A Phase 2a Multicenter, Randomized, Double Blind, Parallel, Proof of Concept Study Evaluating the Efficacy and Safety of Nipocalimab and Certolizumab Combination Therapy in Participants With Active Rheumatoid Arthritis Despite Prior Treatment With Advanced Therapies (bDMARD or tsDMARD)
Phase: PHASE2
Conditions: Arthritis, Rheumatoid
Sponsor: Janssen Research & Development, LLC

CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved, Date: 05 October 2023
Janssen Research & Development*
Clinical Protocol
A Phase 2a Multicenter, Randomized, Double Blind, Parallel, Proof of concept Study Evaluating
the Efficacy and Safety of Nipocalimab and Certolizumab Combination Therapy in Participants
with Active Rheumatoid Arthritis despite Prior Treatment with Advanced Therapies (bDMARD
or tsDMARD)
DAISY
Protocol 80202135ARA2002; Phase 2
Version:Amendment-3
JNJ-80202135(nipocalimab)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries/territories. Therefore, the legal entity acting as the sponsor for Janssen Research &
Development studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP;
Janssen Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen
Sciences Ireland UC; Janssen Biopharma Inc., or Janssen Research & Development, LLC. The term
“sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is identified
on the Contact Information page that accompanies the protocol.
United States (US) sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
Regulatory Agency Identifier Number(s)
Registry  
ID
IND  
154,384
EU Trial Number 
2023-504045-31
Status: 
Approved
Document Date: 
05 October 2023
Prepared by: 
Janssen Research & Development, LLC
EDMS Number: 
EDMS-RIM-929994, 4.0
GCP Compliance:This study will be conducted in compliance with Good Clinical Practice, Regulation [EU] No 536/2014, 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.
NCT06028438

JNJ-80202135 (nipocalimab)
Clinical Protocol 80202135ARA2002 Amendment-3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status: Approved, Date: 05 October 2023
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Country/Territory Affected  
Date
Amendment 3 
All 
05 October 2023
Amendment 2 
All 
27 September 2023
Amendment 1 
All 
7 September 2023
Original Protocol 
All 
28 March 2023
Amendment 3 (05October 2023)
Overall Rationale for the Amendment:To address FDA comments regarding rescue criteria.
The changes made to the clinical protocol 80202135ARA2002 as part of Protocol Amendment 3 are listed
below, including the rationale of each change and a list of all applicable sections. Changes made in the
previous protocol amendments are listed in Section 10.11 Appendix 11: Protocol Amendment History.
Section Number 
and Name
Description of Change 
Brief Rationale
1.3. SoA  
Weight assessment has been removed from Week
24.
Footnote a) has been modified as:
“Participants who permanently discontinue study
intervention, but do not withdraw from study
participation, will be followed at all subsequent
study visits through Week 30. At a minimum,
participants who permanently discontinue study
intervention, but do not withdraw from study
participation, should return for a safety follow-up
visit 8 weeks after the last dose of study
intervention.Participants who complete dosing at
Week 22 or discontinue study intervention
administration early should return to the site after
approximately 8 weeks after the last dose for a
final safety follow up visit.”
Since no study intervention will be
administered during this visit,
weight assessment is not necessary.
To clarify follow-up of
discontinued participants
2.3.1. Risks for
Study participation
Table 2: Important Risks of Certolizumab for the
treatment of Rheumatoid Arthritis has been
modified:
Deletion of exceptions for participants with
malignancy or history of malignancy
To align with EU-CTR
recommendation
3. Objectives and
Endpoints
Evaluation timepoints for tertiary or exploratory
Endpoints have been updated.
To align that efficacy and PRO
endpoint evaluations are all set to
Week 24 while Safety/PK/PD
endpoint evaluations are all set to
Week 30.
4.1. Overall Design  
Sentence below has been added:
“At Week 14, participants who have not achieved
low disease activity (CDAI ≤10) will receive
rescue medication”.
To follow current SOC in RA.
4.4. End of Study 
Definition 
Completion of the safety follow-up visit was added
to the definition of participants who complete the
study.
Further clarification on the
definition of completing the study.
5.1 Inclusion 
Criteria; 5.2. 
Inclusion and exclusion criteria concerning
COVID-19 have been modified:
To align with sponsor protocol
template update.

JNJ-80202135 (nipocalimab)
Clinical Protocol 80202135ARA2002 Amendment-3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
3
Status: Approved, Date: 05 October 2023
Section Number 
and Name
Description of Change 
Brief Rationale
Exclusion Criteria; 
5.3. Lifestyle 
Considerations 
IC#27 has been removed and guidance is now
included in Section 6.8.7.
EC#25 has been modified to reduce the time
interval participants have to be free of COVID-19
prior to baseline from 6 to 4 weeks.
IC#22 has been modified.
5.4. Screen Failures 
Updated the text regarding screening logs. 
To conform to the current sponsor
protocol template.
6.3. Measures to 
Minimize Bias: 
Randomization and 
Blinding 
Blinding sub-section has been modified to add: 
“At the Week 12 DBL, data will be unblinded for 
analysis to some Sponsor personnel while 
participants are still participating in the study. 
Identification of Sponsor personnel who will have
access to the unblinded subject-level data will be
documented prior to unblinding. Investigative
study sites and participants will remain blinded to
initial treatment assignment until after the final
database is locked.”
To clarify that the Sponsor only has
defined and limited persons to
access to unblinded data after Week
12 DBL.
6.4. Study 
Intervention 
Compliance
Weighing of IV infusion bag has been removed. 
Weighing of IV infusion bag is not
part of the study procedures.
6.8. Concomitant 
Therapy  
Table 3 outlining permitted concomitant 
medication use and dose stabilization requirements 
prior to randomization was added. 
To clarify permitted concomitant
medication use and dose
stabilization requirements prior to
randomization.
6.8.6. Rescue 
Medication 
Rescue medication guidance at Week 14 was 
updated. 
The guidance is updated to follow
current SOC in RA.
8.2.3. 
Electrocardiograms 
Section has been modified to add: 
“A 12-lead ECG will be performed locally at 
screening. Additional ECGs can be performed 
locally based on the investigator’s judgment.” 
Information about triplicate ECGs has been
removed.
To follow the study design and
SOA notes that ECG will be
performed and evaluated per local
practices.
8.2.13. Tuberculosis 
Evaluation  
Added a Section to detail the assessments to be 
done for initial and continuous TB assessment. 
To provide more detailed guidance
to investigators.
8.3.5. Pregnancy  
Updated text from template: 
“Any participant who becomes pregnant during the
study must discontinue further study intervention.”
To conform to the current sponsor
protocol template.
9.4.2.1. Primary 
Estimand of Change 
from Baseline in
DAS28-CRP at
Week 12
ICE category 5 has been deleted. 
To align with sponsor protocol
template update.
9.4.4. Safety 
Analyses 
Added information on the on-study Safety 
Analysis-Set, as well as details on exposure- 
adjusted supplementary on-treatment analysis for 
treatment emergent AEs. 
The primary safety analysis will
use the on-study Safety Analysis-
Set, ie, participants who received at
least one dose (complete or partial)
of any study intervention.
Appendix 2: 
Clinical laboratory 
tests
Details have been added on the urine pregnancy 
testing: 
To follow suggested contraception
period on Cimzia label.

JNJ-80202135 (nipocalimab)
Clinical Protocol 80202135ARA2002 Amendment-3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
4
Status: Approved, Date: 05 October 2023
Section Number
and Name
Description of Change 
Brief Rationale
“Participants of childbearing potential will be
given urine pregnancy tests to be self-administered
at home until 5 months after their last dose of the
study intervention. The site is responsible for
contacting these participants on a monthly basis to
confirm that the pregnancy test has been
performed. If a participant tests positive for
pregnancy, the site is required to report this to the
sponsor within 24 hours of becoming aware of the
event”.
10.3.6. Long-term
Retention of
Samples for
Additional Future
Research
Updated text from template: 
“No additional research on study participants, study
samples, or data derived from the study will be
conducted by the institution(s) or by a third party,
without the prior written consent of the Sponsor.”
To conform to the current sponsor
protocol template.
10.3.11. Source
Documents
Updated text from template: 
“Given that patient-reported outcomes (PROs) are
reports of a patient’s health condition that come
directly from the patient, without interpretation by
a clinician or anyone else, the responses to PRO
measures entered by study participants into source
records cannot be overridden by site staff or
investigators.”
To conform to the current sponsor
protocol template.
10.5. Appendix 5:
Contraceptive and
Barrier Guidance
Updated text from template: 
Replaced “woman” by “female participant”.
Deletion of footnote b).
To conform to the current sponsor
protocol template.
Throughout the
protocol
Minor grammatical, formatting, or spelling changes 
were made.
Minor errors were noted.

JNJ-80202135 (nipocalimab)
Clinical Protocol 80202135ARA2002 Amendment-3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
5
Status: Approved, Date: 05 October 2023
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 8
TABLES ........................................................................................................................................................ 8
1. 
PROTOCOL SUMMARY..................................................................................................................... 9
1.1. 
Synopsis........................................................................................................................................... 9
1.2. 
Schema.......................................................................................................................................... 14
1.3. 
Schedule of Activities (SoA)........................................................................................................... 15
2. 
INTRODUCTION................................................................................................................................ 20
2.1. 
Study Rationale.............................................................................................................................. 20
2.2. 
Background .................................................................................................................................... 21
2.2.1. 
Combination Therapy ................................................................................................................. 23
2.3. 
Benefit-risk Assessment................................................................................................................. 23
2.3.1. 
Risks for Study Participation....................................................................................................... 23
2.3.2. 
Benefits for Study Participation .................................................................................................. 30
2.3.3. 
Benefit-risk Assessment for Study Participation......................................................................... 31
3. 
O BJECTIVES AND ENDPOINTS .................................................................................................... 32
4. 
STUDY DESIGN ................................................................................................................................ 35
4.1. 
Overall Design................................................................................................................................ 35
4.2. 
Scientific Rationale for Study Design............................................................................................. 36
4.2.1. 
Participant Input into Design....................................................................................................... 37
4.2.2. 
Study-specific Ethical Design Considerations ............................................................................ 37
4.3. 
Justification for Dose...................................................................................................................... 38
4.3.1. 
Nipocalimab................................................................................................................................ 38
4.3.2. 
Certolizumab............................................................................................................................... 39
4.3.3. 
Nipocalimab and Certolizumab Combination ............................................................................. 39
4.4. 
End of Study Definition................................................................................................................... 40
5. 
STUDY POPULATION ...................................................................................................................... 41
5.1. 
Inclusion Criteria............................................................................................................................ 41
5.2. 
Exclusion Criteria........................................................................................................................... 44
5.3. 
Lifestyle Considerations................................................................................................................. 48
5.4. 
Screen Failures.............................................................................................................................. 49
5.5. 
Criteria for Temporarily Delaying Administration of Study Intervention ......................................... 49
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY............................................................ 50
6.1. 
Study Intervention(s) Administered................................................................................................ 50
6.1.1. 
Authorization Status in the EU (EU-CTR)................................................................................... 50
6.1.2. 
Administration ............................................................................................................................. 50
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 52
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 52
6.4. 
Study Intervention Compliance...................................................................................................... 54
6.5. 
Dose Modification........................................................................................................................... 54
6.6. 
Continued Access to Study Intervention After the End of the Study ............................................. 54
6.7. 
Treatment of Overdose .................................................................................................................. 54
6.8. 
Concomitant Therapy..................................................................................................................... 55
6.8.1. 
Acetaminophen/Paracetamol ..................................................................................................... 56
6.8.2. 
Nonsteroidal Anti-inflammatory Drugs and Other Analgesics .................................................... 56
6.8.3. 
Disease Modifying Antirheumatic Drugs/Systemic Immunosuppressives.................................. 56
6.8.4. 
Corticosteroid Therapy ............................................................................................................... 57

JNJ-80202135 (nipocalimab)
Clinical Protocol 80202135ARA2002 Amendment-3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 05 October 2023
6.8.5. 
Prohibited Medications ............................................................................................................... 57
6.8.6. 
Rescue Medication ..................................................................................................................... 58
6.8.7. 
Vaccinations (Including COVID-19)............................................................................................ 58
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 60
7.1. 
Discontinuation of Study Intervention ............................................................................................ 60
7.1.1. 
Liver Chemistry Stopping Criteria............................................................................................... 61
7.1.2. 
Study Stopping Rules ................................................................................................................. 61
7.2. 
Participant Discontinuation/Withdrawal From the Study................................................................ 61
7.2.1. 
Withdrawal From the Use of Research Samples ....................................................................... 62
7.3. 
Lost to Follow up............................................................................................................................ 63
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 64
8.1. 
Efficacy Assessments .................................................................................................................... 65
8.1.1. 
Evaluations ................................................................................................................................. 65
8.1.2. 
Definitions ................................................................................................................................... 66
8.2. 
Safety Assessments....................................................................................................................... 69
8.2.1. 
Physical Examinations................................................................................................................ 70
8.2.2. 
Vital Signs................................................................................................................................... 70
8.2.3. 
Electrocardiograms..................................................................................................................... 70
8.2.4. 
Clinical Safety Laboratory Assessments .................................................................................... 70
8.2.5. 
Pregnancy Testing...................................................................................................................... 71
8.2.6. 
Concomitant Medication Review ................................................................................................ 71
8.2.7. 
Adverse Events Temporally Associated with Infusion................................................................ 71
8.2.8. 
Infusion Reactions ...................................................................................................................... 71
8.2.9. 
Injection Site Reactions .............................................................................................................. 71
8.2.10. 
Hypersensitivity Reactions.......................................................................................................... 71
8.2.11. 
Infections .................................................................................................................................... 72
8.2.12. 
Increased Lipids.......................................................................................................................... 72
8.2.13. 
Tuberculosis Evaluation.............................................................................................................. 72
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting ....................................... 73
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information.................................................................................................................................. 73
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 74
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 75
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events and Anticipated
Events......................................................................................................................................... 75
8.3.5. 
Pregnancy................................................................................................................................... 75
8.3.6. 
Adverse Events of Special Interest............................................................................................. 76
8.4. 
Pharmacokinetics........................................................................................................................... 76
8.4.1. 
Evaluations ................................................................................................................................. 76
8.4.2. 
Analytical Procedures................................................................................................................. 77
8.4.3. 
Pharmacokinetic Parameters and Evaluations........................................................................... 77
8.5. 
Genetics and Pharmacogenomics................................................................................................. 77
8.6. 
Biomarkers..................................................................................................................................... 78
8.6.1. 
Pharmacodynamics .................................................................................................................... 78
8.6.2. 
Serum and Plasma Biomarkers.................................................................................................. 79
8.6.3. 
Whole Blood Gene Expression Profile ....................................................................................... 79
8.6.4. 
Peripheral Blood Mononuclear Cells .......................................................................................... 79
8.7. 
Immunogenicity Assessments ....................................................................................................... 79
8.8. 
Health Economics .......................................................................................................................... 80
9. 
STATISTICAL CONSIDERATIONS.................................................................................................. 81
9.1. 
Statistical Hypotheses.................................................................................................................... 81
9.2. 
Sample Size Determination ........................................................................................................... 81
9.3. 
Participant Analysis Sets................................................................................................................ 82
9.4. 
Statistical Analyses ........................................................................................................................ 82

