’s law
case.
8.7 Immunogenicity 
Assessments  
The following text was deleted: 
Serum samples will be used to evaluate the
immunogenicity of anti guselkumab antibodies.
Samples collected for immunogenicity analyses
may additionally be used to evaluate safety or
efficacy aspects that address concerns arising
durin  g or after the stud y period.
Deleted duplicated sentence.
10.5 Appendix 5: 
Contraceptive and 
Barrier Guidance, 
Examples of 
Contraceptives
The following were deleted: 
 Diaphragm 
 A combination of male condom with diaphragm 
(double barrier method)
Deleted as diaphragm is not
approved for contraception.in
Japan.
1.1 Synopsis, 
STATISTICAL 
METHODS, Sample 
Size Determination 
The following text was modified: 
A 95% confidence interval (CI) of [−4.7, −1.7] in
mRSS change from baseline to 6 months is
considered a clinically meaningful change. The
lower bound of this 95% CI, -4.7, has been taken as
the expected effect size treatment difference in the
sample size calculation of this study, assuming
guselkumab can achieve a clinically meaningful
change in most of guselkumab-treated participants
For Clarification.
 
1.1 Synopsis, 
STATISTICAL 
METHODS, 
Efficac y Analysis
The following text was modified:
The p-values for the LS mean differences along
with the 2-sided 80% CI 95%Cis will be presented.
1.1 Synopsis, 
STATISTICAL 
METHODS, 
Biomarkers 
Analyses
The following text was modified:
If feasible, a non-lesional (unaffected) skin sample
will be collected at Week 0; lesional (at Week 0)
samples to be collected at both Weeks 0 and 24.
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Section Number 
and Name
Description of Change 
Brief Rationale
 
1.1 Synopsis, 
Hypothesis, 
3 Objectives and 
Endpoints, 
HYPOTHESIS 
9 Statistical  
Considerations, 9.1
Statistical
Hypotheses
The following text was modified:
Due to the PoC nature of this study, a 2-sided alpha
of 0.2 is allocated for testing this PoC hypothesis.
The PoC objective will be considered met if the
calculated p-value for testing this PoC hypothesis is
less than or equal to 0.2.
 
 
1.3 Schedule of 
Activities, Table 1 
The following was added and modified as footnote:
c. 
All PRO assessments should be conducted
before other assessments in the order listed
in the above SoA table.
d. 
The pharmacogenomic (DNA) sample
should be collected at the specified time
points (EDTA tube sample for DNA at
Week 0 and Paxgene tube samples for RNA
at Week 0, 4, and 24), but it may be
collected at a later time point without
constituting a protocol deviation.
i. 
Pulmonary function tests include forced
vital capacity (FVC) and diffusing capacity
of the lung for carbon monoxide (DLCO). If
decline in FVC% predicted ≥15% (relative)
is seen, another FVC test needs to be
performed within a month.
k. Participants with potential active
tuberculosis need to pause the study
intervention administration until the
tuberculosis assessment is completed.
l. 
For participants with stent, HRCT cannot be
centrally read.
m. For screening, information on ACR CRISS
step 1 will be collected as SSc Condition of
Interest.
4.1 Overall Design 
8.6 Biomarkers 
The following text was modified:
An optional biomarker sub-study will obtain a
biopsy sample of non-lesional (unaffected) skin
sample at Week 0, and lesional (at Week 0) skin at
Week 0 and 24 from all participants who consent.
5.1 Inclusion 
Criteria 18 
The following text was modified:
Male participants must agree to the following
during the intervention period study and for at least
12 weeks after the last dose of stud y intervention:
8 Study Assessments 
and Procedures, 
Table 2 
The following text was modified:
b. A blood sample will be collected only from
participants who have consented to provide an
optional DNA and RNA samples for research.
8.2.5 Interstitial 
Lung Disease 
Monitoring  
The following text was modified:
The presence of ILD must be evaluated at
screening using chest x-ray,/lung HRCT (centrally
read), and/or PFTs (FVC and DLCO). All
participants must be monitored with lung HRCT
(centrall y read), and/or PFTs (FVC and DLCO) as
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Section Number 
and Name
Description of Change 
Brief Rationale
scheduled in Section 1.3 durin  g the study.
8.4.3 
Pharmacokinetic 
Parameters and 
Evaluations 
The following text was modified:
Based on the individual serum plasma
concentration-time data, using the actual dose taken
and the actual sampling times, PK parameters and
exposure information of guselkumab may be
derived using population PK modeling.
 
The following was added for
pharmacokinetic/pharmacodynamic evaluations:
Details will be given in a population PK/PD
analysis plan if explored.
9 Statistical 
Considerations, 9.2 
Sample Size 
Determination 
The following text was modified:
The lower bound of this 95% CI, -4.7, has been
taken as the expected effect size treatment
difference in the sample size calculation of this
study, assuming guselkumab can achieve a
clinically meaningful change in most of
guselkumab-treated participants.
 
9 Statistical  
Considerations, 9.4.2 
Primary Endpoint 
The following text was modified:
The p-values for the LS mean differences along
with the 2-sided 95% Cis 80% CI will be
presented.
 
9.4.6 Other 
Analyses, 
Biomarkers 
Analyses 
The following text was modified:
Characterization of gene expression changes in the
skin during treatment would be analyzed as
determined by RNA-seq at Weeks 0 and 24. If
feasible, a non-lesional (unaffected) skin sample
will be collected at Week 0; lesional (at Week 0)
samples to be collected at both Weeks 0 and 24
11 References  
References were added and removed as necessary. 
The updating of the protocol text
resulted in the addition and
deletion of references.
Throughout the 
protocol 
Minor grammatical, formatting, and/or spelling 
changes were made.
Minor errors were noted.
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11. 
REFERENCES
Brodalumab (A Phase 3 Study of KHK4827 in Patients With Systemic Sclerosis, ClinicalTrials.gov Identifier:
NCT03957681). Available at: https://clinicaltrials.gov/ct2/show/NCT03957681
Brodalumab (A Study of KHK4827 in Patients With Systemic Sclerosis, ClinicalTrials.gov Identifier:
NCT04368403). Available at: https://clinicaltrials.gov/ct2/show/NCT04368403
Chifflot H (2008), Fautrel B, Sordet C, Chatelus E, Sibilia J. Incidence and prevalence of systemic sclerosis: a
systematic literature review. Semin Arthritis Rheum. 2008;37(4):223-235.
Ch'ng, SS (2013), Roddy J, Keen HI. A systematic review of ultrasonography as an outcome measure of skin
involvement in systemic sclerosis Int J Rheum Dis. 2013;16:264-272.
Food and Drug Administration. Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical
Evaluation. July 2009 Drug Safety. https://www.fda.gov/media/116737/download. Accessed 10 December 2019.
Ho KT (2003), Reveille JD. The clinical relevance of autoantibodies in scleroderma. Arthritis Res Ther. 2003;5:80-
93.
Ichihara A (2017), Jinnin M, Ihn H. Treatment of psoriasis with ustekinumab improved skin tightening in systemic
sclerosis. Clin Exp Rheumatol. 2017;35 Suppl 106(4):208-210.
Investigator's Brochure: CNTO1959 (guselkumab) Edition 11. Janssen &Janssen (28 August 2020).
Khanna D (2020), Allanore Y, Denton CP, et al. Riociguat in patients with early diffuse cutaneous systemic
sclerosis (RISE-SSc): randomised, double-blind, placebo-controlled multicentre trial. Ann Rheum Dis.
2020;79(5):618-625.
Khanna D (2016), Berrocal VJ, Giannini EH, et al. The American College of Rheumatology Provisional Composite
Response Index for Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis. Arthritis Rheumatol.
2016b;68(2):299-311.
Khanna D (2016), Denton CP, Jahreis A, et al. Safety and efficacy of subcutaneous tocilizumab in adults with
systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial [published correction appears in Lancet. 2018
Apr 7;391(10128):1356]. Lancet. 2016a;387(10038):2630-2640.
Khanna D (2006), Furst DE, Hays RD, et al. Minimally important difference in diffuse systemic sclerosis: results
from the D-penicillamine study. Ann Rheum Dis. 2006;65(10):1325-1329.
Khanna D (2007), Merkel PA. Outcome measures in systemic sclerosis: an update on instruments and current
research. Curr Rheumatol Rep. 2007;9(2):151-157.
Komura K (2008), Fujimoto M, Hasegawa M, et al. Increased serum interleukin 23 in patients with systemic
sclerosis. J Rheumatol. 2008;35(1):120-125.
Kurasawa K(2000), Hirose K, Sano H, et al. Increased interleukin-17 production in patients with systemic sclerosis.
Arthritis Rheum. 2000;43(11):2455-2463.
Li H (2018), Furst DE, Jin H, et al. High-frequency ultrasound of the skin in systemic sclerosis: an exploratory study
to examine correlation with disease activity and to define the minimally detectable difference. Arthritis Research &
Therapy. 2018;20:181.
Matsuda Y (2003), Singh G, Yamanaka H, et al. Validation of a Japanese Version of the Stanford Health
Assessment Questionnaire in 3,763 Patients With Rheumatoid Arthritis. Arthritis Rheum. 2003;49(6):784–788.
Mundt (2013), JC, Greist, JH, Jefferson, JW, et al. Prediction of suicidal behavior in clinical research by lifetime
suicidal ideation and behavior ascertained by the electronic Columbia-Suicide Severity Rating Scale. J Clin Psych.
2013; 74(9):887-893.
Nihtyanova SI (2010), Tang EC, Coghlan JG, Wells AU, Black CM, Denton CP. Improved survival in systemic
sclerosis is associated with better ascertainment of internal organ disease: a retrospective cohort study. QJM.
2010;103(2):109-115.
Posner (2011), K, Brown, GK, Stanley, B, et al. The Columbia-Suicide Severity Rating Scale: Initial validity and
internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry.
2011;168(12):1266-1277.
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Status: Approved,  Date:  15 November 2022
Rodriguez-Bolanos F (2019), Gooderham M, Papp K. A Closer Look at the Data Regarding Suicidal Ideation and
Behavior in Psoriasis Patients: The Case of Brodalumab. Skin Therapy Lett. 2019;24(4):1-4.
Rolla G (2016), Fusaro E, Nicola S, et al. Th-17 cytokines and interstitial lung involvement in systemic sclerosis. J
Breath Res. 2016;10(4):046013.
Smith V (2020), Vanhaecke A, Guerra MG, et al. May capillaroscopy be a candidate tool in future algorithms for
SSC-ILD: Are we looking for the holy grail? A systematic review. Autoimmun Rev. 2020 Sep;19(9):102619.
Smith V (2012), Decuman S, Sulli A, et al. Do worsening scleroderma capillaroscopic patterns predict future severe
organ involvement a pilot study. Ann Rheum Dis. 2012;71(10):1636–1639.
Smith V (2010), Pizzorni C, De Keyser F, et al. Reliability of the qualitative and semiquantitative nailfold
videocapillaroscopy assessment in a systemic sclerosis cohort: a two-centre study. Ann Rheum Dis.
2010;69(6):1092-1096.
Weatherley ND (2019), Eaden JA, Stewart NJ, et al Experimental and quantitative imaging techniques in interstitial
lung disease. Thorax. 2019 Jun;74(6):611-619.
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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
 
Date:
  
 
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
 
Date:
  
 
(Day Month Year)
 
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Janssen Pharmaceutical K.K.
Signature: 
electronic signature appended at the end of the protocol 
Date:
  
 
(Day Month Year)
 
Note: If the address or telephone number of the investigator changes during the course of the study, written
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD
NCT04683029


Signature
User 
Date 
Reason
15-Nov-2022
03:12:59
(GMT)
Document Approval
PPD
NCT04683029

SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
1 
Status: Approved,  Date: 7 June 2023 
Janssen Pharmaceutical K.K. 
Statistical Analysis Plan  
A Multicenter, Randomized, Placebo-controlled, Double-blind, Proof-of-concept Study of 
Guselkumab in Participants with Systemic Sclerosis 
Protocol CNTO1959SSC2001; Phase 2a 
 CNTO1959  (Guselkumab) 
*This study is being conducted by Janssen Pharmaceutical K.K. in Japan. The term “sponsor” is used
throughout the protocol to represent Janssen Pharmaceutical K.K.
Status: 
Approved  
Date: 
7 June 2023 
Prepared by: 
Janssen Pharmaceutical K.K.   
Document No.: EDMS-RIM-330901 
Compliance:  The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement 
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient 
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise. 
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Statistical Analysis Plan CNTO1959SSC2001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
2 
Status: Approved,  Date: 7 June 2023 
TABLE OF CONTENTS 
TABLE OF CONTENTS .......................................................................................................................... 2 
1. 
INTRODUCTION ............................................................................................................................ 4 
1.1. 
Objectives and Endpoints ............................................................................................................ 4 
1.2. 
Study Design .............................................................................................................................. 7 
2. 
STATISTICAL HYPOTHESES........................................................................................................ 9 
3. 
SAMPLE SIZE DETERMINATION .................................................................................................. 9 
4. 
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS .................................................................. 11 
5. 
STATISTICAL ANALYSES .......................................................................................................... 12 
5.1. 
General Considerations............................................................................................................. 12 
5.1.1. 
Level of Significance .............................................................................................................. 12 
5.1.2. 
Missing Data .......................................................................................................................... 12 
5.1.3. 
Intervention Group ................................................................................................................. 12 
5.1.4. 
Visit Windows ........................................................................................................................ 12 
5.2. 
Participant Dispositions ............................................................................................................. 12 
5.3. 
Primary Endpoint Analysis......................................................................................................... 13 
5.3.1. 
Definition of Endpoint ............................................................................................................. 13 
5.3.2. 
Estimands .............................................................................................................................. 13 
5.3.3. 
Analysis Methods ................................................................................................................... 15 
5.3.4. 
Supplementary Analyses ....................................................................................................... 15 
5.3.4.1. 
Supplementary Analysis 1 (Hypothetical Estimand) ............................................................. 15 
5.3.4.2. 
Supplementary Analysis 2 (Treatment Policy Estimand) ...................................................... 15 
5.3.5. 
Sensitivity Analyses ............................................................................................................... 16 
5.3.6. 
Subgroup Analysis ................................................................................................................. 17 
5.4. 
Secondary Endpoints Analysis .................................................................................................. 17 
5.4.1. 
Multiplicity Adjustment ........................................................................................................... 17 
5.4.2. 
Secondary Efficacy Endpoints ................................................................................................ 17 
5.4.2.1. 
Definition of Endpoints ........................................................................................................ 18 
5.4.2.2. 
Estimands ........................................................................................................................... 20 
5.4.2.3. 
Analysis Methods ................................................................................................................ 21 
5.4.2.4. 
Supplementary Analysis for Change from Baseline in MRSS at Week 52 ............................ 22 
5.5. 
Tertiary/Exploratory Efficacy Endpoints Analysis ....................................................................... 22 
5.5.1. 
Definition of Endpoints ........................................................................................................... 24 
5.5.2. 
Analysis Methods ................................................................................................................... 26 
5.6. 
Other Efficacy Analyses ............................................................................................................ 27 
5.7. 
Safety Analyses ........................................................................................................................ 27 
5.7.1. 
Extent of Exposure ................................................................................................................ 28 
5.7.2. 
Adverse Events ..................................................................................................................... 28 
5.7.3. 
Additional Safety Assessments .............................................................................................. 29 
5.7.3.1. 
Clinical Laboratory Tests ..................................................................................................... 29 
5.7.3.2. 
Vital Signs and Physical Examination Findings .................................................................... 30 
5.7.3.3. 
Electrocardiogram ............................................................................................................... 31 
5.8. 
Other Analyses ......................................................................................................................... 31 
5.8.1. 
Pharmacokinetics .................................................................................................................. 31 
5.8.2. 
Immunogenicity ..................................................................................................................... 33 
5.8.3. 
Pharmacodynamics ............................................................................................................... 33 
5.8.4. 
Pharmacokinetic/Pharmacodynamic Relationships ................................................................. 34 
5.9. 
Interim Analyses ....................................................................................................................... 35 
6. 
SUPPORTING DOCUMENTATION .............................................................................................. 36 
6.1. 
Appendix 1 List of Abbreviations ............................................................................................... 36 
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CNTO1959  (Guselkumab)  
 
 
 
Statistical Analysis Plan CNTO1959SSC2001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
3 
Status: Approved,  Date: 7 June 2023 
6.2. 
Appendix 2 Changes to Protocol-Planned Analyses .................................................................. 38 
6.3. 
Appendix 3 Demographics and Baseline Characteristics ........................................................... 39 
6.4. 
Appendix 4 Protocol Deviations ................................................................................................. 40 
6.5. 
Appendix 5 Prior and Concomitant Medications ......................................................................... 41 
6.6. 
Appendix 6 Medical History ....................................................................................................... 42 
6.7. 
Appendix 7 Intervention Compliance ......................................................................................... 43 
6.8. 
Appendix 8 Adverse Events of Special Interest .......................................................................... 44 
6.9. 
Appendix 9 Medications of Special Interest ............................................................................... 45 
6.10. 
Appendix 10 Laboratory Toxicity Grading .................................................................................. 46 
6.11. 
Appendix 11 A Prohibited Change in SSC Medication ............................................................... 53 
7. 
REFERENCES ............................................................................................................................. 54 
 
 
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CNTO1959  (Guselkumab)  
 
 
 
Statistical Analysis Plan CNTO1959SSC2001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
4 
Status: Approved,  Date: 7 June 2023 
1. 
INTRODUCTION 
This protocol CNTO1959SSC2001 is a Phase 2a Proof-of-Concept (PoC) study of Guselkumab in 
participates with Systemic Sclerosis (SSc).  
This Statistical Analysis Plan (SAP) contains definitions of analysis sets, derived variables and 
statistical methods for all planned analyses for CNTO1959SSC2001 including both main study 
period and long-term extension (LTE) period.  
1.1. 
Objectives and Endpoints  
Objectives and endpoints of this study are listed in Table 1. 
Table 1: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
To evaluate the efficacy of guselkumab 
in participants with SSc 
 
Change from baseline in Modified Rodnan 
Skin Score (mRSS) at Week 24 
Secondary 
 
To evaluate the additional efficacy of 
guselkumab in participants with SSc 
 
Change from baseline in mRSS at Week 52 
 
The proportion of participants who 
experience worsening of mRSS at Week 24 
and Week 52 
 
The proportion of participants achieving a 
score of 0.6 in American College of 
Rheumatology Combined Response Index 
in dcSSc (ACR CRISS) at Week 24 and 
Week 52 
 
Change from baseline in forced vital 
capacity (FVC) and percent predicted FVC 
at Week 24 and Week 52 
 
Change from baseline in the measured 
absolute diffusing capacity of the lung for 
carbon monoxide (DLCO) and the derived 
percent predicted DLCO at Week 24 and 
Week 52 
 
Change from baseline in digital ulcer counts 
at Week 24 and Week 52 
 
Change from baseline in Health Assessment 
Questionnaire-Disability Index (HAQ-DI) 
score at Week 24 and Week 52 
 
To evaluate the safety and tolerability 
of guselkumab in participants with 
SSc 
 
Number and proportion of participants with 
treatment-emergent adverse events (AEs) 
and serious adverse events (SAEs) or 
adverse events of special interest (AESI) 
NCT04683029


CNTO1959  (Guselkumab)  
 
 
 
Statistical Analysis Plan CNTO1959SSC2001  
 
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Status: Approved,  Date: 7 June 2023 
Objectives 
Endpoints 
through Week 24, Week 52, Week 76 and 
Week 104 
 
To evaluate the pharmacokinetic(s) 
and immunogenicity of guselkumab 
 
Serum guselkumab concentrations 
 
Incidence of anti-guselkumab antibody 
Exploratory 
 
To evaluate the efficacy of 
guselkumab in SSc 
 
Time to disease worsening: increase from 
baseline ≥5 and ≥20% in mRSS or decrease 
>10% from baseline in FVC % 
 
The proportion of participants who 
experience FVC decline compared with 
baseline at Week 24 and Week 52 
 
The proportion of participants who 
experience worsening of FVC at Week 24 
and Week 52 
 
Change from baseline in fibrotic change 
assessed with high-resolution computed 
tomography (HRCT) at Week 24 and Week 
52 in participants with baseline 
fibrosis/fibrotic changes 
 
The proportion of participants who 
experience worsening of fibrotic change 
assessed with HRCT at Week 24 and Week 
52 
 
Change from baseline in Frequency Scale 
for the Symptoms of Gastroesophageal 
reflux disease (FSSG) score at Week 24 and 
Week 52 
 
Assessment of nailfold capillaries at Week 
24 and Week 52 
 
Change from baseline in Patients global 
assessment (PGA) at Week 24 and Week 52 
 
Change from baseline in Physician global 
assessment (PhGA) at Week 24 and Week 
52 
 
 
To evaluate the long-term efficacy of 
guselkumab in participant with SSc 
 
Change from baseline and Week 52 in mRSS 
at Week 76 and Week 104 
 
The 
proportion 
of 
participants 
who 
experience worsening of mRSS at Week 76 
and Week 104 
NCT04683029


CNTO1959  (Guselkumab)  
 
 
 
Statistical Analysis Plan CNTO1959SSC2001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
6 
Status: Approved,  Date: 7 June 2023 
 
The proportion of participants achieving a 
score of 0.6 in American College of 
Rheumatology Combined Response Index in 
dcSSc (ACR CRISS) at Week 76 and 
Week 104 
 
Change from baseline in forced vital capacity 
(FVC) and percent predicted FVC at 
Week 76 and Week 104 
 
The 
proportion 
of 
participants 
who 
experience worsening of FVC at Week 76 
and Week 104 
 
Change from baseline in the measured 
absolute diffusing capacity of the lung for 
carbon monoxide (DLCO) and the derived 
percent predicted DLCO at Week 76 and 
Week 104  
 
Change from baseline in Health Assessment 
Questionnaire-Disability Index (HAQ-DI) 
score at Week 76 and Week 104 
 
Change from baseline in digital ulcer counts 
at Week 76 and Week 104 
 
Change from baseline in fibrotic change 
assessed with high-resolution computed 
tomography (HRCT) at Week 76 and 
Week 104 in participants with baseline 
fibrosis/fibrotic changes 
 
The 
proportion 
of 
participants 
who 
experience worsening of fibrotic change 
assessed with HRCT at Week 76 and 
Week 104 
 
Change from baseline in Frequency Scale for 
the Symptoms of Gastroesophageal reflux 
disease (FSSG) score at Week 76 and 
Week 104 
 
To evaluate the effect of guselkumab 
vs placebo on the pharmacodynamic 
(PD) and SSc disease biomarkers 
 
Change from baseline levels of skin 
(optional) and circulating (blood based) 
biomarkers over time to enable: 
Evaluation of target engagement in 
tissue/efficacy pharmacodynamic (PD) 
readouts 
 
Single nucleotide polymorphisms (SNPs) 
frequency associated with IL-23 pathway 
NCT04683029


CNTO1959  (Guselkumab)  
 
 
 
Statistical Analysis Plan CNTO1959SSC2001  
 
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Status: Approved,  Date: 7 June 2023 
1.2. 
Study Design 
This is a randomized, double-blind, placebo-controlled, parallel, multicenter, interventional study 
to evaluate the efficacy of guselkumab in men and women between the ages of 18 to 75 years, 
inclusive, with a diagnosis of SSc according to American College of Rheumatology (ACR) and 
European League Against Rheumatism (EULAR) 2013 criteria with a disease duration of 
≤36 months (defined as time from first non-Raynaud phenomenon manifestation), and Modified 
Rodnan Skin Score (mRSS) of ≥10 to ≤22 units. 
Participants will be randomly assigned in a 1:1 ratio, based on randomization strata of presence of 
interstitial lung disease (ILD [yes, no]), baseline mRSS (low [≥10 to ≤15] or high [≥16 to ≤22]), 
and baseline anti-topoisomerase I antibody status (positive, negative), to 1 of the following 
treatment groups: 
 
Guselkumab (Group/Arm A): Guselkumab 400 mg IV administration at Weeks 0, 4, and 8 
(induction) followed by guselkumab 200 mg subcutaneous (SC) administration every 4 weeks 
(Q4W) from Week 12 until Week 48 (maintenance)  
 
Placebo (Group/Arm B): Matching placebo IV administration at Weeks 0, 4, and 8 (induction) 
followed by matching placebo SC administration Q4W from Week 12 until Week 48 
(maintenance) 
The main study will be conducted in 3 phases: a maximum 6-week screening phase, a 52-week 
double-blind intervention phase, and a safety follow-up phase with a postintervention follow-up 
visit at 12 weeks after the participant’s last dose of study intervention to collect any adverse events 
(AEs) since the last study visit. The duration of individual participation will be approximately 
66 weeks without LTE.  
Participants who complete the main study (Week 0 through 52: ie, after the Week 48 evaluation, 
prior to Week 52 evaluation) and who, in the opinion of the investigator, may benefit from 
continued treatment, will participate in the LTE by signing the ICF before or at Week 52. The 
duration of individual participation will be approximately 66 weeks without LTE and 118 weeks 
with LTE.  
 