JNJ-80202135 (nipocalimab)
Clinical Protocol 80202135ARA2002 Amendment-3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
7
Status: Approved, Date: 05 October 2023
9.4.1. 
General Considerations.............................................................................................................. 82
9.4.2. 
Primary Endpoint(s).................................................................................................................... 83
9.4.3. 
Secondary Endpoint(s)............................................................................................................... 84
9.4.4. 
Safety Analyses.......................................................................................................................... 85
9.4.5. 
Tertiary or Exploratory Efficacy Endpoints ................................................................................. 85
9.4.6. 
Other Analyses ........................................................................................................................... 86
9.5. 
DMC ............................................................................................................................................... 87
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 88
10.1. 
Appendix 1: Abbreviations and Definitions .................................................................................... 88
10.2. 
Appendix 2: Clinical Laboratory Tests ........................................................................................... 91
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations......................................... 93
10.3.1. 
Regulatory and Ethical Considerations ...................................................................................... 93
10.3.2. 
Financial Disclosure.................................................................................................................... 96
10.3.3. 
Informed Consent Process ......................................................................................................... 96
10.3.4. 
Recruitment Strategy.................................................................................................................. 97
10.3.5. 
Data Protection ........................................................................................................................... 98
10.3.6. 
Long-term Retention of Samples for Additional Future Research.............................................. 98
10.3.7. 
Committees Structure................................................................................................................ . 99
10.3.8. 
Publication Policy/Dissemination of Clinical Study Data............................................................ 99
10.3.9. 
Data Quality Assurance............................................................................................................ 100
10.3.10. Case Report Form Completion................................................................................................. 101
10.3.11. Source Documents ................................................................................................................... 101
10.3.12. Monitoring ................................................................................................................................. 102
10.3.13. On-site Audits ........................................................................................................................... 103
10.3.14. Record Retention...................................................................................................................... 103
10.3.15. Study and Site Start and Closure ............................................................................................. 104
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............................................................................................................................... 105
10.4.1. 
Adverse Event Definitions and Classifications ......................................................................... 105
10.4.2. 
Attribution Definitions................................................................................................................ 106
10.4.3. 
Severity Criteria........................................................................................................................ 106
10.4.4. 
Special Reporting Situations .................................................................................................... 107
10.4.5. 
Procedures ............................................................................................................................... 107
10.4.6. 
Product Quality Complaint Handling......................................................................................... 109
10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality........................................... 109
10.5. 
Appendix 5: Contraceptive and Barrier Guidance ....................................................................... 110
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments................................ 113
10.6.1. 
Stopping Algorithm ................................................................................................................... 113
10.6.2. 
Follow-up Assessments............................................................................................................ 113
10.7. 
Appendix 7: Study Conduct During a Pandemic.......................................................................... 117
10.8. 
Appendix 8: Hepatitis B Virus (HBV) Screening with HBV DNA Testing..................................... 118
10.9. 
Appendix 9: Criteria for Assessing Potential Cases of Anaphylaxis............................................ 119
10.10. Appendix 10: Definition of Inadequate Initial Response, and Loss of Response to
Advanced Therapies (bDMARD or tsDMARD) in RA .................................................................. 120
10.11. Appendix 11: Protocol Amendment History................................................................................. 122
11. REFERENCES................................................................................................................................. 125
INVESTIGATOR AGREEMENT............................................................................................................... 126

JNJ-80202135 (nipocalimab)
Clinical Protocol 80202135ARA2002 Amendment-3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
8
Status: Approved, Date: 05 October 2023
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Important Potential Risks of Nipocalimab for the Treatment of Rheumatoid Arthritis .............. 24
Table 2: 
Important Risks of Certolizumab for the treatment of Rheumatoid Arthritis ............................. 28
Table 3: 
Permitted Concomitant Medications for 80202135ARA2002, the Minimum
Stabilization Period before Randomization, and the Maximum Allowed Doses at Study
Randomization.......................................................................................................................... 56
Table 4: 
DAS28 Response Criteria......................................................................................................... 67
Table 5: 
Statistical Power for Treatment Difference in Change from Baseline in DAS28-CRP at
Week 12.................................................................................................................................... 81
FIGURES
Figure 1: Schematic Overview of the Study............................................................................................. 14

JNJ-80202135 (nipocalimab)
Clinical Protocol 80202135ARA2002 Amendment-3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
9
Status: Approved, Date: 05 October 2023
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
A Phase 2a Multicenter, Randomized, Double Blind, Parallel, Proof of concept Study Evaluating
the Efficacy and Safety of Nipocalimab and Certolizumab Combination Therapy in Participants
with Active Rheumatoid Arthritis despite Prior Treatment with Advanced Therapies (bDMARD
or tsDMARD)
DAISY
DESCRIPTION OF COMPOUND
Nipocalimab (also referred to as JNJ-80202135 and M281) is a fully human aglycosylated IgG1
monoclonal antibody designed to selectively bind, saturate, and block the IgG binding site on the
endogenous neonatal Fc receptor.
Certolizumab (Cimzia®) is an approved anti-TNFα agent indicated for active Crohn’s disease,
RA, PsA, AS, nr-axSpA, and PsO.
BENEFIT-RISK ASSESSMENT
The study population with moderately to severely active RA has already had inadequate initial
response, loss of response, or intolerance to ≥1 advanced therapy (bDMARDs or tsDMARDs),
therefore combination therapy may provide a higher chance of lower disease activity and
remission. Multiple risk mitigation measures are in place to manage a potential increase in
infections risk with certolizumab and nipocalimab combination therapy.  Based on the well
characterized safety profile of certolizumab and the available safety data of nipocalimab to date,
the overall anticipated benefits outweigh the risks of participation in this clinical study.
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
To evaluate the efficacy of combination therapy with 
nipocalimab and certolizumab compared to 
certolizumab monotherapy in participants with
moderately to severely active RA despite ≥1 advanced
therapy (bDMARDs or tsDMARDs).
Change from baseline in
DAS28-CRP at Week 12
Secondary
To evaluate the efficacy of combination therapy with 
nipocalimab and certolizumab compared to 
certolizumab monotherapy in participants with
moderately to severely active RA
ACR20, ACR50, ACR70, and
ACR90 responses at Week 12
DAS28-CRP remission at Week 12
DAS28-CRP LDA at Week 12
Change from baseline in HAQ-DI
score at Week 12
Change from baseline in CDAI at
Week 12

JNJ-80202135 (nipocalimab)
Clinical Protocol 80202135ARA2002 Amendment-3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
10
Status: Approved, Date: 05 October 2023
Objectives 
Endpoints
To evaluate the safety and tolerability of combination 
therapy with nipocalimab and certolizumab
Treatment-emergent AE
Treatment-emergent SAEs
Treatment-emergent AEs leading to
discontinuation of study
intervention
Treatment-emergent AESIs
HYPOTHESIS
The primary hypothesis is that treatment with nipocalimab in combination with certolizumab is superior to
certolizumab monotherapy in participants with moderately to severely active RA despite treatment with ≥1
advanced therapy (bDMARDs or tsDMARDs) as assessed by the mean change from baseline in
DAS28-CRP at Week 12.
OVERALL DESIGN
This is a randomized, double-blind, parallel, multicenter, interventional study in participants with
moderately to severely active RA despite ≥1 advanced therapy (bDMARDs or tsDMARDs).
The total duration of the study is up to 36 weeks, consisting of 3 study periods, a 6-weekscreening period,
a 24-weekdouble-blind study period (22 weeks of treatment), and 6 weeks of safety follow-up (8 weeks
after last dose).
Participants who have had an IR to at least one advanced therapy (bDMARDs or tsDMARDs) but are
certolizumab naïve, will be enrolled. Participants will be randomized into 1 of 2 arms. The experimental
arm will receive nipocalimab and certolizumab combination therapy. A placebo and certolizumab control
arm will be used to allow for blinded evaluation of the efficacy and safety of certolizumab and nipocalimab
combination therapy in participants with moderately to severely active RA.
Efficacy, safety, PK, immunogenicity, and biomarkers will be assessed according to the SoA.
Pharmacogenomic blood samples will be collected from participants who consent to the collection (and
where local regulations permit).
The primary endpoint (change from baseline in DAS28-CRP at Week 12) and secondary endpoints will be
evaluated after all participants have completed the Week 12 visit or have discontinued. Tertiary or
exploratory efficacy endpoints will be evaluated by visit through Week 24 (efficacy and PRO endpoints)
or Week 30 (safety/PK/PD endpoints) after all participants have completed the Week 24 visit or have
discontinued.
An external independent DMC will be commissioned for this study.
NUMBER OF PARTICIPANTS
A total of approximately 85 participants are planned to be enrolled.
INTERVENTION GROUPS AND DURATION
Participants will be randomly assigned to 1 of 2 treatment groups using a 2:3 randomization ratio.
Control arm: placebo matching nipocalimab and certolizumab (certolizumab monotherapy)
Experimental arm: Nipocalimab and certolizumab (combination therapy)

JNJ-80202135 (nipocalimab)
Clinical Protocol 80202135ARA2002 Amendment-3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 05 October 2023
Nipocalimab will be administered at 30 mg/kg Q2W. Certolizumab will be administered at 400 mg as a
loading dose at Week 0, 2, 4 and then reduced to 200 mg Q2W as a maintenance dose. Both groups will
receive their assigned treatment for 22 weeks (Week 0 through Week 22).
EFFICACY EVALUATIONS
Patient-reported outcomes and clinician-reported outcomes of efficacy include the following:
• 
Patient-reported outcomes
Patient’s Global Assessment of Disease Activity
Pain visual analog scale
Joint Pain Severity Numeric Rating Scale
Health Assessment Questionnaire –Disability Index
• 
Clinician-reported outcomes
Joint assessment
Physician’s Global Assessment of Disease Activity
PHARMACOKINETIC EVALUATIONS
Serum samples will be used to evaluate the PK of nipocalimab and certolizumab.
IMMUNOGENICITY EVALUATIONS
Antibodies to nipocalimab will be evaluated in serum samples collected from all participants according to
the SoA. Additionally, serum samples should be collected at the final visit from participants who
discontinued study intervention or were withdrawn from the study.
PHARMACODYNAMIC,BIOMARKER EVALUATIONS
Samples for the analysis of PD biomarkers will be collected from all participants as specified in the SoA,
where local regulations permit. Serum or plasma concentrations of immunoglobulins, albumin, and disease
biomarkers (eg, autoantibodies, circulating immune complexes) will be measured to assess the PD effect
of nipocalimab and certolizumab combination therapy.
Blood samples for serum and plasma biomarker analyses will be collected from all participants where local
regulations permit. Serum and plasma will be analyzed for levels of circulating proteins, autoantibodies
(eg, ACPA, RF), and other inflammation-related molecules and disease-associated serologies relevant to
RA, treatment, and response to nipocalimab and certolizumab combination therapy.
PHARMACOGENOMIC (DNA) EVALUATIONS
A pharmacogenomic blood sample may be collected to allow for pharmacogenomic research, as necessary
and where local regulations permit. Participation in the pharmacogenomic research is optional.
SAFETY EVALUATIONS
Key safety assessments include AEs, SAEs, AESIs, clinical laboratory parameters (ie, hematology,
chemistry, lipid panel), vital signs, and physical examination.

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STATISTICAL METHODS
Sample Size Determination
Approximately 85 participants are planned to be randomized in a 2:3 ratio to the control and
experimental arm. The sample size selection was determined based on the primary endpoint of the
change from baseline in DAS28-CRP at Week 12. For this study, assuminga difference of 0.67 in
the change from baseline in DAS28-CRP and a pooled standard deviation of 1.2 between control
arm and experimental arm, a sample size of
Control arm: 34 participants receivingcertolizumab + placebo
Experimental arm: 51 participants receiving combination therapy of nipocalimab +
certolizumab
will provide a power of approximately 80% to detect a significant treatment difference at a 1-sided
significance level of α=0.05 using a T-test. The difference of 0.67 is a meaningful improvement in
this population over an effective monotherapy treatment in RA.
Statistical Analysis
General Considerations
In general, descriptive statistics (eg, mean, median, SD, interquartile range, minimum, and
maximum) will be used to summarize continuous variables. Counts and percentages will be used
to summarize categorical variables. Graphical data displays (eg, line plots) may also be used to
summarize data.
Analyses suitable for categorical data (eg, chi-square tests, CMH tests or logistic regression, as
appropriate) will be used to compare the proportions of participants achieving selected endpoints
(eg, ACR response). In cases of rare events, the Fisher’s exact test will be used for treatment
comparisons. Continuous response parameters will be compared using ANCOVA, a MMRM, or a
cLDA, as appropriate.
Primary Endpoint
Unless otherwise specified, efficacy analyses will be based on the Full Analysis Set, defined as all
randomized participants who had at least one study intervention administration. Participants will
be analyzed according to the study treatment arm to which they were randomized regardless of the
study intervention they received.
The primary endpoint is the mean change from baseline in DAS28-CRP at Week 12. Analysis will
be based on the primary estimand, ie, a precise definition of the primary targeted treatment effect,
that is defined by 5 attributes (treatment, population, variable, ICE, and population-level summary)
for the primary endpoint as stated below.
The comparison for the primary endpoint will be tested at a 1-sided α level of 0.05. Nominal
p-values (1-sided) will be displayed for all other endpoint comparisons. Full details of the analysis
of the primary, secondary, and exploratory endpoints will be included in SAP.
Secondary Endpoints
Secondary efficacy endpoints are:

JNJ-80202135 (nipocalimab)
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ACR20, ACR50, ACR70, and ACR90 at Week 12
DAS28-CRP remission at Week 12
DAS28-CRP LDA at Week 12
Change from baseline in HAQ-DI score at Week 12
Change from baseline in CDAI at Week 12
Analyses will compare between combination therapy (certolizumab + nipocalimab) and
monotherapy (certolizumab+ placebo). The methods of analysis, as well as the data handling rules,
will be provided in the SAP.
Safety Analyses
Safety data including but not limited to, AEs, SAEs, AESIs, vital signs, and changes in laboratory
assessments, will be summarized by study treatment arm for the safety analysis set, defined as all
participants who received at least 1 dose of study intervention.
Listings of all participants with MACE (nonfatal MI, nonfatal stroke, and cardiovascular death)
will be provided.
Other Analyses
Pharmacokinetic Analyses: Serum nipocalimab concentrations over time will be summarized for
each treatment arm using descriptive statistics. Descriptive statistics will be calculated at each
sampling timepoint. If sufficient data are available, a population PK analysis using a nonlinear
mixed-effects modeling approach will be used to characterize the disposition characteristics of
nipocalimab and certolizumab. Details will be given in a population PK analysis plan and the results
of the population PK analysis will be presented in a separate technical report.
Biomarker Analyses:Changes in biomarkers over time may be summarized by treatment arm.
Associations between baseline levels and changes from baseline in select biomarkers and clinical
response will be explored. Results ofbiomarker analyses will be presented in a separate report.
Pharmacokinetic/Pharmacodynamic Analyses:If data permit, the relationship between serum
concentrations of nipocalimab and certolizumab and the efficacy measures and relevant PD
biomarkers may be explored when appropriate. If any visual pattern is observed, additional analysis
may be conducted. Results of analyses will be summarized in a separate technical report.
Pharmacogenomic analyses:Genetic (DNA) analyses may be conducted only in participants who
sign the consent form to participate in the pharmacogenomic sampling. These analyses are
considered exploratory. Results of analyses will be presented in a separate technical report.
Immunogenicity Analyses:The incidence and titers of antibodies to nipocalimab will be
summarized for all exposed participants who received at least 1 administration of nipocalimab and
have appropriate samples for detection of antibodies to nipocalimab (ie, participants with at least 1
sample obtained after their first dose of nipocalimab). The incidence of NAbs to nipocalimab will be
summarized for participants who are positive for antibodies to nipocalimab and have samples
evaluable for NAbs.

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1.2. 
Schema
Figure 1: 
Schematic Overview of the Study

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Period  
Screening 
Double-blind Study Intervention 
Follow-up
Week  
≤6 weeks 
0 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
30 or Final
Safety
Follow-up
Visit (8
weeks
after last
dose)a
Visit Window  
±3 days 
±7 days
Study Procedure 
Notes
Serum biomarkers d 
X 
X 
X 
X 
X 
X 
X 
X
Plasma biomarkers 
X 
X 
X 
X 
X
Whole blood (bulk 
RNAseq)
X 
X 
X 
X
PBMCs (cellular 
analysis)e
X 
X 
X
Pharmacogenomic 
(DNA) (optional)
Xf 
Xf
Footnotes:
a. 
Participants who permanently discontinue study intervention, but do not withdraw from study participation, will be followed at all subsequent study visits
through Week 30. At a minimum, participants who permanently discontinue study intervention, but do not withdraw from study participation, should return
for a safety follow-up visit 8 weeks after the last dose of study intervention.
b. 
Participants will be observed for safety during and for 1 hour after the first 3 study intervention administrations at the study site (Week 0, 2, and 4); if no
clinically relevant AEs related to the study intervention administrations are observed, the post-intervention administrations observation period may be
reduced to 30 minutes for the remaining study intervention administrations.
c.
i) 
2x means 2 samples (for nipocalimab or placebo concentrations) will be collected (1 sample will be collected prior to IV infusion and the other
collected 45 minutes [±15 minutes] after the end of the IV infusion) for all participants. The sample should be drawn from the opposite arm ofthe IV
line. For all other visits, only a predose serum sample will be collected
ii) 
For visits with study intervention administration, all blood samples for assessing predose nipocalimab and certolizumab concentrations and antibodies
to nipocalimab MUST be collected BEFORE the administration of the study intervention
iii) One random population PK nipocalimab concentration sample will be collected from all participants any time between 3 to 7 days after the Week 0 or
Week 2 visit other than the scheduled samples
iv) One random population PK certolizumab concentration sample will be collected from all participants any time between Week 2 and Week 8 other than
at the time of the Week 2, Week 4, Week 6, and Week 8 visits; this sample must be collected at least 24 hours prior to or after a study intervention
administration and must not be collected at a regularly scheduled visit.
v) 
When samples for both PK (“nipocalimab and certolizumab concentration”) and ADA (“antibodies to nipocalimab”) are collected, 1 sample (instead
of 2) will be collected for both assays
d. 
Serum biomarkers may include but are not limited to ACPA, RF, and cytokines
e. 
Samples for PBMC collection will only be done at sites where it is logistically feasible
f. 
The sample should be collected at the specified time point, but may be collected at a later point without constituting a protocol deviation

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Status: Approved, Date: 05 October 2023
2. 
INTRODUCTION
For the most comprehensive nonclinical and clinical information regarding nipocalimab, refer to
the latest version of the IB and Addenda for nipocalimab. For nonclinical and clinical information
regarding certolizumab refer to available SmPC and USPI.
The term “study intervention” throughout the protocol, refers to study drugs as defined in
Section 6.1.
The term “sponsor” used throughout this document refers to the entities listed in the Contact
Information page(s), which will be provided as a separate document.
2.1. 
Study Rationale
The goal of RA treatment is to achieve low arthritis disease activity and remission if possible,
minimizing joint damage, and enhancing physical function and quality of life. The available
treatment options, including csDMARDs, and more notably the bDMARDs and tsDMARDs, have
revolutionized the clinical management of RA. A therapeutic approach has included combining
multiple interventions to address the significant unmet medical need in patients with RA with
inadequate responses to advanced therapies (Smolen 2020). However, despite multiple approved
drugs in RA, about 20 to 30% of patients continue to have refractory disease (Smolen 2020). This
reflects the complex and heterogenous nature as well as the unmet need of the disease (Lin 2020;
Smolen 2020).
A meta-analysis of studies combining an anti-TNFα agent and anakinra, an anti-TNFα agent and
abatacept, an anti-TNFα agent and rituximab, abatacept and anakinra, and rituximab combined
with tocilizumab showed no clear evidence of an efficacy advantage in participants with RA while
the risk of SAEs and total AEs appeared to increase (Boleto 2019), most likely due to significant
exacerbation of immunosuppression.
A combination therapy of the anti-FcRn agent nipocalimab with the anti-TNFα agent certolizumab
has been chosen as mechanistic observations suggest that these treatment agents modulate the RA
disease driving pathways and cellular functions in an orthogonal and complementary manner.
Specifically, nipocalimab uniquely and significantly suppresses pathogenic processes downstream
of autoantibodies, while anti-TNFα agents prominently suppress the myeloid immune system and
reduce joint inflammation resulting in decreased joint damage. In addition, downstream effects of
nipocalimab could suppress pro-inflammatory cytokines and osteoclastogenesis which are
potential disease modifying mechanisms shared with anti-TNFα agents. Moreover, certolizumab
has a well-established safety and efficacy profile in the treatment of patients with active RA
(Cimzia EMA SmPC, USPI). Therefore, certolizumab was chosen for further evaluation in this
study.
CCI

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PK of nipocalimab in participants with gMG was generally consistent with PK in healthy
participants. Pharmacokinetic accumulation appeared to be negligible based on Ctrough  and Ceoi at
the dose regimens tested (ie, 5 mg/kg and 30 mg/kg q4w, and 60 mg/kg q2w).
PK of nipocalimab was generally comparable between Japanese and non-Japanese healthy
participants after single IV administration of 10, 30, and 60 mg/kg doses based on cross-study
comparisons.
Following a single 30 mg/kg IV dose in healthy participants, nipocalimab exposure (Cmax and
AUC) was largely similar regardless of infusion rate (0.5 mg/kg/min to 4 mg/kg/min when given
during 7.5 to 60 minutes), as were the terminal t1/2 values.
Human Pharmacodynamics
The efficacy of nipocalimab is related to saturation of the FcRn target, thereby lowering the total
serum IgG concentrations, including the levels of IgG-based pathogenic autoantibodies.
Pharmacodynamic responses of full target saturation measured as FcRn receptor occupancy
(defined as <10% unoccupied receptors) and asymptomatic, self-limited, recoverable decreases
from baseline in total serum IgG concentrations of up to 85% were observed in the completed
Phase 1 and Phase 2 studies, confirming the MoA of nipocalimab. Asymptomatic, self-limited,
dose-dependent, recoverable decreases from baseline in serum albumin of up to 25% were also
observed.
Efficacy/Safety Studies
The Phase 2a study  (80202135ARA2001), a double-blind, parallel-group, placebo-controlled,
PoC, multicenter study of nipocalimab in participants with moderately  to severely  active RA
despite standard therapy has been completed.
)
CCI
CCI

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2.2.1. 
Combination Therapy
More detailed information about the known and expected benefits and risks of nipocalimab can be
found in the IB and addenda. For risks associated with certolizumab, please refer to the Cimzia
country-approved label.
2.3. 
Benefit-risk Assessment
No new risks were identified in Study 80202135ARA2001 in participants with moderate to severe
RA.
The important potential risks of exposure to nipocalimab based on its MoA as well as the relevant
risks ofexposure to certolizumabbased on the Special Warnings and Precautions for Use described
in the USPI for Cimzia are summarized in Section 2.3.1.
More detailed information about the known and expected benefits and risks of nipocalimab may
be found in the IB and addenda. For risks associated with certolizumab, please refer to the Cimzia
country-approved label.
The inclusion and exclusion criteria have been chosen based on the risks of both compounds. In
cases of differing risks, the most conservative approach has been chosen.
2.3.1. 
Risks for Study Participation
Inclusion and exclusion criteria based on the below risks of nipocalimab and certolizumab for the
treatment of RA can be found in Section 5. Study intervention stopping criteria can be found in
Section 7.1, and study stopping criteria in Section 7.1.2. The study safety review process by an
independent DMC can be found in Section 9.5.
CCI

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Table 1: Important Potential Risks of Nipocalimab for the Treatment of Rheumatoid Arthritis
Potential Risks of
Clinical 
Significance 
Summary of Data/
Rationale for Risk  
Mitigation Strategy
Lack of clinical 
benefit/Clinical 
worsening of RA  
The benefit-risk of certolizumab and 
nipocalimab combination therapy in 
treatment of RA has not been established. 
During the study, participants will be
permitted to continue treatment of RA
with certain standard-of-care
medications (Section 6.8).
Participants may discontinue study
intervention if it is not in their best
interest or if they need to initiate
certain protocol-prohibited medications
including certain biologics
(Section 6.8.5).
Participants will be allowed to use
rescue medication from Week 14
(Section 6.8.6).
Risks Due to Study Intervention(s)
Potential increased 
risk for infection 
due to decreased 
serum IgG 
concentrations 
As predicted based on its MoA, nipocalimab 
was associated with dose-dependent 
reductions in IgG of up to 80% to 85% of 
baseline in cynomolgus monkey and human 
studies. However, nipocalimab did not
increase the incidence, severity, or duration
of infection in any of the nonclinical and
clinical studies conducted to date.
Participants with severe acute or
chronic infections requiring
anti-infective therapies are excluded
from participation in the study.
Participants with serum total
IgG <6 g/L (<600 mg/dL) at screening
will be excluded from the study.
Study intervention stopping criteria for
profound hypogammaglobulinemia
(serum total IgG <1 g/L [<100 mg/dL])
and infections are included in in the
protocol.
Study stopping rules based on serious
infections are included in the protocol.
All infections will be monitored
closely. Treatment-emergent infections
meeting the AESI criteria must be
reported to the sponsor within 24 hours
(Section 8.3.6).
Participants who have had a live
vaccine within 4 weeks prior to the first
administration of study intervention or
longer as either indicated on the
package insert of the relevant vaccine
or according to local regulations (or
within 12 months prior to first
administration of study intervention for
BCG), or has a known need to receive
a live vaccine during the study, or
within at least 8 weeks after the last
dose of study intervention in this study
are excluded from participation in the
study.

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Table 1: Important Potential Risks of Nipocalimab for the Treatment of Rheumatoid Arthritis
Potential Risks of
Clinical 
Significance 
Summary of Data/
Rationale for Risk  
Mitigation Strategy
DDI study (MOM-M281-008) is completed 
as of IB data cutoffdate (28 April 2022). The 
DDI observed in this study was consistent 
with the MoA of nipocalimab and confirmed 
the hypothesis that nipocalimab could reduce 
the PK exposure of IgG-based mAbs via 
inhibition of FcRn-mediated recycling 
High doses of nipocalimab may reduce 
serum albumin up to 25%. The concomitant 
use of drugs with both high protein binding
(>95%) and narrow therapeutic index may
lead to higher free drug concentrations which
could increase the risk for potential
toxicities.
Participants treated with nipocalimab
and who are on concomitant
medications which have high protein
binding (>95%) and narrow therapeutic
index (such as but not limited to
warfarin, sulfasalazine, mycophenolate
mofetil, leflunomide), should be
monitored for potential impacts of
nipocalimab on efficacy and safety of
those medications.
Increased lipids 
Elevations in total cholesterol and LDL were 
reported recently with another experimental 
drug in the same pharmacologic class of 
FcRn antagonists. 
In the MOM-M281-001 and 
MOM-M281-004 studies, asymptomatic, 
dose-dependent, reversible elevations in 
nonfasting mean total cholesterol were 
observed up to 25% of baseline. In both
studies, elevations in total cholesterol appear
to mirror the kinetics of the decreases in
albumin observed with nipocalimab. 
In pregnant women, a preliminary review 
suggested a possible treatment-emergent 
increase in non-fasting total cholesterol 
higher than published reference values 
expected during normal pregnancies 
(ie, physiologic increases for the appropriate 
gestational age). The cholesterol elevations 
observed in pregnant women decreased after 
nipocalimab discontinuation and returned to 
baseline values after delivery. 
Participants with recent MI, stroke, or
unstable angina within 12 weeks of
study entry will be excluded from
participation in the study.
Routine laboratory investigations for
lipid panel (total cholesterol, HDL,
LDL, triglycerides) will be performed
in the study.
Lipids levels are routinely monitored in
participants throughout the study.
In participants with elevated lipids at
any time during the study, it is
recommended that investigators initiate
or continue appropriate therapy for
dyslipidemia as per local health
guidelines. In participants with
persistently elevated lipids (above the
LDL threshold of 190 mg/dL or the
triglyceride threshold of 1000 mg/dL),
it is strongly recommended that
investigators initiate appropriate
therapy or modify current therapy for
dyslipidemia per local health
guidelines.
Placental infarction 
Abnormal placental infarctions were 
observed in 4/26 available placentas from 55 
pregnant cynomolgus monkeys exposed to 
nipocalimab in a reproductive and 
developmental toxicology study. While 3 of
the 4 cases resulted in fetal mortality, there
was no evidence of growth restriction or
hypoxia; and one of the 3 fetuses was
observed with umbilical entrapment. Overall
fetal loss in the study was not different
between nipocalimab-treated and placebo
Pregnant women are excluded from
this study and participants must agree
to use highly effective methods of
contraception (Section 10.5).
Pregnancy tests are conducted
throughout. Participants who become
pregnant will be withdrawn and
followed up until delivery or
termination of pregnancy.

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Table 1: Important Potential Risks of Nipocalimab for the Treatment of Rheumatoid Arthritis
Potential Risks of
Clinical 
Significance 
Summary of Data/
Rationale for Risk  
Mitigation Strategy
treated groups and no nipocalimab-related
developmental toxicity was identified.
One patient with IUGR and another with
placental abruption have been reported from
a study involving antenatal treatment of
pregnant women at risk of EOS-HDFN.
Low IgG in infants 
born to mothers 
with EOS-HDFN 
receiving 
nipocalimab during
pregnancy 
Low IgG concentrations in infants born to 
mothers with EOS-HDFN receiving 
nipocalimab during pregnancy (between 
Week 14 and Week 35) were observed. 
The IgG concentrations at or below the lower
limit of normal occurred in 5/5 infants with 
available IgG data at 24 weeks (n=3), 34 
weeks (n=1), and 1-year (n=1) post birth. As 
the study is ongoing, the duration of low IgG 
in these infants is currently unknown.
As of 31-December-2020, there have been no
infections reported in these infants, with the
exception ofone infant who had a
self-limited episode ofthrush reported at
2.5 months of age and lasting 2 weeks.
Pregnant women are excluded from
this study and participants must agree
to use highly effective methods of
contraception (Section 10.5).
Pregnancy tests are conducted
throughout. Participants who become
pregnant will be withdrawn and
followed up until delivery or
termination of pregnancy.

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Table 2: 
Important Risks of Certolizumab for the treatment of Rheumatoid Arthritis
Risks for Study
Participation
Summary of Data/
Rationale for Risk
Mitigation Strategy
Serious infections
and reactivation of
latent infections
Serious infections, including sepsis and 
tuberculosis (including miliary, disseminated 
and extrapulmonary disease), and 
opportunistic infections (eg, histoplasmosis, 
nocardia, candidiasis) have been reported in
patients receiving certolizumab. Some of 
these events have been fatal. 
Participants with a history of, or
ongoing chronic or recurrent
infectious disease, including HIV,
HBV, and HCV will be excluded.
Monitoring for signs and symptoms of
infection, including TB, is part of the
protocol. Participants with evidence
of active or untreated latent TB will
be excluded from the study.
Participants who received BCG
vaccine within 1 year or any other
live vaccine within 4 weeks before
the first dose of study intervention
will be excluded from the study. In
addition, participants must agree not
to receive a live viral or live bacterial
vaccine during the study and for 12
weeks after receiving the last dose of
study intervention.
A participant’s study intervention
must be discontinued if the
participant develops a (1) an
infection that is unresponsive or
worsening while on anti-infective
therapy, (2) any serious infection
(i.e., meets AE seriousness criteria),
(3) a clinically significant
opportunistic infection, or (4) any of
the TB-related conditions
Study stopping rules for serious
infection are included.
Malignancies and
lymphoproliferative
disorders
The potential role of TNF-antagonist therapy 
in the development of malignancies is not 
known. With the current knowledge, a 
possible risk for the development of 
Lymphomas, leukemia or other malignancies 
in patients treated with an anti-TNFα agent 
cannot be excluded. 
Those participants who currently
have a malignancy or have a history
of malignancy within 5 years prior to
screeningwill 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.
During the conduct of the study,
participants will undergo regular
clinical monitoring including routine

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Table 2: 
Important Risks of Certolizumab for the treatment of Rheumatoid Arthritis
Risks for Study  
Participation 
Summary of Data/
Rationale for Risk
Mitigation Strategy
safety laboratory assessments to
evaluate any changes in health status
that may indicate a possible
malignancy.
Participants who develop a
malignancy during the study will be
discontinued from study intervention.
CHF  
Cases of worsening CHF and new onset CHF
have been reported with certolizumab.
Participants with a history of, or
concurrent CHF including medically
controlled, asymptomatic CHF, will
be excluded from the study.
Any participant who develops CHF
during the study must discontinue
study intervention.
Hematological
reactions
Reports of pancytopenia, including aplastic
anemia, have been rare with anti-TNFα
agents. Adverse reactions of the hematologic
system, including medically significant
cytopenia (e.g., leukopenia, pancytopenia,
thrombocytopenia) have been reported with
certolizumab.
Participants medically unstable based
on clinical laboratory tests performed
at screening will be excluded from
the study. All participants should be
advised to seek immediate medical
attention if they develop signs and
symptoms suggestive of blood
dyscrasias or infection (e.g.,
persistent fever, bruising, bleeding,
pallor) in study.
Participants with confirmed
significant hematological
abnormalities during the study must
discontinue study intervention.
Neurological events 
Use of anti-TNFα agents has been associated
with rare cases of new onset or exacerbation
of clinical symptoms and/or radiographic
evidence of demyelinating disease, including
multiple sclerosis. Rare cases of neurological
disorders, including seizure disorder,
neuritis, and peripheral neuropathy, have
been reported in patients treated with
certolizumab.
Participants with a history of
demyelinating disorders, such as MS
or optic neuritis, will be excluded
from the study.
Any participant who develops a
demyelinating disorder during the
study must discontinue study
intervention.
Hypersensitivity
reactions, including
serious
hypersensitivity
reactions and
anaphylaxis
Severe hypersensitivity reactions have been
reported rarely following certolizumab
administration. Some of these reactions
occurred after the first administration of
certolizumab.
Participants with known allergy,
hypersensitivity, or intolerance to
certolizumab or its recipients will be
excluded from the study.
All participants must be observed
carefully for signs and symptoms of

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Table 2: 
Important Risks of Certolizumab for the treatment of Rheumatoid Arthritis
Risks for Study  
Participation 
Summary of Data/ 
Rationale for Risk
Mitigation Strategy
Hypersensitivity reactions to natural rubber 
latex of CIMZIA prefilled syringe cannot be 
completely excluded in latex-sensitive 
individuals. 
a hypersensitivity reaction (eg,
urticaria, pruritis, angioedema,
wheezing, dyspnea, or hypotension;
Section 8.2.10).
Any participant who develops a
serious hypersensitivity reaction such
as anaphylaxis must discontinue
study intervention.
Autoimmunity/
Lupus-like
syndrome
Treatment with certolizumab may result in
the formation of antinuclear antibodies
(ANA) and, uncommonly, in the
development of a lupus-like syndrome
Participants with a history of severe,
progressive, or uncontrolled
rheumatologic disturbances, or signs
and symptoms thereof that, in the
opinion of the investigator, would
pose a risk to participant safety will
be excluded from the study.
Any participant who develops
symptoms suggestive of lupus-like
syndrome and is positive for
antibodies to double-stranded DNA
must discontinue from study
intervention.
aPTT assay  
Interference with certain coagulation assays
has been detected in patients treated with
certolizumab. Certolizumab may cause
erroneously elevated aPTT assay results in
patients without coagulation abnormalities.
This effect has been observed with the PTT-
LA test and STA-PTT Automate tests from
Diagnostica Stago, and the HemosIL APTT-
SP liquid and HemosIL lyophilised silica
tests from Instrumentation Laboratories.
Other aPTT assays may be affected as well.
There is no evidence that certolizumab
therapy influences coagulation in vivo.
After patients receive certolizumab,
careful attention should be given to
interpretation of abnormal
coagulation results. Interference with
TT and PT assays have not been
observed.
*For full list of certolizumab risks and mitigation measures, please refer to certolizumab SmPC or USPI
2.3.2. 
Benefits for Study Participation
This study will enroll participants who are naïve to certolizumab and all participants in the study
will receive certolizumab. Certolizumab is an approved anti-TNFα agent mAb for the treatment of
RA and has been shown to effectively reduce pain, swelling, and improve physical function in
patients with RA.
Participation in the study may provide access to new treatment options, including certolizumab
and nipocalimab combination therapy. 
 Combination
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of the orthogonal MoAs of certolizumab and nipocalimab may provide broader suppression of
pathogenic pathways and potential greater clinical efficacy in participants with RA refractory to
previous treatments.
Participants in the study will also help in evaluating this study intervention in the treatment of RA.
Thus, the knowledge gained from this study has the potential to benefit patients suffering from RA
and thus offers potential public health benefits.
Participants may also experience some benefit from participation in a clinical study irrespective of
receiving study intervention, due to regular visits and assessments monitoring their overall health.
2.3.3. 
Benefit-risk Assessment for Study Participation
The study population with moderately to severely active RA has already had inadequate initial
response, loss of response, or intolerance to ≥1 advanced therapy (bDMARDs or tsDMARDs),
therefore combination therapy may provide a higher chance of lower disease activity and remission.
Multiple risk mitigation measures are in place to manage a potential increase in infections risk
with certolizumab and nipocalimab combination therapy. Based on the well characterized safety
profile of certolizumab and the available safety data of nipocalimab to date, the overall anticipated
benefits outweigh the risks of participation in this clinical study.

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3. 
O BJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
To evaluate the efficacy of combination therapy with 
nipocalimab and certolizumab compared to 
certolizumab monotherapy in participants with
moderately to severely active RA despite ≥1 advanced
therapy (bDMARDs or tsDMARDs).
Change from baseline in
DAS28-CRP at Week 12
Secondary
To evaluate the efficacy of combination therapy with 
nipocalimab and certolizumab compared to 
certolizumab monotherapy in participants with
moderately to severely active RA
ACR20, ACR50, ACR70, and
ACR90 responses at Week 12
DAS28-CRP remission at Week 12
DAS28-CRP LDA at Week 12
Change from baseline in HAQ-DI
score at Week 12
Change from baseline in CDAI at
Week 12
To evaluate the safety and tolerability of combination 
therapy with nipocalimab and certolizumab
Treatment-emergent AE
Treatment-emergent SAEs
Treatment-emergent AEs leading to
discontinuation of study
intervention
Treatment-emergent AESIs
Tertiary OR Exploratory
To evaluate the safety and tolerability of combination 
therapy with nipocalimab and certolizumab 
Laboratory parameters and change
from baseline in laboratory
parameters through Week 30
Vital sign parameters and change
from baseline in vital sign
parameters through Week 30
To evaluate the PK and immunogenicity of 
combination therapy with nipocalimab and 
certolizumab 
Serum nipocalimab and
certolizumab concentrations through
Week 30 in participants receiving
active study intervention
Incidence and titers of antibodies to
nipocalimab (ADA and NAbs)
through Week 30
To evaluate the efficacy of combination therapy with 
nipocalimab and certolizumab in participants with 
baseline ACPA high (#1) and baseline csDMARD use
(#2)
Change from baseline in DAS28-
CRP through Week 24
ACR20, ACR50, ACR70, and
ACR90 responses through Week 24

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Objectives 
Endpoints
DAS 28-CRP remission through
Week 24
DAS28-CRP LDA through Week
24
Change from baseline in HAQ-DI
score through Week 24
Change from baseline in CDAI
through Week 24
CDAI LDA through Week 24
CDAI remission through Week 24
To evaluate the efficacy of combination therapy with 
nipocalimab and certolizumab 
ACR20, ACR50, ACR70, and
ACR90 responses through Week 24
Percent improvement from baseline
in ACR components through
Week24
Change from baseline in ACR
components through Week 24
DAS28-CRP (and DAS28-ESR)
LDA through Week 24
DAS28-CRP (and DAS28-ESR)
remission through Week 24
Change from baseline in
DAS28-CRP (and DAS28-ESR)
through Week 24
CDAI LDA through Week 24
Change from baseline CDAI
through Week 24
CDAI remission through Week24
Change from baseline in SDAI
through Week 24
SDAI LDA through Week 24
SDAI-based ACR/EULAR
remission through Week 24
Boolean-based ACR/EULAR
remission through Week 24
To evaluate the efficacy on PROs of combination 
therapy with nipocalimab and certolizumab 
Proportion of participants achieving
a decrease of ≥0.22 points from
baseline in HAQ-DI score through
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Objectives 
Endpoints
Change from baseline in Joint Pain
severity score through Week24
To evaluate the impact of combination therapy with 
nipocalimab and certolizumab on PD and disease 
biomarkers 
Change from baseline in serum
Immunoglobulin profile
(IgG/M/E/A) and IgG subtype
levels through Week 30
Change from baseline in biomarker
levels through Week 30 by
treatment group
ESTIMANDS
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
HYPOTHESIS
The primary hypothesis is that treatment with nipocalimab in combination with certolizumab is
superior to certolizumab monotherapy in participants with moderately to severely active RA
despite treatment with ≥1 advanced therapy (bDMARDs or tsDMARDs) as assessed by the mean
change from baseline in DAS28-CRP at Week 12.