Group/Arm A (guselkumab arm from the main study): Guselkumab 200 mg SC and placebo 
IV at LTE Weeks 52, 56, and 60 followed by guselkumab 200 mg SC Q4W from LTE Week 
64 until Week 100.   
 
Group/Arm B (placebo arm from the main study): Placebo SC and guselkumab 400 mg IV at 
LTE Weeks 52, 56, and 60 followed by guselkumab 200 mg SC Q4W from LTE Week 64 
until Week 100. 
The objective of LTE is to evaluate the long-term safety and efficacy of guselkumab in SSc patients. 
The LTE begins with the completion of the assessments at the Week 52, and LTE continues 
through LTE Week 104. The LTE includes a safety follow-up phase with a postintervention 
follow-up visit at LTE Week 112 (12 weeks after the participant’s last dose of study intervention). 
Two planned database locks (DBLs) will occur: EOS of the main study (Week 52 visit for 
participants who entered LTE or safety follow up visit for participants who did not enter LTE, 
NCT04683029


CNTO1959  (Guselkumab)  
 
 
 
Statistical Analysis Plan CNTO1959SSC2001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
8 
Status: Approved,  Date: 7 June 2023 
hereinafter referred to as “Week 52 DBL”), and EOS of LTE (Week 112 visit, hereinafter referred 
to as “Final DBL”). 
A target of 56 participants will be randomly assigned in this study with 28 participants planned per 
intervention group. 
A diagram of the main study design is provided in the following schema. 
 
Abbreviations: DBL=database lock; IV=intravenous; N=number of participants; PE=primary endpoint; 
R=randomization; SC=subcutaneous; SE=secondary endpoints 
 
A diagram of the LTE period is provided in the following schema. 
 
Abbreviations: DBL=database lock; IV=intravenous; SC=subcutaneous; SE=secondary endpoints 
 
NCT04683029


CNTO1959  (Guselkumab)  
 
 
 
Statistical Analysis Plan CNTO1959SSC2001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
9 
Status: Approved,  Date: 7 June 2023 
2. 
STATISTICAL HYPOTHESES 
This PoC study aims at detecting an early efficacy signal of guselkumab in participants with SSc, 
compared to placebo, to support further clinical development. 
The primary efficacy endpoint is defined as the change from baseline in mRSS at Week 24. 
 
The null hypothesis is that the treatment difference between guselkumab and placebo for the 
primary endpoint is =0. 
 
The alternative hypothesis is that the treatment difference between guselkumab and placebo 
for the primary endpoint is ≠0. 
Due to the PoC nature of this study, a 2-sided alpha of 0.2 is allocated for testing this hypothesis. 
The objective will be considered met if the calculated p-value is less than 0.2. 
3. 
SAMPLE SIZE DETERMINATION 
There is lack of positive placebo-controlled trials in dcSSc. 
Taking into account the following 4 Phase 2/3 placebo-controlled trials (see Table 2) in SSc with 
mRSS results reported in the ClinicalTrials.gov registry, a reasonable estimate of the standard 
deviation (SD) to be used in the sample size calculation of this study has been taken as 8.0. 
Table 2: 
Standard deviations of mRSS in Referenced Phase 2/3 Placebo-controlled Trials in SSc 
Trial 
Treatment group 
Placebo group 
N 
Estimated 
SD 
N 
Estimated 
SD 
A Double-Blind, Randomised, Placebo-
controlled Trial Evaluating Efficacy and 
Safety of Oral Nintedanib Treatment for at 
Least 52 Weeks in Patients With Systemic 
Sclerosis Associated Interstitial Lung 
Disease (SSc-ILD) (NCT02597933) 
288 
4.582 
288 
4.412 
A Phase 3, Multicenter, Randomized, 
Double-Blind, Placebo-Controlled, Parallel-
Group Study to Assess the Efficacy and 
Safety of Tocilizumab Versus Placebo in 
Patients With Systemic Sclerosis 
(NCT02453256) 
104 
8.169 
106 
8.142 
A Phase 2/3, Multicenter, Randomized, 
Double-blind, Placebo-controlled Study To 
Assess The Efficacy And Safety Of 
Tocilizumab Versus Placebo In Patients 
With Systemic Sclerosis (NCT01532869) 
43 
8.266 
41 
8.933 
NCT04683029


CNTO1959  (Guselkumab)  
 
 
 
Statistical Analysis Plan CNTO1959SSC2001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
10 
Status: Approved,  Date: 7 June 2023 
Trial 
Treatment group 
Placebo group 
N 
Estimated 
SD 
N 
Estimated 
SD 
A Phase 2 Study to Evaluate Subcutaneous 
Abatacept vs. Placebo in Diffuse Cutaneous 
Systemic Sclerosis- a Double-blind, Placebo-
controlled, Randomized Controlled Trial 
(NCT02161406) 
44 
7.562 
44 
7.562 
 
Khanna et al (2006) revealed that a 95% confidence interval (CI) of [-4.7, -1.7] in mRSS change 
from baseline to 6 months was considered a clinically meaningful change. The lower bound of this 
95% CI, -4.7, has been taken as the expected treatment difference in the sample size calculation of 
this study, assuming guselkumab can achieve a clinically meaningful change in most of 
guselkumab-treated participants. 
Assuming an SD of 8 points, an 80% power at a 2-sided significance level of 0.20, with a 1:1 
randomization ratio, to detect a treatment effect of -4.7 points, a total of at least 54 participants 
will be required. 
Allowing for up to 2 participants randomized but without postbaseline efficacy assessments, 
approximately 56 (28 each) randomized participants are planned. In order to evaluate the 
interobserver and intraobserver variability of the mRSS to support Phase 3 planning, it is desirable 
for each center to randomize 3 participants at least. 
NCT04683029


CNTO1959  (Guselkumab)  
 
 
 
Statistical Analysis Plan CNTO1959SSC2001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
11 
Status: Approved,  Date: 7 June 2023 
4. 
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS 
For purposes of analysis, the following analysis sets are defined: 
Table 3: 
Definition of Analysis Sets 
Analysis Sets 
Description 
Enrolled 
All participants who sign the ICF. 
Randomized 
All participants who were randomized in the study. 
Full Analysis 
Set (FAS) 
All randomized participants who received at least 1 dose (complete or 
partial) of study intervention.  
Note: Efficacy and participant information analyses will be based on the 
randomized intervention groups, regardless of the intervention they actually 
received. 
Full Analysis 
Set for LTE 
Period 
All randomized participants who received at least 1 dose (complete or 
partial) of study intervention during LTE period.  
 
Safety 
All randomized participants who received at least 1 dose (complete or 
partial) of study intervention.  
Note: Safety will be analyzed based on the intervention they received, 
regardless of the intervention groups to which they are assigned. 
Safety Analysis 
Set for LTE 
Period 
All participants who received at least 1 dose (complete or partial) of study 
intervention during LTE period.  
 
PK 
All participants who received at least 1 complete administration of 
guselkumab and have at least 1 observed post dose PK data. 
Immunogenicity All participants who received at least 1 administration of guselkumab and 
have at least 1 observed post dose immune response data. 
PK/PD Analysis 
Set for mRSS 
All participants who were randomized to guselkumab and received at least 
1 complete administration of guselkumab during main study period,  have 
evaluable data of both PK and PD (mRSS) at the same visit which includes 
Week 0, and at least one postbaseline timepoint at Week 12, or Week 24 or 
Week 52 visit. 
PK/PD Analysis 
Set for ACR 
CRISS 
All participants who were randomized to guselkumab and received at least 
1 complete administration of guselkumab during main study period, have 
evaluable data of both PK and PD (ACR CRISS) at the same visit of at least 
one postbaseline timepoint at Week 12, or Week 24 or Week 52 visit. 
NCT04683029


CNTO1959  (Guselkumab)  
 
 
 
Statistical Analysis Plan CNTO1959SSC2001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
12 
Status: Approved,  Date: 7 June 2023 
5. 
STATISTICAL ANALYSES 
5.1. 
General Considerations 
Descriptive summary statistics, such as n, mean, standard deviation (SD), median, inter quantile 
range, minimum, and maximum for continuous variables, and counts and percentages for discrete 
variables will be used to summarize data as appropriate unless otherwise specified. 
5.1.1. 
Level of Significance 
As a PoC study, a 2-sided alpha of 0.2 is allocated for all hypothesis testing throughout the study. 
As the reference of the internal GO/NO-GO decision making, 95% CIs as well as 80% CIs will be 
provided for primary endpoint analysis and secondary endpoint analysis. 
5.1.2. 
Missing Data 
Unless otherwise specified, a missing-at-random (MAR) missing data mechanism is assumed for 
all efficacy endpoints and there will be no imputation of missing data prior to the analysis.   
5.1.3. 
Intervention Group 
The population will be the FAS defined in Section 4 for all the efficacy analysis, and the assigned 
treatment group for each participate will be used regardless of the actual treatment received.   
All the safety analyses will be performed on safety analysis set, and by the actual treatment 
participants received regardless of the assigned treatment.  
5.1.4. 
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 time delineated in the Schedule of Activities as 
described in the protocol. 
5.2. 
Participant Dispositions 
Screened participants and the number of screen failures will be summarized overall in all enrolled 
participants. 
The number of participants in the following disposition categories will be summarized in the main 
study period and LTE period by intervention group and overall: 
 
Participants randomized 
 
Participants who received study intervention 
 
Participants who completed the study 
 
Participants who discontinued study intervention 
 
Reasons for discontinuation of study intervention 
 
Participants who terminated study prematurely 
 
Reasons for termination of study 
NCT04683029


CNTO1959  (Guselkumab)  
 
 
 
Statistical Analysis Plan CNTO1959SSC2001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
13 
Status: Approved,  Date: 7 June 2023 
Listings of participants will be provided for the following categories: 
 
Participants who discontinued study intervention 
 
Participants who terminated study prematurely 
5.3. 
Primary Endpoint Analysis 
The primary endpoint is the change from baseline in mRSS at Week 24. This section outlines the 
definitions and analysis of this primary endpoint. 
5.3.1. 
Definition of Endpoint 
The mRSS is a validated physical examination method for estimating skin induration. It correlates 
with biopsy measures of skin thickness and reflects prognosis and visceral involvement, especially 
in early disease. It is scored on 0 (normal) to 3 (severe induration) ordinal scales over 17 body 
areas, with a maximum score of 51 and is used to categorize severity of SSc (Khanna 2007).  
This assessment should be performed by a physician who is experienced and trained in skin scoring. 
To prevent interobserver variability, the same physician must perform skin scoring for the same 
participant throughout the entire study. 
5.3.2. 
Estimands 
1. 
Primary Estimand (Composite Estimand) 
The primary estimand is defined as the following components: 
Primary Trial Objective: to evaluate the efficacy of guselkumab in participants with SSc 
Estimand Scientific Question of Interest: what is the efficacy, as is measured by change from 
baseline in mRSS at Week 24 for participants who are assigned to guselkumab versus placebo 
Study Intervention: 
 
Experimental: guselkumab  
 
Control: placebo 
Population: participants between 18 to 75 years (inclusive) with diagnosis of SSc according to 
ACR and EULAR 2013 criteria with a disease duration of ≤36 months (defined as time from first 
non-Raynaud phenomenon manifestation), and mRSS ≥10 to ≤22 units 
Variable: change from baseline in mRSS at Week 24. Participants with an intercurrent event 
before Week 24 will have a zero change from baseline in the mRSS since the intercurrent event 
occurs, regardless of the observed data.  
Summary measure (Population-level summary): difference in least-square means (LSMs) of 
change from baseline in mRSS at Week 24 between guselkumab vs placebo 
NCT04683029


CNTO1959  (Guselkumab)  
 
 
 
Statistical Analysis Plan CNTO1959SSC2001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
14 
Status: Approved,  Date: 7 June 2023 
Intercurrent events and their corresponding strategies: 
Intercurrent Events 
Strategy for Addressing Intercurrent Events 
and Its Description 
A prohibited change in SSc 
medication (for details, see 
Appendix 11) 
Composite Strategy: A participant with this 
intercurrent event is considered to have a zero 
change at and after the event occurred. 
Discontinuation of study 
intervention due to lack of efficacy 
or an AE of Systemic Sclerosis 
Composite Strategy: Same as above 
2. 
Supplementary Estimand (Hypothetical Estimand) 
This supplementary estimand will be used to complement the primary estimand. The components 
of the supplementary estimand are the same as those for the primary estimand with the exception 
of definitions in Variable and Intercurrent event strategies (hypothetical strategy), which are 
described as follows:   
Variable: change from baseline in mRSS at Week 24. Participants with an intercurrent event 
before Week 24 will have their mRSS set to missing since the intercurrent event occurs. 
Intercurrent events and their corresponding strategies: 
Intercurrent Events 
Strategy for Addressing Intercurrent Events 
and Its Description 
A prohibited change in SSc 
medication (for details, see 
Appendix 11) 
Hypothetical Strategy: A participant with this 
intercurrent event is considered to have missing 
data at and after the event occurred. 
Discontinuation of study 
intervention due to lack of efficacy 
or an AE of Systemic Sclerosis 
Hypothetical Strategy: Same as above 
3. 
Supplementary Estimand (Treatment Policy Estimand) 
In this estimand, the components are almost the same as those for the primary estimand with the 
exception of definitions in Variable and Intercurrent event strategies (treatment policy strategy), 
which are described as follows: 
Variable: change from baseline in mRSS at Week 24  
NCT04683029


CNTO1959  (Guselkumab)  
 
 
 
Statistical Analysis Plan CNTO1959SSC2001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
15 
Status: Approved,  Date: 7 June 2023 
Intercurrent events and their corresponding strategies: 
Intercurrent Events 
Strategy for Addressing Intercurrent Events 
and Its Description 
A prohibited change in SSc 
medication (for details, see 
Appendix 11) 
Treatment Policy Strategy: The intercurrent event 
does not affect the outcome, and the data collected 
at and after the event will be used for analysis. 
Discontinuation of study 
intervention due to lack of efficacy 
or an AE of Systemic Sclerosis 
Treatment Policy Strategy: Same as above 
5.3.3. 
Analysis Methods 
The primary analysis will use a Mixed-Effect Model Repeated Measure (MMRM) model. Under 
the assumption of MAR, the missing data will be accounted for through correlation of repeated 
measures in the model.  
The MMRM model includes treatment group, baseline mRSS, stratification factors (presence of 
ILD [yes, no] and baseline anti-topoisomerase I antibody status [positive, negative]), visit, 
treatment group by visit interaction, and baseline mRSS by visit interaction as fixed effects. 
Stratification factor of baseline mRSS is not included as baseline mRSS is already addressed in 
the model as a continuous covariate. Treatment effects will be estimated based on least-square 
means (LSMs) of the differences. The p-values for the LSM differences along with the 2-sided 
80% and 95% CIs will be presented. The degree of freedom will be calculated as the error degrees 
of freedom for the model minus the number of extra random effects estimated. 
An unstructured covariance matrix for repeated measures within a participant will be used. In case 
of lack of convergence, empirical structured covariances will be used in the following order until 
convergence is reached: 1) Toeplitz 2) first order Autoregressive Moving Average. If the normality 
assumption is in question, an appropriate transformation will be used.   
5.3.4. 
Supplementary Analyses 
5.3.4.1. 
Supplementary Analysis 1 (Hypothetical Estimand) 
The analysis will be performed using the Hypothetical Estimand. The treatment comparison will 
use the similar MMRM model as in the primary analysis. LSMs, together with the 2-sided 80% 
CIs for the LSMs and p-value will be calculated based on the MMRM.  
5.3.4.2. 
Supplementary Analysis 2 (Treatment Policy Estimand) 
The analysis will be performed using the Treatment Policy Estimand. The treatment comparison 
will use the similar MMRM model as in the primary analysis. LSMs, together with the 2-sided 
80% CIs for the LSMs and p-value will be calculated based on the MMRM.  
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CNTO1959  (Guselkumab)  
 
 
 
Statistical Analysis Plan CNTO1959SSC2001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
16 
Status: Approved,  Date: 7 June 2023 
5.3.5. 
Sensitivity Analyses 
If at least one data through Week 24 is missing and p-value is <0.2 with the primary analysis, a 
sensitivity analysis for primary estimand (Composite Estimand) will be performed, using multiple 
imputation.  
Step #1: Utilize a Markov Chain Monte Carlo (MCMC) approach to impute intermediate 
(nonmonotone) missing data and convert the dataset into a monotone missing data pattern. One 
hundred monotone datasets will be imputed using the seed 12345, by treatment group. 
Step #2: After imputing nonmonotone data, the remaining missing value will be imputed using the 
PROC MI monotone regression procedure. This approach imputes missing data in a sequential 
manner, for each time point, a regression model based on all available data at this timepoint (either 
observed or imputed) is fitted and used to impute values still missing at this timepoint. The 
ancillary variable includes in the model will be treatment group, the stratification factors, and the 
mRSS scores by visit. The seed is 54321. In this way, one thousand complete datasets are generated. 
Step #3: Analyze each of the 100 imputed datasets using the same model specified for the primary 
analysis and the results will be combined using the PROC MIANALYZE procedure. 
The tipping point analysis will be implemented to assess the robustness of conclusions. A constant 
delta is added or subtracted to the imputed data in the direction of lack of efficacy for guselkumab 
and in the direction of improvement for placebo. A range of evenly spaced deltas will be used to 
adjust imputed values in the guselkumab and placebo group independently in order to produce a 
grid of delta adjustments to missing values in both groups. The size of the deltas will be chosen 
pragmatically, so that adjustments that lead to p-value >= 0.2 encompassed in the grid. In particular, 
assuming MAR on placebo, ie, no delta adjustment, an adjustment on the guselkumab arm that 
just tips the analysis into p-value >= 0.2 will be included.  
For each pair of delta adjustments, the point estimate of treatment effect, and corresponding p-
value combined from results from 1000 adjusted datasets through the PROC MIANALYZE 
procedures will be presented.  
Ukyo and Noma proposed the permutation-based inference methods for the analyses using 
MMRM that is considered to be more appropriate under small sample settings (Ukyo 2019). Their 
method will be applied to examine the robustness of the primary analysis result. 
Step #1: Permutate the treatment group indicator of the mRSS dataset. The seed is defined as 127. 
Step #2: Calculate the t-statistics (ܶ(௕)൫ߚଵ
௡௨௟௟൯) for the coefficient (ߚଵ) that indicates treatment 
effect by the MMRM used for the primary analysis using the mRSS dataset prepared in Step #1. 
Step #3: Repeat Step #1 and #2 for B times (B=1000 in this analysis) to obtain the t-statistics. Note 
that the t-statistics obtained in this procedure follow the empirical null distribution estimated by 
the actual dataset. Therefore, statistical test and inference are considered valid even if the sample 
size is small and longitudinal dataset is incomplete. 
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The p-value will be calculated as the following equation, where ܶ(ߚଵ) is the t-statistics obtained 
by the original mRSS dataset: 
݌=
1
ܤ+ 1 ൝1 + ෍ܫ൛หܶ(௕)(ߚଵ
௡௨௟௟)ห> |ܶ(ߚଵ)|ൟ
஻
௕ୀଵ
ൡ 
After calculating the 10% (ܶ଴.ଵ൫ߚଵ
௡௨௟௟൯) and 90% (ܶ଴.ଽ൫ߚଵ
௡௨௟௟൯) quantiles of the t-statistics obtained 
in Step #3, the 2-sided 80% CIs for ߚଵ will be ߚ where the following equation holds: 
ܶ଴.ଵ(ߚଵ
௡௨௟௟) ≤
ߚመଵ−ߚ
ටܸܽݎ(ߚመଵ)
≤ܶ଴.ଽ(ߚଵ
௡௨௟௟) 
5.3.6. 
Subgroup Analysis 
Descriptive statistics of the primary efficacy endpoint will be presented by the subgroups as 
follows: 
 
Gender: Male, Female 
 
Age: <65 years, ≥65 years 
 
Weight: <=median, >median 
 
Corticosteroid use at baseline: yes, no 
 
Presence of ILD: Yes, No 
 
Baseline mRSS: Low [≥10 to ≤15], High [≥16 to ≤22] 
 
Baseline anti-topoisomerase I antibody status: Positive, Negative 
 
Disease duration at baseline: 0-18 months, >18-36 months 
5.4. 
Secondary Endpoints Analysis 
5.4.1. 
Multiplicity Adjustment 
No adjustments for multiple comparisons will be made across all the primary and secondary 
efficacy endpoints. Nominal p-values will be presented for efficacy analyses. 
5.4.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
 
Change from baseline in mRSS at Week 52 
 
The proportion of participants who experience worsening of mRSS at Week 24 and Week 52 
 
The proportion of participants achieving a score of 0.6 in American College of Rheumatology 
Combined Response Index in dcSSc (ACR CRISS) at Week 24 and Week 52 
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Statistical Analysis Plan CNTO1959SSC2001  
 
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 
Change from baseline in forced vital capacity (FVC) and percent predicted FVC at Week 24 
and Week 52 
 
Change from baseline in the measured absolute diffusing capacity of the lung for carbon 
monoxide (DLCO) and the derived percent predicted DLCO at Week 24 and Week 52 
 
Change from baseline in digital ulcer counts at Week 24 and Week 52 
 
Change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) score 
at Week 24 and Week 52 
5.4.2.1. 
Definition of Endpoints 
Worsening of mRSS 
An increase from baseline ≥5 points and ≥20% in mRSS. 
American College of Rheumatology Combined Response Index in dcSSC (ACR CRISS) 
ACR CRISS is a composite response index for clinical trials in early dcSSc. Application of ACR 
CRISS algorithm in a randomized clinical trial is a 2-step process.  
Step 1: if a patient develops any of the following conditions, they will be assigned a probability of 
improving equal to 0.0. Investigators will evaluate if the participants have the criterion. 
 
new scleroderma renal crisis 
 
decline in percent predicted FVC ≥15% relative to baseline confirmed by a second FVC within 
one month, HRCT to confirm ILD (if previous HRCT did not show ILD) and FVC <80% of 
predicted attributable to systemic sclerosis 
 
new onset of left ventricular failure (defined as left ventricular ejection fraction ≤45%) 
requiring treatment, attributable to systemic sclerosis 
 