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4. 
STUDY DESIGN
4.1. 
Overall Design
This is a randomized, double blind, parallel, multicenter, PoC interventional study to evaluate the
efficacy and safety of a combination therapy with nipocalimab and certolizumab in participants
between 18 and 75 years old, with moderately to severely active RA despite ≥1 advanced therapy
(bDMARDs or tsDMARDs) but are certolizumab naïve.
The total study duration is up to 36 weeks, consisting of a 6-week screening period, a 24-week
double-blind period (22 weeks of treatment), and a 6-week safety follow-up period (8 weeks after
last dose).
A target of approximately 85 participants will be randomly assigned in this study  with  34
participants in the certolizumab monotherapy and 51 participants in the nipocalimab in
combination with certolizumab group.
An IV administered placebo will be used in the certolizumab monotherapy group to allow for
double blinded evaluation of efficacy and safety.
Efficacy, safety, PK, PD, immunogenicity, and biomarkers will be assessed according to the SoA
(Section 1.3). Pharmacogenomic blood samples will be collected from participants who consent
and where local regulations permit.
The primary endpoint (change from baseline in DAS28-CRP at Week 12 in participants receiving
nipocalimab with certolizumab combination therapy compared to participants receiving
certolizumab monotherapy) will be evaluated after all participants have completed the Week 12
visit (or have discontinued study participation). At Week 14, participants who have not achieved
low disease activity (CDAI ≤10) will receive rescue medication (see Section 6.8.6).
Every reasonable effort will be made to keep concomitant therapy stable (Section 6.8). All
concomitant therapies, as well as changes to concomitant therapy will be recorded throughout the
study including screening.
Key safety assessments include AEs, SAEs, AESIs, clinical laboratory parameters (eg, hematology,
chemistry, lipid panel), physical examinations, and vital signs.
The PK ofnipocalimab and certolizumab, as well as antibodies to nipocalimab will be evaluated
in serum samples. Blood-based biomarkers will be evaluated for inflammation associated proteins
and other analytes to improve understanding of the biology of RA and the biologic response to
treatment in participant with moderately to severely active RA; more specifically, to elucidate the
difference between responders and non-responders, to assess loss of response, and the potential of
biomarkers to predict treatment outcomes in individual participants.
Two DBLs are planned at Week 12 and at the end of the study, defined as the last follow-up
assessment for the last participant.
An independent DMC is commissioned for this study (Section 9.5).
A diagram of the study design is provided in Section 1.2.

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4.2. 
Scientific Rationale for Study Design
Blinding, Control, Study Phase/Periods, Treatment Arm
Randomization will be used to minimize bias in the assignment of participants to treatment arms,
to increase the likelihood that known and unknown participant attributes (eg, demographic and
baseline characteristics) are evenly balanced across treatment arms, and to enhance the validity of
statistical comparisons across treatment arms. Blinded intervention will be used to reduce potential
bias during data collection and evaluation ofclinical endpoints.
In this study, all participants will receive certolizumab. Participants in the experimental arm will
receive both nipocalimab and certolizumab, while participants in the control arm will receive
certolizumab and placebo. The placebo in the control arm will be used to establish the frequency
and magnitude of changes in clinical endpoints that may occur in the absence of nipocalimab
intervention.
Specific laboratory tests that may be unblinding (eg, nipocalimab concentrations, IgG, albumin,
total protein, CICs, autoantibody levels) will not be reported (eg, will remain masked) to the
investigator, study team members, or participants during study conduct after randomization.
However, test results required for decisions on screening or randomization will be available to the
investigator and study team. Given that albumin laboratory results are masked, the Investigator
will be notified if their participant has hypoalbuminemia <20 g/L (<2.0 g/dL). These AESI cases
will be handled similarly to an SAE for reporting purposes and reviewed by an independent DMC
as they occur.
Stratification is implemented to minimize the risk for baseline imbalance(s) across treatment arms
on potentially confounding variables such as concomitant therapy, ACPA levels, disease markers,
and study site. Baseline imbalances of these factors could impact efficacy and safety assessments
of combination therapyversus certolizumab monotherapy. For details on stratification, please refer
to Section 6.3.
DNA and Biomarker Collection
Biomarker samples will be collected, where local regulations permit, to evaluate the cellular and
molecular MoA ofnipocalimab and certolizumab or help to explain interindividual variability in
clinical outcomes or may help to identify population subgroups that respond differently to an
intervention. Biomarkers will be analyzed in blood samples to evaluate disease activity and to
assess PD markers associated with nipocalimab and certolizumab. The goal of the biomarker
analyses is to evaluate the PD of nipocalimab and certolizumab and aid in evaluating the
intervention-clinical response relationship.
Optional pharmacogenomic samples may be obtained from participants only when specific consent
is provided by signing the optional genetic research ICF. It is recognized that genetic variation can
be an important contributory factor to interindividual differences in intervention distribution and
response and can also serve as a marker for disease susceptibility and prognosis.
Pharmacogenomic research may help to explain interindividual variability in clinical outcomes
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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, PD, efficacy, safety, and tolerability ofnipocalimab and certolizumab
and to identify genetic factors associated with RA or the response to nipocalimab and certolizumab
treatment. Additionally, pharmacogenomic samples may be collected after exposure to
nipocalimab and certolizumab. Epigenetic data from these samples may be compared with baseline
samples to identify epigenetic changes that may associate with the disease or the treatment.
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. Collection of
biomarker samples, including samples from the optional pharmacogenomic collection, will only
occur where local regulations permit and may not occur at all clinical sites.
4.2.1. 
Participant Input into Design
In setting the strategy for the development of a novel treatment of RA, patients were engaged early,
systematically, and directly across important aspects of the drug development process. Specifically
for this study, the Sponsor sought feedback from RA patients on the trial protocol to identify key
drivers and barriers to enrollment with the aim to improve patient experience and optimizing
protocol design.
Patient input was used to design the following elements of this study:
The Schedule of Activities was modeled to ensure the number of visits, frequency of visits,
and tests within each visit were manageable for a patient with moderately to severely active
RA.
Number of PRO and ClinRO assessments were reduced to shorten visits
A visit window of ±3 days was added to increase flexibility to accommodate participant’s
schedule
Sample taking was designed to be done in as few blood draws as possible to avoid
unnecessary needle sticking
The results of the study may  be made available to all participants through a plain language
summary; a technical summary of results on clinicaltrials.gov and/or clinicaltrialsregister.eu
and/or other national registries at the conclusion of the study according to local
standards/restrictions.
4.2.2. 
Study-specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study, and during
the study, participants will be given any new information that may affect their decision to continue
participation. They will be told that their consent to participate in the study is voluntary and may
be withdrawn at any time with no reason given and without penalty or loss of benefits to which
they would otherwise be entitled. Only participants who are fully able to understand the risks,
benefits, and potential AEs of the study, and provide their consent voluntarily will be enrolled.
Written consent/assent may be obtained through various sources (eg, paper or electronic such as
eConsent, eSignature, or digital signature) as determined by regulations as well as study and/or
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The primary ethical concern is that nipocalimab is currently not approved in any indication. 
 The hypothesis
of superior efficacy of combination therapy  of certolizumab and nipocalimab compared to
monotherapy with either compound is based on the theoretical assessment of their orthogonal MoA.
Both groups will receive certolizumab at the approved dose for treatment of RA including the
control group. Additionally, the study population will consist exclusively of participants refractory
to available treatments (including anti-TNFα agents).
The total blood volume to be collected will be below 710 mL over a 24-week period and 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 American Red Cross standard limit for
whole blood donation (475 mL q8w).
4.3. 
Justification for Dose
The objective of this Phase 2a study is to establish PoC for a combination therapy approach with
an anti-FcRn and an anti-TNFα agent in participants with moderately to severely active RA despite
≥1 advanced therapy (bDMARDs or tsDMARDs) by demonstrating clinically relevant benefit of
nipocalimab and certolizumab combination therapy compared to certolizumab monotherapy.
Nipocalimab will be administered at the 30 mg/kg IV Q2W dose and certolizumab will be
administered at the approved dosing regimen for RA, 400 mg SC injections at Week 0, 2, and 4,
followed by 200 mg SC injections Q2W.
4.3.1. 
Nipocalimab
Nipocalimab as an anti-FcRn agent, was specifically engineered to bind to FcRn and block FcRn-
mediated IgG recycling and redirect internalized IgG from early endosomes to lysosomes for
catabolism. 
Population PK/PD modeling and simulation analysis using the SAD and MAD data from the FIH
study in healthy participants (MOM-M281-001) was performed to guide the dose selection for
participants with RA. Nipocalimab PK and the interaction with FcRn (ie, RO) was described by a
one-compartment, target-mediated drug disposition model. Effects from nipocalimab on IgG
reduction and albumin lowering, through the bound nipocalimab-FcRn complex, were described
by 2 independent indirect response models, where nipocalimab effects were assumed to facilitate
degradation of IgG and albumin lowering, respectively. The nipocalimab PK-RO-IgG/albumin
models adequately described the relationships between nipocalimab dosing, PK, FcRn RO, and
total serum IgG reduction/serum albumin lowering which also agreed with observed data from the
Phase 2a nipocalimab monotherapy study. Pharmacokinetic/PD simulations for the RA population
were performed using the aforementioned PK/RO/PD model and incorporating the typical RA
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population body weight. 
 Study results from
In terms of safety, the predicted exposure of nipocalimab 
Using the PK-RO-IgG model, simulations were performed on 1000 virtual participants to evaluate
the risk of a steady-state IgG nadir from crossing 1 g/L, a threshold set as the exit criterion due to
the chance of increased infections below this threshold.
Based on the above, the safety profile of the 
 dose regimen in RA is expected to be
acceptable.
4.3.2. 
Certolizumab
Certolizumab pegol is an anti-TNFα agent which is a Fab fragment targeted against TNF which is
conjugated to PEG. The planned certolizumab dose regimen is
For detailed information regarding the safety and efficacy profile, please refer to the Cimzia
package insert/ SmPC.
4.3.3. 
Nipocalimab and Certolizumab Combination
In nonclinical toxicology studies, neither nipocalimab nor certolizumab presented any apparent
overlapping toxicities that could be expected to be potentiated when administered in combination.
In consideration of specific anti-TNFα agents which may be optimal to combine with nipocalimab,
specific attention was paid to the potential DDI between the combination partners. Nipocalimab
could reduce the PK exposure of IgG-based mAbs via inhibition of FcRn-mediated recycling. As
certolizumab lacks an Fc region, no drug-drug interactions are foreseen with nipocalimab.
Moreover, certolizumab has a well-established safety and efficacy profile in the treatment of
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patients with active RA consistent with the class of anti-TNFα agents and was chosen as the
combination agent with nipocalimab.
Given the acceptable nonclinical and clinical safety profiles for nipocalimab and certolizumab and
the duration of the combination administration (approximately 22 weeks), any potential safety risk
in the combination setting is considered to be manageable with careful monitoring and early
intervention, including risk mitigation strategy, discontinuation of study intervention rules, and
pre‑defined stopping rules (Section 2.3 and Section 7).
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
visit at that study site, in the time frame specified in the Clinical Trial Agreement.
For participants who complete treatment and who are eligible for continued access program (post
study access or other open-label extension study under a different/separate protocol), the end of
study is defined as the end of treatment visit.
For participants who complete this study and who are eligible for a continued access program (see
Section 6.6 or other long-term extension under a different/separate protocol) the safety follow-up
period will be waived. In such case enrollment into the continued access program should occur on
the same day as the last visit in this study, ie, end of study visit.
Participant Study Completion Definition
A participant will be considered to have completed the study if the participant has completed
assessments at Week24 of the double-blind phase and the final safety follow-up visit.
Participants who prematurely discontinue study intervention for any reason before completion of
the double-blind phase, or miss the final safety follow-up visit, will not be considered to have
completed the study.

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5. 
STUDY POPULATION
Screening for eligible participants will be performed within 6 weeks before administration of the
study intervention. Refer to Section 5.4. for conditions under which the repetition of any screening
procedures is allowed.
The inclusion and exclusion criteria for enrolling participants in this study are described below. If
there is a question about these criteria, the investigator must consult with the appropriate sponsor
representative and resolve any issues before enrolling a participant in the study. Waivers are not
allowed.
For a discussion of the statistical considerations of participant selection, refer to Section 9.2.
5.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
Age
1. 
Criterion modified per Amendment 1
1.1 18 to 75 years of age, inclusive
Type of Participant and Disease Characteristics
2. 
Medically stable on the basis of physical examination, medical history, vital signs,
and 12-lead ECG performed at screening. Any abnormalities must be consistent with
the underlying illness in the study population and this determination must be recorded
in the participant's source documents and initialed by the investigator.
3. 
Medically stable on the basis of clinical laboratory tests performed at screening. If the
results of the serum chemistry panel, 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.
See exclusion criterion 13 for permitted laboratory reference ranges.
4. 
Diagnosis of RA and meeting the 2010 ACR/ EULAR Criteria for RA for at least 12
weeks before screening.
5. 
Has moderate to severe active RA as defined by persistent disease activity with at
least 6 of 66 swollen joints and 6 of 68 tender joints at the time of screening and at
baseline.
6. 
Is positive for ACPA or RF by the central laboratory at the time of screening.
7. 
Has CRP ≥0.3 mg/dL by the central laboratory at the time of screening.
8. 
Criterion modified per Amendment 1
8.1 If has received prior anti-TNF agent (including biosimilars), has demonstrated IR
to ≥1 anti-TNF agent (including biosimilars), as assessed by the treating physician
(see Appendix 10 [Section 10.10]):
a. After at least 12 weeks dosage of etanercept, adalimumab, golimumab
(including biosimilars), and/or
b. After at least 14 weeks dosage (ie, at least 4 doses) of infliximab (including
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  Documented IR may include inadequate improvement or loss in response after initial
improvement in joint counts or other parameters of disease activity.
9. 
Criterion modified per Amendment 1
9.1 If has received prior bDMARDs (or biosimilars) other than anti-TNF agent in RA,
has demonstrated IR or intolerance to the therapy based on one of the following:
a. IR to at least 1bDMARD (or the biosimilars) other than anti-TNF agents, as
assessed by the treating physician (see Appendix 10 [Section 10.10]), after at
least 12 weeks of therapy including but not limited to abatacept, anakinra,
tocilizumab, and sarilumab or at least 16 weeks of therapy with rituximab.
Documented IR may include inadequate improvement or loss in response after initial
improvement in joint counts or other parameters of disease activity.
b. Intolerance to bDMARD (or biosimilars) other than anti-TNF agent, as
assessed by the treating physician. Documented intolerance includes side
effects and injection/infusion reactions.
10. 
Criterion modified per Amendment 1
10.1 If has received prior JAKi therapy for RA, has demonstrated IR or intolerance to
the therapy based on 1 of the following:
a. IR to at least 1 JAKi agent, as assessed by the treating physician (see
Appendix 10 [Section 10.10]), after at least 12 weeks of therapy with a JAKi
which includes but is not limited to tofacitinib, baricitinib, upadacitinib.
Documented IR may include inadequate improvement or loss in response after initial
improvement in joint counts or other parameters of disease activity.
b. Intolerance to JAKi agent as assessed by the treating physician. Documented
intolerance includes side effects.
Concomitant or Previous Medical Therapies Received
11. 
If using csDMARDs (eg, MTX, SSZ, HCQ, CQ, or leflunomide), has started
treatment at least 12 weeks prior to the first administration of study intervention, is on
a stable dosage for at least 8 weeks prior to the first administration of study
intervention, and has no serious toxic side effects attributable to the csDMARDs:
a. If using MTX: on stable dosage of no more than 25 mg/week IM, SC or PO
b. If using SSZ: on stable dosage of 1000-2000 mg/day
c. If using HCQ or CQ: on a stable dosage of 200-400 mg/day
d. If using leflunomide: on stable dosage of 10-20 mg/day.
12. 
If currently not using csDMARDs (ie, MTX, SSZ, HCQ, CQ, or leflunomide), has
not received these DMARDs for at least 4 weeks prior to the first administration of
the study intervention.
13. 
If using MTX, is on a stable dosage of oral folic/folinic acid (>5 mg/week) for at
least 4 weeks prior to the first administration of study intervention.
14. 
If using oral corticosteroids, is on a stable dosage equivalent to ≤10 mg/day of
prednisone for at least 2 weeks prior to the first administration of study intervention.
If not currently using corticosteroids, the participant must not have received oral
corticosteroids for at least 2 weeks prior to the first administration of study
intervention.
15. 
If using nonsteroidal anti-inflammatory drugs (NSAIDs) or other analgesics for RA,
is on a stable dosage for at least 2 weeks prior to the first administration of study
intervention.

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Sex and Contraceptive/Barrier Requirements
16. 
A female participant of childbearing potential must have a negative urine pregnancy
test at screening and Week 0 prior to administration of study intervention.
17. 
Criterion modified per Amendment 2
17.1 Is not currently breastfeeding, pregnant, intends to become pregnant during the
study, or within 5 months after the last administration of study intervention.
18. 
Criterion modified per Amendment 2
18.1 A female participant must be (as defined in Appendix 5, Contraceptive and
Barrier Guidance)
a. Not of childbearing potential
OR
b. Of childbearing potential and
o Practicing a highly effective method of contraception (failure rate of <1% per
year when used consistently and correctly) and agrees to remain on a highly
effective method while receiving study intervention and until 5 months after
last dose - the end of relevant systemic exposure. The investigator must
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
Appendix 5: Contraceptive and Barrier Guidance.
19. 
Criterion modified per Amendment 2
19.1 A female participant must agree not to donate eggs (ova, oocytes) or freeze for
future use for the purposes of assisted reproduction during the study and for a period
of 5 months after the last administration of study intervention.
20. 
A male participant who has not had a vasectomy, must agree not to plan to father a
child while enrolled in this study or within 90 days after the last dose of study
intervention.
21. 
Criterion modified per Amendment 1
21.1 A male participant must wear a condom when engaging in any activity that
allows for passage of ejaculate to another person during the study and for a period of
90 days after the last administration of study intervention; male participants must also
be advised of the benefit for a female partner of childbearingpotential to use a highly
effective method of contraception as condom may break or leak.
22. 
Criterion modified per Amendment 3
22.1 A male participant must agree not to donate or freeze sperm for the purpose of
reproduction during the study and for a minimum of 90 days after receiving the last
dose of study intervention.
Informed Consent
23. 
Criterion modified per Amendment 1
23.1 Must sign an ICF indicating that participant understands the purpose of, and
procedures required for, the study and is willing to participate in the study.
24. 
Criterion modified per Amendment 1

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24.1 Must sign a separate informed consent form if the participant agrees to provide
optional DNA samples for research (where local regulations permit). Refusal to give
consent for the optional DNA research samples does not exclude a participant from
participation in the study. Appendix 3: Regulatory, Ethical, and Study Oversight
Considerations
25. 
Must be willing and able to adhere to the lifestyle restrictions specified in this
protocol.
26. 
Must be able to read and write. Visually impaired subjects may participate with the
support of a legally acceptable representative.
Vaccination history
27. 
Criterion has been removed per Amendment 3
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. 
Has a diagnosed or reported history or current signs or symptoms indicating severe,
progressive, or uncontrolled hepatic, renal, cardiac, vascular, pulmonary,
gastrointestinal, endocrine, neurologic, hematologic, rheumatologic (except RA),
psychiatric, or metabolic disturbances, which are detected at screening assessments
(ie, laboratory testing, physical examination, vital signs) or reported by the
participant.
2. 
Has a confirmed or suspected clinical immunodeficiency syndrome not related to
treatment of RA or has a family history of congenital or hereditary immunodeficiency
unless confirmed absent.
3. 
Has other inflammatory diseases that might confound the evaluation of benefit in this
study, including but not limited to Crohn’s disease, ulcerative colitis, interstitial lung
disease, ankylosing spondylitis, psoriatic arthritis, primary Sjogren’s syndrome, SLE,
and Lyme disease.
4. 
Has a history of any clinically significant adverse reaction to therapeutic proteins (eg,
mABs), including, but not limited to, allergic reactions or severe immediate
hypersensitivity reactions, such as anaphylaxis.
5. 
Allergies, hypersensitivity, or intolerance to nipocalimab or certolizumab or their
excipients (refer to the nipocalimab IB or the Cimzia SmPC).
6. 
Is (anatomically or functionally) asplenic
7. 
Has experienced MI, unstable ischemic heart disease, or stroke ≤12 weeks of
screening.
8. 
Has a diagnosis of congestive heart failure including medically controlled,
asymptomatic congestive heart failure.
9. 
Has a history of known demyelinating disease such as multiple sclerosis or optic
neuritis.
10. 
Had an organ transplant (with exception of corneal transplant >12 weeks prior to
screening)
11. 
Had major surgery, (eg, requiring general anesthesia) within 8 weeks before
screening, or has undergone surgical treatment for RA, including synovectomy and

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arthroplasty ≤12 weeks prior to first dose of study intervention, or will not have fully
recovered from surgery, or has surgery planned during the time the participant is
expected to participate in the study or ≤14 weeks after the last dose of study
intervention administration .
Note: Participants with planned surgical procedures to be conducted under local
anesthesia may participate.
12. 
Poor tolerability of venipuncture or lacks adequate venous access for required blood
sample collections during the study period.
Laboratory Tests
13. 
Has any of the following screening laboratory test result:
a. 
Hemoglobin <8.0 g/dL (International system of Units [SI]: <80 g/L)
b. 
WBCs <3.0×103 cells/μL (SI:<3.0×109 cells/L)
c. 
Neutrophils <1.0×103 cells/μL (SI: <1.0×109 cells/L)
d. 
Platelet count <75×103 cells/µL (SI: <75×109/L)
e. 
Estimated glomerular filtration rate <30 mL/min per 1.73 m2 using the CKD-
EPI formula (Levey 2009)
f. 
Liver function test (aspartate aminotransferase [AST] OR alanine
aminotransferase [ALT]) results that are ≥2 × the upper limit of normal (ULN)
g. 
Serum total IgG <6 g/L (<600 mg/dL)
Malignancy or Increased Potential for Malignancy
14. 
Criterion modified per Amendment 1
14.1 Currently has or history of malignancy within 5 years before screening
15. 
Has a history of lymphoproliferative disease, including lymphoma, or signs
suggestive of possible lymphoproliferative disease such as lymphadenopathy of
unusual size or location, or splenomegaly
Infections or Predisposition to Infections
16. 
History of HIV positive tests, or tests positive for HIV at screening.
17. 
Tests positive for HBV infection (refer to Protocol Appendix 9).
18. 
Is seropositive for antibodies to HCV, unless they satisfy 1 of the following conditions:
a. 
Has a history of successful treatment, defined as being negative for HCV RNA
at least 24 weeks after completing antiviral treatment, and has a negative HCV RNA
test result at screening,
OR
b. 
While seropositive, has a negative HCV RNA test result at least 24 weeks prior
to screening and a negative HCV RNA test at the screening.
19. 
Has a chronic or recurring infection (eg, bronchiectasis, chronic osteomyelitis,
chronic pyelonephritis) or requires chronic treatment with anti-infectives (e.g.,
antibiotics, antivirals).
20. 
Has a severe infection including opportunistic infections (e.g., pneumonia, biliary
tract infection, diverticulitis, clostridioides difficile infection, cytomegalovirus,
pneumocystosis, and aspergillosis) requiring parenteral anti-infectives and/or
hospitalization, and/or is assessed as serious/clinically significant by the investigator,
within 8 weeks prior to screening. The patient may be rescreened after the 8 weeks
exclusionary period has passed.

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21. 
Has a history of an infected joint prosthesis or has ever received antibiotics for a
suspected infection of a joint prosthesis if that prosthesis has not been removed or
replaced.
22. 
Has a history of latent or active granulomatous infection, including but not limited to
tuberculosis (see exclusion #24 on the detailed TB screening criteria below),
cryptococcosis, histoplasmosis or coccidioidomycosis, prior to screening.
23. 
Has a herpes zoster infection within 8 weeks before the first dose of study
intervention.
24. 
Criterion modified per Amendment 1
24.1 Criterion modified per Amendment 2
24.2 Meet ANY of the following TB screening criteria (See Section 8.2.13):
Note: IGRA testing includes QuantiFERON-TB®.
a. Have a history of active TB or show signs or symptoms suggestive of active TB
upon medical history and/or physical examination at screening.
b. Have a history of untreated latent TB prior to screening.
Note: For participants with a history of treated latent TB there must be documentation
of appropriate completed treatment prior to the first administration of study
intervention. It is the responsibility of the investigator to verify the adequacy of
previous TB treatment and provide appropriate documentation.
c. Have had recent close contact with a person with active TB.
d. Have a positive IGRA test result within 60 days prior to the first administration
of study intervention. An exception is made for participants who:
i. 
have a history of adequately treated latent TB described above.
ii. 
have a false-positive IGRA test as determined by the following:
Participants with indeterminate/borderline results should have the test repeated.
Participants with persistent indeterminate/borderline results or positive results on
repeat test will be excluded. If repeat testing is NOT positive, the participant must be
referred to a physician specializing in TB to determine if the initial test can be
considered a false-positive. This evaluation must be adequately documented prior to
the first administration of study intervention. If repeat testing is positive, however, it
will be considered a true-positive.
e. Have a chest radiograph (posterior-anterior and lateral views, or per country
regulations where applicable), taken within 90 days before the first
administration of study drug and read by a qualified radiologist, with evidence
of current, active TB or old, inactive TB
25. 
Criterion modified per Amendment 3

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25.1Have tested positive for or been exposed to COVID-19 within 4 weeks prior to the
first dose of study intervention.
Exceptions: Participants who have tested positive for or been exposed to COVID-19
may participate if they have both an absence of symptoms and a negative validated
COVID-19 test obtained at least 2 weeks after symptom onset (or the first positive test
for asymptomatic infection) or exposure.
Follow local regulations/guidelines for validated COVID-19 testing procedures and
standard definition of COVID-19 exposure.
Prior/Concomitant Therapy
26. 
Is naïve to bDMARDs and tsDMARDs.
27. 
Has taken any disallowed therapies (within the period of time detailed in
Section 6.8.5) prior to the planned first administration of study intervention.
28. 
Currently taking IgG Fc- related therapies.
29. 
Has received certolizumab or nipocalimab previously.
30. 
Has received plasmapheresis, immunoadsorption therapy, or IVIgwithin 6 weeks
prior to screening.
31. 
Has received BCG vaccine within 1 year or any other live vaccine within 4 weeks
before first dose of study intervention. Non-live vaccines approved or authorized for
emergency use (eg, COVID-19) by local health authorities are allowed. Has a known
need to receive a live vaccine during the study or within 8 weeks of the last study
intervention administration.
32. 
Has received anti-TNF agent (or its biosimilars) within 30 days or 5 half-lives
(whichever is longer), prior to the first administration of study intervention.
33. 
Has received biologic therapy or targeted synthetic DMARDs including but not
limited to the below within 30 days or 5 half-lives, whichever is longer, prior to the
first administration of study intervention:
a. anti-interleukin (IL)-6 receptor mAb (e.g., tocilizumab or sarilumab)
b. anti-IL-1 blockers (e.g., anakinra)
c. Co-stimulatory inhibitors (e.g., abatacept)
d. Janus kinase inhibitors (JAKi, e.g., tofacitinib, baricitinib, upadacitinib).
34. 
Has received rituximab within 26 weeks prior to first administration of study
intervention.
35. 
Currently using MTX and leflunomide combination therapy.
36. 
Has used oral cyclophosphamide within 12 weeks or IV cyclophosphamide within 24
weeks prior to first administration of study intervention.
37. 
Has received cyclosporine A, azathioprine, tacrolimus, mycophenolate mofetil, oral
or parenteral gold, or D-pencillamine within 4 weeks prior to first administration of
study intervention.
38. 
Has received intraarticular, intramuscular, intra-bursal, intra-lesional, intra-vertebral,
epidural, or IV glucocorticoids, including intramuscular adrenocorticotropic hormone
within 4 weeks prior to first study intervention.
39. 
Use of complementary therapies, including traditional/Chinese medicines, herbs,
ointments, or procedures (eg, acupuncture), that have the potential to activate (eg,

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echinacea) or inhibit (eg, Tripterygium wilfordii Hook F) the immune system is
prohibited within 6 weeks of first administration of study intervention. In addition,
use of complementary therapies, including traditional/Chinese medicines and herbs,
that have the potential to interact with antithrombotic agents (eg, St. John’s Wort) is
prohibited within 6 weeks of first administration of study intervention in those taking
antithrombotic agents. Any questions or concerns with the use of these therapies
should be discussed with the study sponsor and/or Medical Monitor.
Prior/Concurrent Clinical Study Experience
40. 
Received an investigational intervention or used an invasive investigational medical
device ≤12 weeks or 5 half-lives (whichever is longer) before the planned first dose
of study intervention or received an investigational biological product within 12
weeks or 5 half-lives, whichever is longer, before the planned study intervention, or is
currently enrolled in an investigational study.
Other Exclusions
41. 
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.
42. 
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.
43. 
History of drug or alcohol abuse according to Diagnostic and Statistical Manual of
Mental Disorders (5th edition; DSM-V) criteria within 1 year before screening or
positive test result(s) for alcohol or drugs of abuse (including barbiturates, opiates,
cocaine, cannabinoids, amphetamines, and benzodiazepines) at screening.
44. 
Currently participating or intends to participate in any other study using an
investigational agent or procedure during the conduct of this study.
45. 
Lives in an institution on court or authority order.
Note: Investigators must 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 the participant no longer meets all eligibility criteria, then the participant must be
excluded from participation in the study. Section 5.4, describes options for retesting. The required
source documentation to support meeting the enrollment criteria is noted in
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 study to be eligible for participation:
1. 
Refer to Concomitant Therapy (Section 6.8) 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 requirements

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3. 
Must agree to not receive a BCG vaccination, live attenuated viral or bacterial
vaccination during the study and for 12 weeks after receiving the last dose of study
intervention
4. 
Must be willing and able to complete study-related questionnaires and document
clinical symptoms, AEs, and concomitant medications
5. 
Avoid donating blood for at least 90 days after completion (ie, final follow-up visit) of
the study
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. This study will use IWRS. The investigator will
not generate screening and enrollment logs directly from IWRS.
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. Rescreened participants must be assigned new participant numbers.
Retesting Criteria
Exceptional and limited retesting of abnormal screening values that lead to exclusion are allowed
only once using an unscheduled visit during the screening period (to reassess eligibility).
In such cases, the first abnormal test result will not constitute a screen failure. If a laboratory
abnormality occurs, the site is encouraged to wait for all laboratory tests to be completed to ensure
other laboratory tests do not need to be repeated, as only 1 retest of laboratory values is allowed.
Participants who have laboratory values that do not meet entry criteria following the retest or do
not meet disease activity inclusion criteria following the repeat procedure are to be deemed screen
failures. A screening laboratory test analyzed by the central laboratory may be repeated more than
once in the event of a suspected error in sample collection or analysis as long as the result is
obtained within the screening period.
Rescreening
Individuals who do not meet the criteria for participation in this study (screen failure) may be
rescreened one time after discussion with the sponsor representative or their designee. Rescreened
participants must be assigned a new participant number, undergo the informed consent process,
and then start a new screening phase.
5.5. 
Criteria for Temporarily Delaying Administration of Study Intervention
Guidelines for study intervention administration affected by the COVID-19 pandemic are found
in Section 10.7.