new onset of pulmonary arterial hypertension on right-sided heart catheterization requiring 
treatment, attributable to systemic sclerosis  
Step 2: for the remaining patients, compute the predicted probability of improving for each 
participant using the following equation (equation to derive predicted probabilities from a logistic 
regression model): 
݁ݔ݌ [−5.54 −0.81 ∗∆ெோௌௌ+ 0.21 ∗∆ி௏஼% −0.40 ∗∆௉௧ି௚௟௢௕−0.44 ∗∆ெ஽ି௚௟௢௕−3.41 ∗∆ு஺ொି஽ூ]
1 + ݁ݔ݌  [−5.54 −0.81 ∗∆ெோௌௌ+ 0.21 ∗∆ி௏஼% −0.40 ∗∆௉௧ି௚௟௢௕−0.44 ∗∆ெ஽ି௚௟௢௕−3.41 ∗∆ு஺ொି஽ூ] 
where, ∆ࡹࡾࡿࡿ indicates the change in mRSS from baseline to follow-up, ∆ࡲࢂ࡯% denotes the change 
in percent predicted FVC from baseline to follow-up, ∆ࡼ࢚ିࢍ࢒࢕࢈ indicates the change in patient 
global assessment, ∆ࡹࡰିࢍ࢒࢕࢈ denotes the change in physician global assessment, and ∆ࡴ࡭ࡽିࡰࡵ is 
the change in HAQ-DI. All changes are absolute change. 
Participants for which the predicted probability is greater or equal to 0.60 are considered improved 
while participants for which the predicted probability is below 0.60 are considered non-improved.  
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Forced Vital Capacity (FVC) 
FVC and % predicted FVC are measurements of lung function and will be performed locally. 
Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) 
DLCO is the measurement of lung function and will be reported locally. 
% predicted DLCO (hemoglobin-corrected) is only collected at screening, while for other visits, it 
will be derived based on following steps: 
1) Compute Body Surface Area (BSA) per formula as below: 
ܤܵܣ (݉2) =  ܹ݁݅݃ℎݐ (݇݃) ଴.ସଶହ × ܪ݁݅݃ℎݐ (ܿ݉) ଴.଻ଶହ ×  0.007184 
The Weight of the same visit should be used, if Weight of the visit is missing then the value 
closest to date of DLCO measurement will be used. 
2) Compute the predicted DLCO (ml/min/mm Hg) per formula as below: 
Male: 
Predicted DLCO (ml/min/mm Hg) =  15.5 ×  BSA − 0.238 ×  age +  6.8 
Female: 
Predicted DLCO (ml/min/mm Hg) =  15.5 ×  BSA − 0.117 ×  age +  0.5 
3) Compute the predicted DLCO (Hgb-corrected) (ml/min/mm Hg) per formula as below: 
Male: 
DLCO (ml/min/mm Hg) × ((10.22 + Hgb )/(1.7 ×  Hgb))  
Female: 
DLCO (ml/min/mm Hg) × ((9.38 + Hgb )/(1.7 ×  Hgb))  
The Hgb (g/dL) of the same visit from central lab will be used. 
4) Compute the % predicted DLCO (Hgb-corrected) per formula as below: 
% predicted DLCO (Hgb corrected) = Predicted DLCO (Hgb corrected) (ml/min/mm Hg)
Predicted DLCO (ml/min/mm Hg)
 × 100  
Health Assessment Questionnaire -Disability Index (HAQ-DI) 
The Stanford HAQ is a brief self-report questionnaire assessing physical function pertaining to 
activities of daily living across 8 domains: dressing and grooming, arising, eating, walking, 
hygiene, reach, grip, and activities. The Stanford HAQ translated into Japanese with culturally 
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Statistical Analysis Plan CNTO1959SSC2001  
 
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appropriate modifications of the arising, eating, and reach category questions will be used in the 
study. (Matsuda 2003).  
5.4.2.2. 
Estimands 
The following describes the attributes of the estimands for the secondary efficacy endpoints. 
Study Intervention: 
 
Experimental: guselkumab  
 
Control: placebo 
Population: participants between 18 to 75 years (inclusive) with diagnosis of SSc according to 
ACR and EULAR 2013 criteria with a disease duration of ≤36 months (defined as time from first 
non-Raynaud phenomenon manifestation), and mRSS ≥10 to ≤22 units 
Variables and Population-level Summary: 
Variable (Endpoint) 
Population-level Summary 
Change from baseline in mRSS 
at Week 52  
Difference in LSMs of change from baseline in mRSS at 
Week 52 between guselkumab vs placebo 
The proportion of participants 
who experience worsening of 
mRSS at Week 24  
Odds ratio of proportion of participants who experience 
worsening of mRSS at Week 24 between guselkumab vs 
placebo 
The proportion of participants 
who experience worsening of 
mRSS at Week 52  
Odds ratio of proportion of participants who experience 
worsening of mRSS at Week 52 between guselkumab vs 
placebo 
The proportion of participants 
achieving a score of 0.6 in 
ACR CRISS at Week 24  
Odds ratio of proportion of participants who achieve a 
score of 0.6 in ACR CRISS at Week 24 between 
guselkumab vs placebo 
The proportion of participants 
achieving a score of 0.6 in 
ACR CRISS at Week 52  
Odds ratio of proportion of participants who achieve a 
score of 0.6 in ACR CRISS at Week 52 between 
guselkumab vs placebo 
Change from baseline in FVC 
and percent predicted FVC at 
Week 24  
Difference in LSMs of change from baseline in FVC 
and % predicted FVC at Week 24 between guselkumab 
vs placebo 
Change from baseline in FVC 
and percent predicted FVC at 
Week 52  
Difference in LSMs of change from baseline in FVC 
and % predicted FVC at Week 52 between guselkumab 
vs placebo 
Change from baseline in the 
measured absolute DLCO and 
the derived percent predicted 
DLCO at Week 24 
Difference in LSMs of change from baseline in the 
measured absolute DLCO and the derived % predicted 
DLCO at Week 24 between guselkumab vs placebo 
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Statistical Analysis Plan CNTO1959SSC2001  
 
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Status: Approved,  Date: 7 June 2023 
Variable (Endpoint) 
Population-level Summary 
Change from baseline in the 
measured absolute DLCO and 
the derived percent predicted 
DLCO at Week 52 
Difference in LSMs of change from baseline in the 
measured absolute DLCO and the derived % predicted 
DLCO at Week 52 between guselkumab vs placebo 
Change from baseline in digital 
ulcer counts at Week 24 
Difference in LSMs of change from baseline in digital 
ulcer counts at Week 24 between guselkumab vs placebo 
Change from baseline in digital 
ulcer counts at Week 52  
Difference in LSMs of change from baseline in digital 
ulcer counts at Week 52 between guselkumab vs placebo 
Change from baseline in HAQ-
DI score at Week 24  
Difference in LSMs of change from baseline in HAQ-DI 
score at Week 24 between guselkumab vs placebo 
Change from baseline in HAQ-
DI score at Week 52  
Difference in LSMs of change from baseline in HAQ-DI 
score at Week 52 between guselkumab vs placebo 
Intercurrent events and their corresponding strategies: 
The intercurrent events for all key secondary endpoints at Week 24 are the same as those in the 
primary estimand, as follows: 
1. A prohibited change in SSc medication (for details, see Appendix 11) 
2. Discontinuation of study intervention due to lack of efficacy or an AE of 
Systemic Sclerosis 
 
As rescue medication is available for participants after Week 24, an additional intercurrent event 
is defined for secondary efficacy endpoints at Week 52. 
3. Initiation of rescue medication after Week 24 
Intercurrent events 1, 2 and 3 are all handled by the composite strategy to assume that the occur 
of intercurrent events indicates an unfavorable outcome. For continuous endpoints, the change 
from baseline will be zero; and for binary endpoints, the participants are considered as not 
achieving an improvement (ACR CRISS score >= 0.6) or experiencing worsening (an increase 
from baseline ≥5 points and ≥20% in mRSS).  
5.4.2.3. 
Analysis Methods 
For continuous endpoint as change from baseline in mRSS at Week 52, an MMRM model with 
treatment group, baseline mRSS, stratification factors (presence of ILD [yes, no] and baseline anti-
topoisomerase I antibody status [positive, negative]), visit, treatment group by visit interaction, 
and baseline mRSS by visit interaction as fixed effects will be applied. The estimates of the 
treatment difference between guselkumab and placebo will be provided by the difference in the 
least squares means (LSMs), as well as the 2-sided 80% and 95% CIs for the differences and p-
values. 
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Statistical Analysis Plan CNTO1959SSC2001  
 
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For continuous endpoints other than change from baseline in mRSS at Week 52, an MMRM model 
with treatment group, baseline value of the endpoint, stratification factors (presence of ILD [yes, 
no], baseline mRSS (low [≥10 to ≤15], high [≥16 to ≤22]) and baseline anti-topoisomerase I 
antibody status [positive, negative]), visit, treatment group by visit interaction, and baseline value 
of the endpoint by visit interaction as fixed effects will be applied. The estimates of the treatment 
difference between guselkumab and placebo will be provided by the difference in the least squares 
means (LSMs), as well as the 2-sided 80% and 95% CIs for the differences and p-values. The 
degree of freedom will be calculated as the error degrees of freedom for the model minus the 
number of extra random effects estimated.  
An unstructured covariance matrix for repeated measures within a participant will be used. In case 
of lack of convergence, empirical structured covariances will be used in the following order until 
convergence is reached: 1) Toeplitz 2) first order Autoregressive Moving Average. If the normality 
assumption is in question, an appropriate transformation will be used.   
For binary endpoints such as proportion of participants achieving an ACR CRISS score of 0.6, a 
logistic regression model that includes factors for treatment group and stratification factors 
(presence of ILD [yes, no], baseline mRSS (low [≥10 to ≤15] or high [≥16 to ≤22]) and baseline 
anti-topoisomerase I antibody status [positive, negative]) will be applied provide the odds ratios, 
p-values, as well as the 2-sided 80% and 95% CIs for comparisons between guselkumab and 
placebo. 
5.4.2.4. 
Supplementary Analysis for Change from Baseline in MRSS at Week 
52 
The analysis is performed on the supplementary estimand of change from baseline in mRSS at 
Week 52 as in Section 5.4.2.2. The similar estimand as described in Section 5.4.2.2 is built except 
that intercurrent event “initiation of rescue therapy medication after Week 24” will be handled by 
treatment policy. An MMRM model similar as described in Section 5.4.2.3 is built and 80% CIs 
will be calculated.  
5.5. 
Tertiary/Exploratory Efficacy Endpoints Analysis 
The exploratory efficacy endpoints are listed as follows: 
 
Time to disease worsening: increase from baseline ≥5 and ≥20% in mRSS or decrease >10% 
from baseline in FVC % 
 
The proportion of participants who experience FVC decline compared with baseline at Week 
24 and Week 52 
 
The proportion of participants who experience worsening of FVC at Week 24 and Week 52 
 
Change from baseline in fibrotic change assessed with high-resolution computed tomography 
(HRCT) at Week 24 and Week 52 in participants with baseline fibrosis/fibrotic changes, 
including: 
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Statistical Analysis Plan CNTO1959SSC2001  
 
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Status: Approved,  Date: 7 June 2023 
1) Change from baseline in quantitative lung fibrosis (QLF) score by whole lung and 
each lobe at Week 24 and Week 52 in participants with baseline QLF score of whole 
lung >0. 
2) Change from baseline in quantitative interstitial lung disease (QILD) score by whole 
lung and each lobe at Week 24 and Week 52 in participants with baseline QILD score 
of whole lung >0. 
3) Change from baseline in the absolute volume of consolidation, emphysema-like, 
ground glass, honeycombing, normal lung, reticulation texture pattern by whole lung 
and each lobe at Week 52. 
 
The proportion of participants who experience worsening of fibrotic change assessed with 
HRCT at Week 24 and Week 52, including: 
1) The proportion of participants who experience worsening of fibrotic change by 
whole lung and each lobe assessed with QLF of HRCT at Week 24 and Week 52, in 
participants with baseline QLF score of whole lung >0.  
2) The proportion of participants who experience worsening of fibrotic change by 
whole lung and each lobe assessed with QILD of HRCT at Week 24 and Week 52, 
in participants with baseline QILD score of whole lung >0.  
 
Change from baseline in frequency scale for the symptoms of gastroesophageal reflux disease 
(FSSG) score at Week 24 and Week 52 
 
Assessment of nailfold capillaries at Week 24 and Week 52, including: 
1) Change from baseline in average total number of capillaries/ length of nailfold; 
average total number of capillaries/ length of nailfold = sum (total number of 
capillaries of each finger) / sum (length of nailfold of each finger) 
2) Change from baseline in average number of enlarged capillaries (20-50μm)/ length 
of nailfold; average number of enlarged capillaries (20-50μm)/ length of nailfold = 
sum (Number of enlarged capillaries (20-50μm) of each finger) / sum (length of 
nailfold of each finger) 
3) Change from baseline in average Number of giant capillaries (>50μm)/ length of 
nailfold; average Number of giant capillaries (>50μm)/ length of nailfold = sum 
(Number of giant capillaries (>50μm) of each finger) / sum (length of nailfold of 
each finger) 
4) Change from baseline in average total number of abnormal formed capillaries/ length 
of nailfold; average Total number of abnormal formed capillaries/ length of nailfold 
= sum (Total number of abnormal formed capillaries of each finger) / sum (length of 
nailfold of each finger) 
5) Change from baseline in average number of nailfold bleeding/ length of nailfold; 
average Number of nailfold bleeding/ length of nailfold = sum (Number of nailfold 
bleeding of each finger) / sum (length of nailfold of each finger) 
6) Change from baseline in capillary pattern (shift table, based on worst capillary 
pattern) 
7) Change from baseline in average Blood velocity (mm/s) 
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Statistical Analysis Plan CNTO1959SSC2001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 7 June 2023 
 
Change from baseline in patient global assessment (PGA) at Week 24 and Week 52 
 
Change from baseline in physician global assessment (PhGA) at Week 24 and Week 52 
And LTE efficacy endpoints: 
 
Change from baseline and Week 52 in mRSS at Week 76 and Week 104 
 
The proportion of participants who experience worsening of mRSS at Week 76 and Week 104 
 
The proportion of participants achieving a score of 0.6 in ACR CRISS at Week 76 and Week 
104 
 
Change from baseline in FVC and percent predicted FVC at Week 76 and Week 104 
 
The proportion of participants who experience worsening of FVC at Week 76 and Week 104 
 
Change from baseline in the measured absolute DLCO and the derived percent predicted 
DLCO at Week 76 and Week 104 
 
Change from baseline in digital ulcer counts at Week 76 and Week 104 
 
Change from baseline in fibrotic change assessed with HRCT at Week 76 and Week 104 in 
participants with baseline fibrosis/fibrotic changes, including: 
1) Change from baseline in QLF score by whole lung and each lobe at Week 76 and 
Week 104 in participants with baseline QLF score of whole lung >0. 
2) Change from baseline in QILD score by whole lung and each lobe at Week 76 and 
Week 104 in participants with baseline QILD score of whole lung >0. 
 
The proportion of participants who experience worsening of fibrotic change assessed with 
HRCT at Week 76 and Week 104,  including: 
1) The proportion of participants who experience worsening of fibrotic change by 
whole lung and each lobe assessed with QLF of HRCT at Week 76 and Week 104, 
in participants with baseline QLF score of whole lung >0.  
2) The proportion of participants who experience worsening of fibrotic change by 
whole lung and each lobe assessed with QILD of HRCT at Week 76 and Week 104, 
in participants with baseline QILD score of whole lung >0.  
 
Change from baseline in Frequency Scale for the FSSG score at Week 76 and Week 104 
5.5.1. 
Definition of Endpoints 
Time to Disease Worsening 
Time to disease worsening is calculated as the time from the date of randomization to the date of 
first occurrence of disease worsening, defined as: an increase from baseline ≥5 and ≥20% in mRSS 
or decrease >10% from baseline in FVC %. 
FVC Decline Compared with Baseline 
FVC decline compared with baseline is defined as a decrease in postbaseline visits compared with 
baseline in FVC. 
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Statistical Analysis Plan CNTO1959SSC2001  
 
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Worsening of FVC 
Worsening of FVC is defined as an absolute change of % predicted FVC <-10.  
High-resolution Computed Tomography (HRCT) Assessment 
Lung involvement is one of the most important cause of morbidity and mortality in patients with 
SSc. Because of recent advancement of computer-based scoring, analysis of CT images is drawing 
attention as a method to assess fibrotic changes in ILD. Texture-based analysis and computer 
vision-based approaches can be applied to imaging data, and used to evaluate the extent of lung 
fibrosis in chest CT images. The main assessed parameters QLF, which included fibrotic 
reticulation patterns only; quantitative honeycomb (QHC); and quantitative ground glass (QGG). 
QILD scores represented the total ILD pattern and consisted of the sum of all three scores (ie, 
QLF+QGG+QHC). The score will be reported by central image reading.  
Worsening of Fibrotic Change 
Worsening of fibrotic change will be assessed by whole lung and each lobe with different 
parameters QLF and QILD separately, which is defined as increases of 2% or more compared to 
baseline score. 
Symptoms of Gastroesophageal Reflux Disease (FSSG)  
The FSSG is a succinct questionnaire to evaluate esophageal symptoms of gastroesophageal reflux 
disease (GERD) which is validated based on endoscopic esophagitis. The original version of FSSG 
consists of the most prevalent 7 acid-reflux related and 5 dysmotility-related symptoms of GERD 
with higher scores being more indicative of underlying GERD. Each score was determined as 
follows: 0 = never, 1 = occasionally, 2 = sometimes, 3 = often, and 4 = always. A negative change 
from baseline indicates improvement. 
Nailfold Capillaroscopy 
Nailfold capillaroscopy is a non-invasive method to visualize the nailfold capillaries and assess 
microvascular morphology. Nailfold capillary abnormalities are evaluated by using nailfold 
capillaroscopy. The typical changes of the nailfold capillaries during SSc include the total number 
of capillaries, capillary dimension, capillary morphology, hemorrhages, blood flow velocity in 
capillaries, and length of nailfold. 
Patient Global Assessment (PGA) 
Participant’s overall health will be assessed using the patient-reported outcome instrument of PGA. 
The PGA would rate participant’s overall health related to SSc in the past 7 days, using a 10 cm 
visual analogue scale where 0 = excellent and 10 = extremely poor. A negative change from 
baseline indicates improvement. 
Physician Global Assessment (PhGA) 
PhGA rated participant’s overall health related to SSc in the past 7 days, using a 10 cm visual 
analogue scale where 0 = excellent and 10 = extremely poor. A negative change from baseline 
indicates improvement. 
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5.5.2. 
Analysis Methods 
The analyses of exploratory efficacy endpoints will be based on the FAS. 
Descriptive statistics, such as n, mean, SD, median, IQ range, minimum and maximum for 
continuous variables and counts and percentages for discrete variables will be used to summarize 
data when applicable. The analysis will be based on the observed data; therefore, no imputation of 
missing data will be performed. 
All statistical testing will be performed between treatment groups at the 2-sided 0.2 significance 
level.  
Continuous efficacy endpoints collected at multiple post baseline time points (ie, the endpoints of 
change from baseline) will be compared using a MMRM model. The model will include all 
available data through Week 24 (for endpoints at Week 24) or through Week 52 (for endpoints at 
Week 52).  
The explanatory variables of the MMRM model will include treatment group, baseline value of 
the endpoint, stratification factors (presence of ILD, baseline mRSS and baseline anti-
topoisomerase I antibody status), visit, treatment group by visit interaction, and baseline value of 
the endpoint by visit interaction as fixed effects. The estimates of the treatment difference between 
treatment groups will be provided by the difference in LSMs. The 80% CI for the differences in 
LSMs will be calculated based on the MMRM.  
The analysis of change from baseline in fibrotic change assessed with HRCT at Week 24 and 
nailfold capillaries change at Week 24 will be performed using ANCOVA (analysis of covariance) 
model with baseline value of the endpoint as covariate, and stratification factors (presence of ILD, 
baseline mRSS and baseline anti-topoisomerase I antibody status) and treatment group as factors.  
A logistic regression model will be used to compare the proportion of participants achieving 
selected endpoints (eg, worsening of % predicted FVC) between guselkumab and placebo. The 
analyses will include treatment group, stratification factors (presence of ILD, baseline mRSS and 
baseline anti-topoisomerase I antibody status) as factors. The same intercurrent events and 
composite strategy defined in Section 5.4.2.2 will be applied to following endpoints as well: 
 
The proportion of participants who experience FVC decline compared with baseline through 
Week 52 
 
The proportion of participants who experience worsening of FVC through Week 52 
A summary of baseline values and change from baseline at Week 24 and Week 52 will be presented 
for nailfold capillaroscopy. 
As to time to event endpoint, ie, time to disease worsening, it will be summarized by Kaplan-Meier 
method, with the median, 25th, and 75th percentiles and 95% CI for the quartiles. The comparison 
between guselkumab and placebo will use a Cox proportional hazards model adjusting for the 
stratification factors at randomization. An 80% CI for the hazard ratio (HR) will be produced. The 
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same intercurrent events and handling strategy defined in Section 5.4.2.2 will be applied to this 
endpoint as well, the detailed definition of censoring and event is described as below: 
No. 
Situation 
Date 
of 
Event 
or 
Censoring 
Outcome 
1 
Disease worsening: an increase from 
baseline ≥5 and ≥20% in mRSS or 
decrease >10% from baseline in FVC % 
First 
occurrence 
of 
disease worsening 
Event 
2 
A prohibited change in SSc medication 
on or before Week 52 
First 
occurrence 
of 
prohibited change 
Event 
3 
Discontinuation of study intervention 
due to lack of efficacy or an AE of SSc 
before Week 52 
Date of discontinuation 
of study intervention 
Event 
4 
Initiation of rescue medication after 
Week 24 and through Week 52 
Date of initiation of 
rescue medication 
Event 
5 
Other  
Date of last mRSS or 
FVC 
assessment 
through Week 52 
Censored 
Note: if participants had more than one items of 1,2,3,4 occurred, the date of first occurrence will 
be considered as event date. 
Unless otherwise specified, LTE efficacy endpoints will only be summarized using descriptive 
statistics.  
5.6. 
Other Efficacy Analyses 
Descriptive statistics of primary, secondary and exploratory efficacy endpoints will be provided 
by study intervention at each scheduled visit through week 24/52/76/104 if applicable. These 
endpoints will be analyzed by the method described in Section 5.3.3, 5.4.2.3 and 5.5.2 respectively.  
LS mean and standard error of LS mean, together with the LS mean difference between treatment 
groups will be calculated for the continuous endpoints, while for the binary endpoints, the odds 
ratio will be calculated. 
Listings of primary, secondary and exploratory efficacy endpoints will be provided. 
5.7. 
Safety Analyses 
All safety analyses will be based on the safety analysis set and presented by actual intervention 
received, unless otherwise specified. 
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For all continuous safety variables, descriptive statistics by intervention group will include the N, 
mean, standard deviation, median, minimum, and maximum. Categorical variables will be 
summarized by intervention group using frequency counts and percentages. 
5.7.1. 
Extent of Exposure 
The number and percentage of participants who receive study interventions will be summarized 
by visit.  
Descriptive statistics for duration of study interventions will be summarized. Study intervention 
duration (weeks) is defined as ((date of last dose of study intervention – date of first dose of study 
intervention) +1)/7. 
For IV doses, the number (%) of participants with a study intervention modification during the 
infusion will be summarized by intervention group and visit.  
Descriptive statistics will be presented for the following parameters: 
 
Number of administrations 
 
Cumulative total dose 
Intervention compliance will be summarized descriptively. See Appendix 7 for further details. 
5.7.2. 
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 intervention is considered to be treatment emergent. If the event 
occurs on the day of the initial administration of study intervention, and either event time or time 
of administration are missing, then the event will be assumed to be treatment emergent. If the event 
date is recorded as partial or completely missing, then the event will be considered to be treatment 
emergent unless it is known to be prior to the first administration of study intervention based on 
partial onset date or resolution date. All reported treatment-emergent adverse events will be 
included in the analysis.  For each adverse event, the number and percentage of participants who 
experience at least 1 occurrence of the given event will be summarized by intervention group. 
Summary tables will be provided for treatment-emergent adverse events in the main study period 
and LTE period: 
 
AEs 
 
Serious AEs (SAEs) 
 
AEs leading to discontinuation of study intervention 
 
AEs by severity 
 
AEs by relationship to study intervention 
 
AEs leading to drug interruption 
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 
Infusion reaction 
 
Injection site reaction 
 
Covid-19 related AEs and SAEs 
In addition to the summary tables, listings will be provided for participants who: 
 
Had SAEs 
 
Had AEs leading to discontinuation of study intervention 
Incidence of other treatment-emergent adverse events of special interest will be summarized. See 
Appendix 8 for list of adverse events in each category. 
Deaths will be displayed by actual intervention received. Frequencies for the following parameters 
will be included in the summary table: 
 
Number of participants who died 
 
Cause of death 
 
Relationship to study intervention (yes/no) 
A listing of participants who died will be provided. 
5.7.3. 
Additional Safety Assessments  
5.7.3.1. 
Clinical Laboratory Tests 
Clinical laboratory tests will be displayed for the participants included in the safety analysis set. 
Descriptive statistics will be presented for selected chemistry, hematology, and urinalysis (pH and 
specific gravity) laboratory tests at scheduled time points. 
Change from baseline over time through Week 52 will be summarized for selected chemistry, 
hematology, and urinalysis (pH, and specific gravity) tests and displayed by intervention group. A 
box plot of change from baseline over time through Week 52 will be provided for the following 
laboratory tests: hematology: hemoglobin, platelets, total WBC, absolute lymphocytes, and 
absolute neutrophils; chemistry: ALT, AST, Alkaline phosphatase and total bilirubin. 
Applicable lab results are to be graded based on National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) version 5.0. The laboratory tests not included in the 
NCI-CTCAE criteria will not be presented in the corresponding tables or listings. 
Summary of maximum postbaseline NCI-CTCAE toxicity grade through Week 52 will be 
presented. Additionally, shift table from baseline laboratory value to the worst toxicity grade 
through Week 52 in chemistry and hematology tests with NCI-CTCAE will be summarized for the 
following lab parameters: hematology: hemoglobin, platelets, total WBC, absolute lymphocytes, 
and absolute neutrophils; chemistry: ALT, AST, Alkaline phosphatase and total bilirubin. 
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Proportion of participants with maximum postbaseline ALT and AST through Week 52 will be 
provided for the categories:   
 