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6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY
6.1. 
Study Intervention(s) Administered
6.1.1. 
Authorization Status in the EU (EU-CTR)
Designation 
Product
IMP  
Unauthorized: nipocalimab, placebo
Authorized: certolizumab
AxMP  
Authorized: csDMARDs (MTX, SSZ, HCQ, CQ,
leflunomide); folinic/folic acid; NSAIDs,
paracetamol/acetaminophen and other analgesics; oral
corticosteroids
6.1.2. 
Administration
Participants will be randomized in a 2:3 ratio to 1 of 2 treatment groups as described in the Table
below
Study intervention administration must be captured in the source documents and the eCRF.
For details on rescue medications, refer to Section 6.8.6. For a definition of study intervention
overdose, refer to Section 6.7.

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Description of Interventions
Arm Name 
Control arm  
Experimental arm
Intervention Name 
Certolizumab+placebo 
Certolizumab+nipocalimab
Type 
Biologic 
Biologic
Dose Formulation 
Certolizumab: prefilled syringe 
Certolizumab: prefilled syringe;
nipocalimab: vial for IV preparation
Unit Dose Strength(s) 
Certolizumab 200 mg/mL 
Certolizumab 200 mg/mL
Nipocalimab 30 mg/mL
Dosage Level(s) 
Certolizumab: 2 injections of 200 mgat 
Week 0, 2, 4 then 200 mg Q2W  
Placebo IV Q2W  
Certolizumab: 2 injections of 200 mg at
Week 0, 2, 4 then 200 mg Q2W
Nipocalimab 30 mg/kg IV Q2W
Route of Administration 
Certolizumab SC; placebo IV  
Certolizumab SC; nipocalimab IV
Use 
Control 
Experimental
Investigational Medicinal Product (IMP) 
yes 
yes
Current/Former Name(s) or Alias(es)a 
Certolizumab/Cimzia 
Certolizumab, Cimzia; nipocalimab, JnJ-
80202135, MOM281
a 
Labels will contain information to meet the applicable regulatory requirements.

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6.2. 
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
Nipocalimab IV solution will be prepared by the unblinded pharmacist or designee according to
the instructions provided to the clinical sites in the IPPI. Saline will be used as placebo.
Refer to the IPPI and study site investigational product and procedures manual for guidance on
study intervention preparation, handling, and storage.
Accountability
The investigator is responsible for ensuring that all study intervention received at the site is
inventoried and accounted for throughout the study.
The study intervention administered to the participant must be documented on the intervention
accountability form. All study intervention will be stored and disposed of according to the
sponsor's instructions. Study site personnel must not combine contents of the study intervention
containers.
Study intervention must be handled in strict accordance with the protocol and the container label,
and must be stored at the study site in a limited access area or in a locked cabinet under appropriate
environmental conditions. Unused study intervention, and study intervention returned by the
participant, must be available for verification by the sponsor’s study site monitor during on-site
monitoring visits. The return to the sponsor of unused study intervention, or used returned study
intervention for destruction, will be documented on the intervention return form. When the study
site is an authorized destruction unit and study intervention supplies are destroyed on-site, this
must also be documented on the intervention return form.
Potentially hazardous materials such as used ampules, needles, syringes, and vials, should be
disposed of immediately in a safe manner and therefore will not be retained for intervention
accountability purposes.
Study intervention should be dispensed under the supervision of the investigator or a qualified
member of the study site personnel, or by a hospital/clinic pharmacist. Study intervention will be
supplied only to participants participating in the study. Returned study intervention must not be
dispensed again, even to the same participant. 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 SIPPM .
6.3. 
Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Procedures for Randomization and Stratification
Dynamic central randomization will be implemented in conducting this study. Participants will be
assigned to 1 of2 treatment arms based on an algorithm implemented in the IWRS before the study.

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Dynamic central randomization minimizes the imbalance in the distribution of the number of
participants across treatment arms within the levels of each individual stratification factor:
1) csDMARDs usage at baseline (yes or no)
2) Screening ACPA level (high ≥400 U/mL; low <400 U/mL)
3) Baseline DAS28-CRP (high ≥5.8; low <5.8, CRP at screening)
4) Study country/territory
5) Investigator site
Based on the algorithm, the IWRS will assign a unique intervention code, which will dictate the
intervention assignment and matching study intervention kit for the participant.
Blinding
The investigator will not be provided with randomization codes. The codes will be maintained
within the IWRS, which has the functionality to allow the investigator to break the blind for an
individual participant.
Data that may potentially unblind the intervention assignment (ie, study intervention serum
concentrations, anti-study intervention antibodies, study intervention preparation/accountability
data, intervention allocation, biomarker or other specific laboratory data) will be handled with
special care to ensure that the integrity of the blind is maintained and the potential for bias is
minimized. This can include making special provisions, such as segregating the data in question
from view by the investigators, clinical team, or others as appropriate until the time of database
lock and unblinding.
At the Week 12 DBL, data will be unblinded for analysis to some Sponsor personnel while
participants are still participating in the study.
Identification of Sponsor personnel who will have access to the unblinded subject-level data will
be documented prior to unblinding. Investigative study sites and participants will remain blinded
to initial treatment assignment until after the final database is locked.
Under normal circumstances, the blind should not be broken until all participants have completed
the study and the database is finalized. Otherwise, the blind should be broken only if specific
emergency intervention/course of action would be dictated by knowing the intervention status of
the participant. In such cases, the investigator may in an emergency determine the identity of the
intervention by contacting the IVRS/IWRS. It is recommended that the investigator contact the
sponsor or its designee, if possible, to discuss the particular situation, before breaking the blind.
Telephone contact with the sponsor or its designee will be available 24 hours per day, 7 days per
week. In the event the blind is broken, the sponsor must be informed as soon as possible. The date,
time, and reason for the unblinding must be documented by the IVRS/IWRS, in the appropriate
section of the eCRF, and in the source document. The documentation received from the
IVRS/IWRS indicating the code break must be retained with the participant's source documents in
a secure manner.

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Participants who have had their intervention assignment unblinded should continue to return for
scheduled evaluations.
In rare circumstances when a potential safety issue that may impact the overall benefit-risk
assessment of the investigational product has been identified in this study, selected Sponsor
personnel may be unblinded to safety-related data in order to investigate the safety issue and
determine if additional actions are required. The safety data should be kept blinded to any
personnel not essential to the safety review.
If other rare, unforeseen circumstances arise that may necessitate unblinding of selected sponsor
personnel, these will be assessed and documented on a case-by-case basis. The data should be kept
blinded to any personnel not essential to the review or investigation.
In general, randomization codes will be disclosed fully only if the study is completed and the
clinical database is closed.
6.4. 
Study Intervention Compliance
Studysite personnel will maintain a log of all study interventions administered. Study intervention
supplies for each participant will be inventoried and accounted for.
Study intervention will be administered as a SC injection for certolizumab and as an IV infusion
for nipocalimab by qualified study  site personnel. The details of each administration will be
recorded in the eCRF (including date, start and stop times of the IV infusion, and volume infused).
6.5. 
Dose Modification
No study intervention dose adjustment will be permitted throughout the study.
6.6. 
Continued Access to Study Intervention After the End of the Study
Investigators may recontact the participant to obtain long-term follow-up information regarding
the participant’s safety or survival status including endpoint status as noted in the ICF (refer to
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations).
No continued access will be proposed for this 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 nipocalimab greater than 10% above the highest dose of a single dosing
visit specified in this protocol will be considered an overdose. The sponsor does not recommend
specific treatment for an overdose. For overdose considerations regarding Cimzia, please refer to
the SmPC/ US package insert.
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 must be interrupted or whether study intervention must be discontinued.

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Closely monitor the participant for adverse event/serious adverse event and laboratory
abnormalities
Obtain a plasma sample for PK analysis if requested by the Medical Monitor (determined on
a case-by-case basis including at what timepoints).
Document the quantity of the excess dose as well as the duration of the overdosing in the
eCRF.
6.8. 
Concomitant Therapy
Prestudy therapies administered up to 60 days before first dose of study intervention must be
recorded at screening.
Concomitant therapies must be recorded throughout the study beginning with start of the first dose
of study intervention to 8 weeks after the last dose of study intervention.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal
supplements; Covid-19 vaccination and anti-Covid-19 mAb for emergency use;
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 CRF. Recorded information will include a description of the type of therapy,
treatment duration, dose regimen, route of administration, and indication. Modification of an
effective pre-existing therapy should not be made for the explicit purpose of entering a participant
into the study.
Every effort should be made to keep participants’ concomitant medications stable through
Week24. The concomitant medication dose may be reduced, or the medication temporarily
discontinued because of abnormal laboratory values, side effects, concurrent illness, or the
performance of surgical procedure(s), but the change and reason for the medication change should
be clearly documented in the subject’s medical record.

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Table 3: 
Permitted Concomitant Medications for 80202135ARA2002, the Minimum
Stabilization Period before Randomization, and the Maximum Allowed Doses at Study
Randomization
outlines permitted concomitant medication use and dose stabilization requirements.

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Table 3: Permitted Concomitant Medications for 80202135ARA2002, the Minimum Stabilization Period
before Randomization, and the Maximum Allowed Doses at Study Randomization
Permitted Concomitant 
Medications for RA  
Stabilization Period Prior to First
Study Intervention
Administration 
Allowable Dosage
csDMARDs 
Treated for ≥12 weeks with stable 
dosage for ≥8 weeks 
MTX: ≤25 mg/week
SSZ: 1000-2000 mg/day
HCQ or CQ: 200-400 mg/day
Leflunomide: 10-20 mg/day
Oral corticosteroids 
Stable dosage for ≥2 weeks 
Equivalent to average of
≤10 mg/day of prednisone
NSAIDs and other analgesics 
≥2 weeks 
No more than the usual marketed
dosages approved in the country
where the study is being conducted
Abbreviations: CQ=chloroquine; csDMARD=conventional synthetic disease-modifying anti-rheumatic drugs;
HCQ=hydroxychloroquine; MTX=methotrexate; NSAIDs=nonsteroidal anti-inflammatory drugs; RA=rheumatoid
arthritis; SSZ=sulfasalazine
6.8.1. 
Acetaminophen/Paracetamol
The use of stable dose acetaminophen during the study is permitted if it does not exceed
recommended dose of 3 g/day. Acetaminophen is not permitted as a part of combination products
such as over‑the-counter “cold remedies” or in combination with opioids if the total
acetaminophen/ paracetamol dose exceeds 3 g/day. Acetaminophen/Paracetamol should not be
initiated within 24 hours before a study visit involving joint counts and pain assessments.
6.8.2. 
Nonsteroidal Anti-inflammatory Drugs and Other Analgesics
Participants treated with NSAIDs, including acetylsalicylic acid (aspirin) and selective
cyclooxygenase-2 inhibitors, and other analgesics should receive the usual marketed doses
approved in the country in which the study is being conducted. In this study, aspirin is considered
an NSAID, except for low-dose aspirin prescribed for CV or cerebrovascular disease. Prescriptions
of NSAIDs and other analgesics generally should not be adjusted for at least 2 weeks prior to the
first administration of the study agent and through Week 24. The dose and the type of NSAIDs or
other analgesics may be changed at the discretion of the investigator if the subject develops
unacceptable side effects or a contraindication to their use. NSAIDs and other analgesics should
not be initiated within 24 hours before a study visit involving joint counts and pain assessments.
6.8.3. 
Disease Modifying Antirheumatic Drugs/Systemic
Immunosuppressives
If using a non-biologic csDMARD such as MTX, SSZ, HCQ, CQ, or leflunomide, the participant
must be on a stable dose for at least 8 weeks prior to the first administration of study intervention
and should have no serious toxic side effects attributable to the DMARD. If using MTX, the
recommended doses are within the range of 7.5 up to 25 mg IM, PO, or SC weekly, and treatment
should have started at least 12 weeks prior to the first administration of study intervention. If using