>1 to ≤3 x ULN 
 
 >3 to ≤5 x ULN 
 
 >5 to ≤10 x ULN 
 
 >10 to ≤20 x ULN 
 
>20 x ULN 
Besides, proportion of participants with total bilirubin >2 x ULN and either AST or ALT ≥3 x 
ULN at the same timepoint will also be provided. 
In addition, proportion of participants with maximum postbaseline alkaline phosphatase through 
Week 52 will be provided for the categories:   
 
≤1 x ULN 
 
>1 to ≤1.5 x ULN 
 
 >1.5 to ≤2.5 x ULN 
 
 >2.5 to ≤5 x ULN 
 
 >5 to ≤20 x ULN 
 
>20 x ULN 
Above analysis will also be summarized through LTE period. 
Listings of participants with any abnormal postbaseline laboratory values of NCI-CTCAE grade 
≥2 or any abnormal postbaseline laboratory values of reference range will also be provided. 
5.7.3.2. 
Vital Signs and Physical Examination Findings 
Continuous vital sign parameters including temperature, respiratory rate, weight, pulse and blood 
pressure (systolic and diastolic) will be summarized at each assessment time point. Change from 
baseline will be summarized through Week 52 and through end of LTE period. Descriptive 
statistics will be presented. 
Incidence of markedly abnormal vital signs during intervention, as defined in Table 4, will be 
summarized. A listing of participants with markedly abnormal vital signs will be presented, along 
with a listing of all vital sign measurements. 
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Table 4: 
Markedly Abnormal Vital Signs 
Vital Sign 
Criteria 
Pulse 
>120 bpm and with ≥15 bpm increase from baseline 
 
<50 bpm and with ≥15 bpm decrease from baseline 
Systolic blood pressure 
>180 mm Hg and with ≥20 mm Hg increase from baseline 
 
<90 mm Hg and with ≥20 mm Hg decrease from baseline 
Diastolic blood pressure 
>105 mm Hg and with ≥15 mm Hg increase from baseline 
 
<50 mm Hg and with ≥15 mm Hg decrease from baseline 
Temperature 
>38 oC  
 
< 36 oC 
Respiratory rate 
>24 breaths per minute 
 
<12 breaths per minute 
5.7.3.3. 
Electrocardiogram 
The interpretation of the ECGs as determined by a qualified physician (investigator or qualified 
designee) will be displayed by the number and percentage of participants meeting the normality 
criteria. The interpretation will be summarized over time. 
Listings will be produced for all ECG data including unscheduled visit data. A listing of clinically 
relevant ECG abnormalities will also be provided. 
5.8. 
Other Analyses 
5.8.1. 
Pharmacokinetics 
Blood samples for measuring serum guselkumab concentrations will be collected from all 
participants at the specified visits as indicated in the Schedule of Activities in protocol. PK 
analyses will be performed on the PK analysis set (Section 4). 
Serum guselkumab concentrations summary and analysis will be based on the observed data; 
therefore, no imputation of missing data will be performed. 
All PK data including actual sampling time will be listed. All serum guselkumab 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 dataset. All 
participants and samples excluded from the analysis will be clearly documented (eg, unknown or 
unreliable drug intake information). 
Serum guselkumab concentrations over time from Week 0 through Week 52 and from Week 52 to 
Week 104 will be summarized in tables for guselkumab treatment group for each scheduled visit 
with arithmetic mean, SD, coefficient of variation (%CV), median, minimum, maximum, 25% 
quartile and 75% quartile. Serum guselkumab concentrations over time from Week 52 through 
Week 104 will be summarized by intervention group. 
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Serum guselkumab concentrations over time from Week 0 to Week 52 and from Week 52 to 104 
will be also summarized in tables by the following subgroups:  
 
Baseline body weight category (≤ median / >median) 
 
Antibodies to guselkumab status by Subject ADA status who have at least one positive ADA 
sample or no positive ADA sample through Week 52/104. 
PK concentration data from Week 0 to Week 52 and from Week 52 to 104 will be also displayed 
graphically by following figures.  
 
Median (IQR) of serum guselkumab concentration time profiles through Week 52 and from 
Week 52 to 104 (in linear and semi-log scales) with nominal sampling time (for analysis from 
Week 52 through Week 104, shown by intervention group).  
 
Median (IQR) of serum guselkumab concentration time profiles through Week 52 and from 
Week 52 to 104 (in linear and semi-log scales) with nominal sampling time by Subject ADA 
status who have at least one positive ADA sample or no positive ADA sample (for analysis 
from Week 52 to Week 104, shown by intervention group). 
For each population including participants who performed self-study intervention administration 
at Week 84, 92 or 100, serum guselkumab concentrations at Week 88, 96 or 104, respectively, will 
be summarized in table by following group: guselkumab arm in DB period and placebo arm in DB 
period. Also, serum guselkumab concentration at Week 76 will be summarized for each population 
(ie, participants who performed self-study intervention administration at Week 84, 92 or 100 and 
whose serum concentrations were summarized at 88, 96 or 104). 
For descriptive statistics of serum concentrations of guselkumab, the following data handling rules 
will be applied: 
 
Participants will be excluded from the PK analysis if their data do not allow for accurate 
assessment of the PK. In particular, all serum concentration summaries will exclude, from the 
time of occurrence, data collected for participants who 1) discontinue guselkumab, 2) skip an 
infusion or injection, 3) receive an incomplete infusion or injection, 4) receive an incorrect 
infusion or injection, 5) receive an additional infusion or injection, and/or 6) receive 
commercial guselkumab. Exclusion data from PK analysis due to such inadequate 
administration will be specified by PK analyst. In addition, PK samples taken outside the 
scheduled visit window (±7 days for all scheduled visits) will be excluded from the summaries. 
Post-infusion samples that occurred more than 24 hours after infusion will be also excluded. 
 
Serum concentrations of guselkumab data will be calculated based on the number of 
participants with observed data, including BQL, at each sampling time. 
 
When more than half (>50%) of the serum concentrations of guselkumab are BQL at each 
scheduled time point, mean, median, minimum and 25% quartile will be shown as ‘BQL’, and 
SD and %CV and 75% quartile will be shown as ‘NC’ (not calculated). Maximum observed 
value will be presented as maximum. 
 
When all serum concentration data are BQL at each scheduled time point, mean and median 
will be reported as ‘BQL’; SD and %CV are reported as ‘NC’ (not calculated); IQ range, 
maximum and minimum will be reported as ‘BQL’. 
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 
When the number of serum concentrations data of guselkumab at each scheduled time point 
is less than or equal to 2, N, mean and median will be calculated, and SD, %CV, 25% quartile 
and 75% quartile will be shown as ‘NC’. Minimum and maximum will be shown as ‘NC’ 
(quantifiable data=1) or will be reported as observed including BQL (quantifiable data =2). 
 
At the time point where no observation is obtained, ‘NA (not applicable)’ is reported. 
 
Data of samples with no information about the sampling date and time and/or the drug 
administration (time and dosage) will be excluded from descriptive statistics. 
 
Sampling time at Week 0 predose will be substituted with “0” in the figure. The data point at 
which mean of serum guselkumab concentration is BQL will be treated as lower limit of 
quantification (LLOQ) value (eg, 0.01 μg/mL) in graph. 
 
Serum guselkumab concentrations below the LLOQ will be imputed as zero in the summary 
statistics. 
The elapsed time from last dosing of next PK sampling point will be described in listing. 
5.8.2. 
Immunogenicity 
Immunogenicity analyses will be performed on the Immunogenicity analysis set (Section 4). The 
anti-guselkumab antibodies summary and analysis will be based on the observed data; therefore, 
no imputation of missing data will be performed.  
The incidence of positive antibodies, neutralizing antibody (Nabs, as appropriate) and the 
maximum titers of antibodies to guselkumab from Week 0 to Week 24/52/104 will be summarized 
by the intervention group.  
The summary of following endpoints at the following visit will be presented by the intervention 
group and Subject ADA status who have at least one positive ADA sample or no positive ADA 
sample evaluated at the same visit: 
 
Change from baseline in mRSS at Week 24/52 
 
ACR CRISS responder (participants who achieve a score ACR CRISS>=0.6) at Week 24/52 
 
Injection-Site Reactions status through Week 52/104 
If appropriate, these summary by category of titer level for positive participants will also be 
considered. 
A listing of individual immune response including antibody status (negative/positive) for both 
sample level and participant level, Nab status, serum maximum titers, serum guselkumab 
concentration, Injection-Site Reactions status and change from baseline in mRSS at all sampling 
time points for all participants will be provided. In addition, self-study intervention administration 
status will also be included in the listing. 
5.8.3. 
Pharmacodynamics 
Serum will be collected from all participants to assess PD markers associated with guselkumab as 
well as markers related to SSc. Measurements may include but are not limited to serum levels of 
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IL 17A, IL-17F, IL-22, beta defensin-2 (BD-2), and SAA. The samples will be collected at Weeks 
0, 4, 12, 16, 24, 28, and 48 and analyzed by immunoassays. Broader proteomic profiling (eg, via 
Olink method) for biomarker discovery may be performed. Additionally, serum samples should 
also be collected at the final visit from participants who discontinued study intervention or were 
withdrawn from the study. 
Blood samples for the isolation of PBMCs will also be collected for subsequent 
immunophenotyping analyses by multiparameter flow cytometry or mass cytometry (CyTOF) 
analysis to measure immune cell populations before and during treatment. The samples will be 
collected at Weeks 0, 4, 24, and 48. Gene expression analysis may also be performed; this may 
include single cell RNA-seq profiling. Additionally, serum samples for isolation of PBMCs should 
also be collected at the final visit from participants who discontinued study intervention or were 
withdrawn from the study. 
Results of pharmacodynamic/biomarker analyses will be presented in a separate report. 
5.8.4. 
Pharmacokinetic/Pharmacodynamic Relationships 
Pharmacokinetic/Pharmacodynamic analyses will be based on the PK/PD analysis set for mRSS 
or for ACR CRISS (Section 4). PK and PD data from those whose PK samples are excluded from 
the summaries of PK analysis at Week 12, 24 and 52 will be excluded from the PK/PD analysis at 
Week 12, 24 and 52, respectively. 
The change from baseline score in mRSS at Week 12, 24 and 52 versus serum guselkumab 
concentrations (same visit point) will be tabulated by quartile of guselkumab concentration, for 
each schedule visit. 
This relationship will be also explored graphically by drawing a bar-chart whose height represents 
the change from baseline score in mRSS total score for each quartile of the median of serum 
guselkumab concentration (<=1st quartile, >1st quartile and <= 2nd quartile, >2nd quartile and <= 
3rd quartile, >3rd quartile). 
The serum guselkumab concentrations at Week 12, 24, and 52 will be summarized by quartile of 
the change from baseline score in mRSS (same visit point) for participants randomized to 
guselkumab at Week 0, for each schedule visit. 
This relationship will be also explored graphically by drawing a bar-chart whose height represents 
the median of serum guselkumab concentration for each quartile of the change from baseline score 
in mRSS total score (<=1st quartile, >1st quartile and <= 2nd quartile, >2nd quartile and <= 3rd 
quartile, >3rd quartile). 
If data permits, relationship between the proportions of ACR CRISS responders who achieve a 
score ACR CRISS ≧ 0.6 at Week 12, 24 and 52 and serum guselkumab concentrations (same visit 
point) for participants randomized to guselkumab will be tabulated by quartile of guselkumab 
concentration, for each schedule visit. 
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This relationship will be also explored graphically by drawing a bar-chart whose height represents 
the proportion of responder for each guselkumab concentration quartile (<=1st quartile, >1st 
quartile and <= 2nd quartile, >2nd quartile and <= 3rd quartile, >3rd quartile). 
The difference in guselkumab concentrations over time between responders and non-responders 
of following endpoints will be also assessed for PK/PD analysis set by summarizing serum 
guselkumab concentrations over time through Week 24/52 by scheduled visit and following 
response status of endpoints. The difference in guselkumab concentrations over time between 
response status will be also explored graphically by drawing a median (IQ range) of serum 
guselkumab concentration time profiles through Week 24/52 with nominal sampling time, by the 
intervention group and following response status of endpoints. 
 
An increase from baseline ≥5 points and ≥20% in mRSS achieve/not achieve at Week 24/52 
 
ACR CRISS responder/ non-responder at Week 24/52 
Other efficacy measures and/or relevant PD endpoints, including biomarkers in blood or in skin 
biopsies, versus serum guselkumab concentrations may be explored graphically when appropriate. 
If any visual trend is observed, additional analysis may be conducted if deemed necessary. 
5.9. 
Interim Analyses 
An interim analysis will be performed when all participants have completed EOS of the main study. 
All sponsor personnel will be unblinded at the analyses for internal decision-making and/or 
interactions with health authorities. 
 
 
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6. 
SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1 List of Abbreviations 
ACR 
American College of Rheumatology 
ACR CRISS 
American College of Rheumatology Combined Response Index in diffuse cutaneous systemic 
sclerosis 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BQL 
Below quantification limit 
CI 
Confidence interval 
COVID-19 
Coronavirus disease 2019 
DBL 
Database lock 
dcSSc 
Diffuse cutaneous systemic sclerosis 
DILI 
Drug-induced Liver Injury 
DLCO 
Diffusing capacity of the lung for carbon monoxide 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EOS 
End of study 
EULAR 
European League Against Rheumatism 
FAS 
Full analysis set 
FOIA 
Freedom of Information Act 
FSSG 
Frequency Scale for the Symptoms of Gastroesophageal reflux disease 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GERD 
Gastroesophageal reflux disease 
HAQ-DI 
Health Assessment Questionnaire-Disability Index 
Hgb 
Hemoglobin 
HR 
Hazard ratio 
HRCT 
High resolution computed tomography 
IL 
Interleukin 
ILD 
Interstitial lung disease 
IQR 
Interquartile range 
LLOQ 
Lower limit of quantification 
LSM 
Lease square mean 
LTE 
Long term extension 
MAR 
Missing at random 
MCMC 
Markov Chain Monte Carlo 
MI 
Multiple imputation 
MMRM 
Mixed-Effect Model Repeated Measure 
mRSS 
Modified Rodnan Skin Score 
NAb 
Neutralizing antibodies 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
PGA 
Patient global assessment 
PhGA 
Physician global assessment 
PoC 
Proof of concept 
PK 
Pharmacokinetic(s) 
PD 
Pharmacodynamic 
Q4W 
Every 4 weeks 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SNP 
Single nucleotide polymorphisms 
SSc 
Systemic sclerosis 
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ULN 
Upper Limit of Normal 
WBC 
White blood cell 
WHO-DD 
World Health Organization Drug Dictionary 
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6.2. 
Appendix 2 Changes to Protocol-Planned Analyses 
Not applicable. 
 
 
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6.3. 
Appendix 3 Demographics and Baseline Characteristics 
The number of participants in each analysis set will be summarized by intervention group and 
overall.  
Table 5 presents a list of the demographic variables that will be summarized by intervention group 
and overall, for the FAS.   
Table 5: 
Demographic Variables 
Continuous Variables: 
Summary Type 
Age (years) 
Descriptive statistics (N, mean, 
standard deviation [SD], median,  
range [minimum and maximum] 
and IQ range). 
Weight (kg) 
Height (cm) 
Body Mass Index (BMI) (kg/m2) 
Categorical Variables 
 
Age (<65 years, and >=65 years) 
Frequency distribution with the 
number and percentage of 
participants in each category. 
Sex (male, female, undifferentiated) 
Racea (Asian, Multiple, Other) 
aIf multiple race categories are indicated, the Race is recorded as 'Multiple' 
 
Table 6 presents a list of the baseline disease characteristic variables that will be summarized by 
intervention group and overall, for the FAS.   
Table 6: 
Baseline Disease Characteristic Variables  
Continuous Variables: 
Summary Type 
Duration of SSc (months) 
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum] and IQ range). 
mRSS 
HAQ-DI 
FSSG 
Physician’s Global VAS 
Patients’ Global VAS 
% predicted FVC 
% DLCO 
Categorical Variables 
 
Duration of SSc (≤18 months, > 18 months) 
Frequency distribution with the 
number and percentage of 
participants in each category. 
Use of corticosteroids at baseline (Yes, No) 
Presence of Digital Ulcer (Yes, No) 
mRSS (10-15, 16-22) 
Presence of ILD (Yes, No) 
Baseline Anti-topoisomerase I Antibody (Yes, No) 
 
The use of alcohol and tobacco at baseline in participants will also be collected and summarized.  
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6.4. 
Appendix 4 Protocol Deviations 
In general, the following list of major protocol deviations may have the potential to impact 
participants’ rights, safety or well-being, or the integrity and/or result of the clinical study. 
Participants with major protocol deviations will be identified prior to database lock and the 
participants with major protocol deviations will be summarized by category for different study 
period (main study period and LTE period). 
 
Developed withdrawal criteria but not withdrawn 
 
Entered but did not satisfy criteria 
 
Received a disallowed concomitant treatment 
 
Received wrong treatment or incorrect dose 
 
Other 
In particular, major and minor protocol deviations related with COVID-19 will be collected and 
summarized separately. Separate listings will also be presented for both COVID-19 induced major 
and minor protocol deviations.  
 
 
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6.5. 
Appendix 5 Prior and Concomitant Medications 
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
(WHO-DD). Concomitant medications are defined as any therapy used on or after the same day as 
the first dose of study intervention, including those that started before and continue on after the 
first dose of study intervention. 
Summary of prior medications includes prior biologic treatment history and prior medication 
history used to treat SSc. Prior biologic treatment history will be summarized by intervention group 
and type of medication (ie, IL-23, IL-12/23, IL-17, IL-6, CD20 and other). Prior medication history 
for SSc will also be summarized by intervention group and medication term. 
Medication taken for SSc at baseline will also be captured in eCRF, and summary will be provided 
by type of medication and intervention group. 
Summaries of concomitant medications will be presented by ATC term and intervention group for 
different study period (main study period and LTE period). The proportion of participants who 
receive each concomitant medication will be summarized as well as the proportion of participants 
who receive at least 1 concomitant medication.  
Listings will be provided for participants with prior medications, baseline medications for SSc, 
concomitant medications and rescue medications separately. 
A summary of rescue medications given to participants after week 24 will be provided by visit. 
 
 
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6.6. 
Appendix 6 Medical History 
Medical history (including general medical history, medical history of interest and systemic 
sclerosis conditions of interest) will be listed.  
 
 
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Statistical Analysis Plan CNTO1959SSC2001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 7 June 2023 
6.7. 
Appendix 7 Intervention Compliance 
Compliance to randomized intervention versus actual intervention will be presented in a summary 
table. 
 
 
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Statistical Analysis Plan CNTO1959SSC2001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
44 
Status: Approved,  Date: 7 June 2023 
6.8. 
Appendix 8 Adverse Events of Special Interest 
Adverse events of special interest are defined as below: 
AE Special Interest Category 
Criteria 
Drug-induced Liver Injury (DILI) 
HEPATIC DISORDERS (SMQ) and 
SUB_SMQ1='DRUG RELATED HEPATIC 
DISORDERS - COMPREHENSIVE SEARCH 
(SMQ)' and SCOPE='Narrow' 
 
AE Special Interest Category 
Criteria 
Malignancy 
AE type=’Malignancy’ as assessed by 
investigator in CRF 
Active TB 
AE type=’Active TB’ as assessed by investigator 
in CRF 
ILD 
AE type=’ILD’ as assessed by investigator in 
CRF 
Other 
AE type=’Other’ as assessed by investigator in 
CRF 
 
AE Special Interest Category 
Criteria 
Hypersensitivity Reactions 
HYPERSENSITIVITY (SMQ) and 
SCOPE='Narrow'  
Opportunistic Infections 
OPPORTUNISTIC INFECTIONS (SMQ) and 
SCOPE='Narrow' 
Adverse Cardiovascular Events 
AESDTH (AE leading to death) = 'Y' or 
UPCASE(AEBODSYS) in ('CARDIAC 
DISORDERS','NERVOUS SYSTEM 
DISORDERS','VASCULAR DISORDERS') 
 
After applying above handling rule for Hypersensitivity Reactions, Opportunistic Infections and 
Adverse Cardiovascular Events, the selected AEs will be sent to clinician for review to flag “Yes” 
if AE is considered as AESI. 
 
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CNTO1959  (Guselkumab)  
 
 
 
Statistical Analysis Plan CNTO1959SSC2001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
45 
Status: Approved,  Date: 7 June 2023 
6.9. 
Appendix 9 Medications of Special Interest 
Not applicable. 
 
 
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CNTO1959  (Guselkumab)  
 
 
 
Statistical Analysis Plan CNTO1959SSC2001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
46 
Status: Approved,  Date: 7 June 2023 
6.10. 
Appendix 10 Laboratory Toxicity Grading 
The grading scale use for lab assessments is based on ‘Common Terminology Criteria for Adverse 
Events (CTCAE) v5.0’. 
If a laboratory value falls within the grading as specified below but also within the local laboratory 
normal limits, the value is considered to be normal and will be reset to grade 0. 
Prebaseline measurements will use the same grading ranges as applied to baseline measurements. 
In case a test has two sets of ranges – one for baseline normal and one for baseline abnormal, the 
one for baseline normal will be applied for all measurements taken prebaseline and on baseline. 
Text in gray italic in the table is present in the grading scale, but is not applied by Janssen when 
grading lab data. 
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CNTO1959  (Guselkumab)  
 
 
 
Statistical Analysis Plan CNTO1959SSC2001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
53 
Status: Approved,  Date: 7 June 2023 
6.11. 
Appendix 11 A Prohibited Change in SSC Medication 
 
New start of prohibited and restricted therapies during the study which are defined in the 
protocol Section 6.8: 
 
IL-23 inhibitor therapy (including but not limited to guselkumab, risankizumab, 
tildrakizumab, brazikumab, mirikizumab) 
 
tocilizumab 
 
sirukumab, sarilumab, mavrilimumab, abatacept, belimumab 
 
IL-12/23 inhibitors (ustekinumab) 
 
IL-17 inhibitors (secukinumab, ixekizumab, brodalumab) 
 
tyrosine kinase inhibitor (nintedanib) 
 
Any live viral or live bacterial vaccination 
 
Rituximab  
 
Any cytotoxic agents (cyclophosphamide, chlorambucil, nitrogen mustard, or other 
alkylating agents) 
 
Intravenous 
immunoglobulin 
(IVIG), 
apheresis 
therapy 
(plasmapheresis 
or 
leukopheresis) 
 
Systemic immunosuppressive agents (including but not limited to cyclosporine A, 
azathioprine, tacrolimus, sirolimus, methotrexate, sulfasalazine, leflunomide with 
cholestyramine washout or mycophenolate mofetil/mycophenolic acid) 
 
Intramuscular, intra-articular, intrabursal, epidural, intralesional or IV GCs  
 
Pirfenidone 
 
Systemic and topical Janus kinase inhibitors (eg, tofacitinib, upadacitinib)  
 
Other biologics 
 
Any investigational agents/treatments 
 
Treat with rescue therapy before Week 24, including: 
1) Oral Corticosteroid ≤20 mg/day of prednisolone or equivalent  
2) Immunomodulator (Azathioprine), within the approved dose for SSc 
 
New start of oral Corticosteroid (prednisolone or equivalent) before Week 24. 
 
Significant increase of oral Corticosteroid (prednisolone or equivalent) before Week 24. 
 
 
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Statistical Analysis Plan CNTO1959SSC2001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 7 June 2023 
7. 
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Khanna D, Furst DE, Hays RD, et al. Minimally important difference in diffuse systemic sclerosis: results from the 
D-penicillamine study. Ann Rheum Dis. 2006;65(10):1325-1329. 
Khanna D, Merkel PA. Outcome measures in systemic sclerosis: an update on instruments and current research. 
Curr Rheumatol Rep. 2007;9(2):151-157. 
Matsuda Y, Singh G, Yamanaka H, et al. Validation of a Japanese Version of the Stanford Health Assessment 
Questionnaire in 3,763 Patients With Rheumatoid Arthritis. Arthritis Rheum. 2003;49(6):784–788. 
Ukyo Y and Noma H. Permutation Inference Methods for the MMRM (Mixed-Effects Model for Repeated 
Measures) in Incomplete Longitudinal Data Analysis. Jpn J Biomet 2019;40(1):15-34. 
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