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SSZ, hydroxychloroquine, or CQ should have started treatment at least 12 weeks prior to the first
administration of study agent. If currently not using MTX, SSZ, HCQ, CQ, or leflunomide, the
participant must not have received these DMARDs for at least 4 weeks prior to the first
administration of the study agent.
All participants receiving MTX will also receive at least 5 mg of oral folic acid or 5 mg folinic
acid weekly. Participants must have been on a stable dose of folic acid (>5 mg) for at least 4 weeks
prior to the first administration of the study intervention. Folic acid or folinic acid should not be
given on the day of MTX dosing. In the event of clinically significant decreases in neutrophils or
platelet counts, MTX should be temporarily or permanently discontinued.
6.8.4. 
Corticosteroid Therapy
Oral Corticosteroids
Participants treated with oral corticosteroids should receive a stable dose equivalent to ≤ 10 mg
prednisone per day for at least 2 weeks prior to their first administration of the study agent and
continue to receive this dose through Week 24. Initiation of oral corticosteroids is prohibited
during the study for any indication (except as rescue therapy after Week 14, see Section 6.8.6).
However, the dose and the type of oral corticosteroid may be changed at the discretion of the
investigator to manage comorbidities or unacceptable side effects. Any changes should be
discussed with the Medical Monitor.
Intraarticular, Intramuscular, and Intravenous Corticosteroids
Intraarticular, intramuscular, and IV administration of corticosteroids for the treatment of RA is
not allowed within 4 weeks before the first administration of study intervention and throughout
the study.
Other Administration of Corticosteroids
Other forms of corticosteroid administration (eg, topical/mucosal [including eye drops or creams],
bronchial or nasal inhalation) for treatment of conditions other than RA may be given as needed
throughout the course of the study.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered.
6.8.5. 
Prohibited Medications
Use of additional immunosuppressants or immunomodulators, other than those explicitly allowed
in the inclusion/exclusion criteria (Section 5.1 and Section 5.2), are prohibited, including (but not
limited to) the following:
Systemic immunosuppressives (other than MTX, SSZ, HCQ, CQ, and leflunomide) such as
azathioprine, oral cyclosporine A, tacrolimus, mycophenolate mofetil, oral or parenteral
gold
Cytotoxic drugs such as cyclophosphamide, chlorambucil, nitrogen mustard, or other
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Anti-TNFα therapy such as: infliximab, golimumab, etanercept, adalimumab, and
biosimilars to those anti-TNFs
Anti-IL-6 receptor mAb (eg, tocilizumab or sarilumab)
Anti-IL-1 receptor mAb (eg, anakinara)
B-cell depleting biologic therapy (eg, rituximab)
Co-stimulatory inhibitors (eg, abatacept)
JAKi (eg, tofacitinib, baricitinib, upadacitinib)
Any other targeted biologic therapy
Any investigational intervention or use of an invasive investigational medical device
Use of complementary therapies or traditional medicine (eg, Chinese, acupuncture,
ayurvedic) through Week 24
Live virus or live bacterial vaccination during the study
As these lists cannot be exhaustive, please consult the Medical Monitor to discuss prior to
starting any biologic or other advanced therapies.
6.8.6. 
Rescue Medication
The following rescue medications may be used:
csDMARDs such as MTX, SSZ, HCQ, CQ, and LEF
oral corticosteroids
At Week 14, participants who have not achieved low disease activity (defined as CDAI ≤10) will
receive the current SoC treatment starting from Week 14 (investigator’s choice of SoC treatment
appropriate for the participant).
If participants initiate or increase their dose of csDMARDs, oral corticosteroids and/or NSAIDs,
there will be no need to discontinue study intervention, and data collection will continue through
Week 30.
The study intervention must be discontinued if rescue medications are the prohibited medications
listed in Section 6.8.5 Prohibited Medications.
It is recommended that participants who permanently discontinue study intervention, but do not
withdraw from study participation, be followed at all subsequent study visits through Week 30. At
a minimum, participants who permanently discontinue study intervention, but do not withdraw
from study participation, should return for a safety follow-up visit 8 weeks after the last dose of
study intervention.
The date of rescue medication administration as well as the name and dosage regimen of the rescue
medication must be recorded.
6.8.7. 
Vaccinations (Including COVID-19)
It is recommended to be up to date on all age-appropriate vaccinations prior to screening per
routine local medical guidelines. It is strongly recommended that participants will have completed

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a locally-approved (or emergencyuse-authorized) COVID-19 vaccination regimen at least 2 weeks
prior to study-related visits or procedures. Study participants should follow applicable local
vaccine labelling, guidelines, and standards-of-care for patients receiving immune-targeted
therapy when determining an appropriate interval between vaccination and study enrolment.
In order to help differentiate between vaccine- and study intervention-related reactions, it is
recommended that vaccine and study intervention be administered on different days, separated by
as large an interval as is practical within the protocol.

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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 participant becomes pregnant. Refer to Section 10.5
The participant develops an infection that is unresponsive or worsening while on anti-infective
therapy
The participant develops any serious infection (ie, meets AE seriousness criteria)
The participant develops a clinically significant opportunistic infection  (eg, active TB,
invasive fungal infection)
The participant develops a malignancy during the study
The participant develops congestive heart failure
The participant is diagnosed with demyelinating disorder
The participant develops symptoms suggestive of a lupus-like syndrome and is positive for
antibodies against double-stranded DNA
The participant develops a severe infusion reaction/ allergic reaction assessed by the
investigator as related to study intervention (eg, anaphylaxis per Sampson’s criteria
[Section 10.9])
The participant develops clinical manifestations of hypoalbuminemia, including 3+ pedal
edema, ascites, or pleural or pericardial effusions assessed by the investigator as related to
study intervention
The participant has serum total IgG<1 g/L (<100 mg/dL)
The participant initiates a prohibited therapy as described in Section 6.8.5.
Discontinuation of a participant’s study intervention should be strongly considered under
the following conditions:
Two sequential absolute neutrophil counts <0.75×103/μL (SI: <0.75×109/L)
Two sequential absolute lymphocyte counts <0.5×103/μL (SI: <0.5×109/L)
Two sequential hemoglobin values <7.5 g/dL (SI: <75.0 g/L) or a decrease of >30% from
baseline
Two sequential platelet counts <75×103/μL (SI: <75×109/L)
Note: These laboratory abnormalities should be discussed with the Medical Monitor or designee,
and study intervention should be withheld until the clinical assessment is complete.

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Discontinuation of a participant’s study intervention should be considered under the
following conditions:
Persistent IR or worsening of RA.
If a participant discontinues study intervention for any reason before the end of the double-blind
phase, then the end-of-intervention assessments must be obtained and scheduled assessments off
study intervention should be continued. Study intervention assigned to the participant who
discontinued study intervention may not be assigned to another participant. Additional participants
will not be entered to ensure the protocol-specified number of participants complete the study.
7.1.1. 
Liver Chemistry Stopping Criteria
Stopping of study intervention for abnormal liver tests is required by the investigator when a
participant meets one of the conditions outlined in 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.
7.1.2. 
Study Stopping Rules
The study will be terminated if any of the following criteria are met:
Death of any participant in which the DMC and sponsor believe that participants would incur
undue risk by continuing the study
Serious Infection: There is a serious infection event that the DMC and sponsor believe would
incur undue risk to participants in the study. A potential serious infection safety concern will
be identified via statistical sequential monitoring framework and evaluated for each event.
Additional details are provided in the DMC charter and DMC SAP.
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 CRF and in the source document. If the reason for withdrawal from the study
is withdrawal ofconsent 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.

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Prior to a participant withdrawing consent for follow-up, the investigator should offer the
participant an opportunity for one of the alternative reduced follow-up mechanisms described
below. Withdrawal of consent must be an infrequent occurrence in clinical studies
(Rodriguez 2015), therefore, prior to the start of the study the sponsor and the investigator must
discuss and reach a clear understanding of what constitutes withdrawal of consent in the context
of the available reduced follow-up mechanisms listed.
Circumstances for Reduced Follow-up
In the situation where a participant may be at risk for withdrawal of consent and is unable to return
for scheduled visits at the protocol-defined frequency, the investigator may consider options for
reduced follow-up. These may include (as local regulations permit):
Less frequent clinical visits
Telephone, email, letter, social media, fax, or other contact with:
o participant
o relatives of the participant
o participant’s physicians (general or specialist)
Review of any available medical records
Details regarding these contacts must be properly documented in source records including
responses by participants.
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 samples:
The collected samples 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 samples, in which case the
samples will be destroyed and no further testing will take place. To initiate the sample
destruction process, the investigator must notify the sponsor study site contact of withdrawal
of consent for the optional research samples and to request sample destruction. The sponsor
study site contact will, in turn, contact the biomarker representative to execute sample
destruction. If requested, the investigator will receive written confirmation from the sponsor
that the samples have been destroyed.
Withdrawal 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 samples will be destroyed. The sample destruction process
will proceed as described above.
Withdrawal from the Use of Samples in Future Research
The participant may withdraw consent for use of samples for research (refer to Long-Term
Retention of Samples for Additional Future Research in  Appendix 3: Regulatory, Ethical, and

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Study Oversight Considerations). In such a case, samples will be destroyed after they are no longer
needed for the clinical study. Details of the sample retention for research are presented in the main
ICF and in the separate ICF for optional research samples.
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 the participant 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
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8. 
STUDY ASSESSMENTS AND PROCEDURES
Overview
The SoA summarizes the frequency and timing ofefficacy, PK, immunogenicity, PD, biomarker,
pharmacogenomic, and safety measurements applicable to this study.
All PRO assessments must be conducted/completed before any tests, procedures, or other
consultations to prevent influencing participant responses. Refer to the PRO completion guidelines
for instructions on the administration of PROs.
If multiple assessments are scheduled for the same timepoint, it is recommended that procedures
be performed in the following sequence: PtGA of disease activity, Pain VAS, Joint Pain Severity
NRS, and HAQ-DI. 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/or the CRF.
Screening Phase
The screening phase is up to 6 weeks before administration of study intervention. After written
ICF has been obtained, all screening evaluations (eg, laboratory test results, clinical data, and
concomitant medication data) that establish participant eligibility will be performed by the
principal investigator or designee to confirm that the participant satisfies all inclusion criteria and
does not violate any exclusion criteria and can therefore be enrolled in the study. Every effort
should be made to adhere to the SoA for each participant. The collection of AEs will start at the
time the ICF is obtained.
Blood Sample Collection
The total blood volume to be collected from each participant will be approximately 710 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the
samples.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the CRF or laboratory
requisition form.
Refer to the SoA for the timing and frequency of all sample collections (Section 1.3).
Instructions for the collection, handling, storage, and shipment of samples are found in  the
Laboratory Manual that will be provided. Collection, handling, storage, and shipment of samples
must be under the specified, and where applicable, controlled temperature conditions as indicated
in the Laboratory Manual.
Study-Specific Materials
The investigator will be provided with the following supplies:
Investigator Site File (includes protocol and nipocalimab IB)

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SmPC/Package Insert for certolizumab
Sample ICFs
Laboratory manual and laboratory kits
IVRS/IWRS Manual
eCRF completion instructions
Electronic ClinRO and PRO equipment (tablet device questionnaires, completion
instructions)
Patient recruitment materials
8.1. 
Efficacy Assessments
It is strongly recommended that the same clinical assessor perform the clinical assessments at
every visit.
The PRO instrument will be provided in the local language in accordance with local
guidelines.
The PRO instrument will be available for regulators and for IRB/IEC submissions and will be
provided separately in a companion manual with the instruments that will be submitted with
the protocol.
The PRO and AE data will not be reconciled with each other.
8.1.1. 
Evaluations
8.1.1.1. 
Patient’s and Physician’s Global Assessment of Disease Activity
The Patient’s and Physician’s Global Assessments of Disease Activity  (Anderson 2011;
Felson 1995) will be recorded on a VAS. The scale for the participant’s assessment ranges from
“very well” to “very poor.” The scale for the physician’s assessment ranges from “no arthritis
activity” to “extremely active arthritis.” The evaluating physician and participant must complete
the global assessment independently of each other. The physician should preferably be the same
person at every study visit for a given participant.
8.1.1.2. 
Pain Assessment
Participants will be asked to assess their average pain during the past week on a VAS. The scale
ranges from “no pain” to “the worst possible pain.” This assessment should be completed prior to
the joint examination. The validity of this assessment has been evaluated and reviewed extensively
as it is a component of the ACR response score (Felson 1993; Hawley 1992).
8.1.1.3. 
Joint Pain Severity NRS
Participants' joint pain will be assessed using a single item that asks the participant to report the
worst severity of their joint pain over the past 7 days on a 0 to 10 NRS. Responses range from
“No joint pain” (0) to “'Severe joint pain” (10).

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8.1.1.4. 
Health Assessment Questionnaire –Disability Index
The functional status of the participant will be assessed using the HAQ-DI (Fries 1980). This
20-question instrument assesses the degree of difficulty a person has in accomplishing tasks in
8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of
daily living). Responses in each functional area are scored from 0, indicating no difficulty, to 3,
indicating inability to perform a task in that area. A score change of (-0.22) is considered the
minimum threshold for a clinically important improvement (Kosinski 2000; Pope 2009;
Wells 1993).
8.1.1.5. 
Joint Assessments
Joint Assessor
Each of 68 joints will be evaluated for tenderness, and each of 66 joints will be evaluated for
swelling (hips are excluded for swelling). All joints will be examined at visits as indicated in the
SoA (Section 1.3). It is recommended that the joint assessor should not be changed during the
study.
The joint assessment should be performed by adequately trained joint assessor. Training on how
the joint count will be performed will be provided by the sponsor. The joint assessor should be a
rheumatologist or a health care provider with at least 1 year of experience in performing joint
assessments. A health care provider with less than 1 year of experience may serve as a joint
assessor based on the approval of the sponsor. The same assessor should perform joint assessments
at every visit. It is recommended that the designated joint assessor identify an appropriate backup
joint assessor in case the designated joint assessor is unavailable.
Nonevaluable Joints
Joints should only be designated as “nonevaluable” by the joint assessor on the Joint Assessment
Worksheet if it is physically impossible to assess the joint (ie, joint inaccessible due to a cast, joint
was replaced, joint not present due to an amputation, joint deformed so as to make it impossible to
assess). In all other cases, the joint assessor should assess each joint for tenderness and swelling
(hips are excluded for swelling) and complete the worksheet with their assessments. This should
be completed regardless of any visual indications of prior surgical procedures (eg, scars) or
knowledge they may have of a participant’s prior joint procedures/injections (eg, if the participant
was the joint assessor’s patient prior to study participation).
8.1.2. 
Definitions
8.1.2.1. 
Disease Activity Index Score 28
8.1.2.1.1. 
DAS28 Using C-reactive Protein
The DAS28-CRP is a statistically derived index combiningtender joints (28 joints), swollen joints
(28 joints), CRP, and PtGA of Disease Activity (van Riel 2000). The DAS28-CRP is a continuous
parameter and is defined as follows:

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DAS28-CRP = 0.56 × SQRT(TEN28) + 0.28 × SQRT(SW28) + 0.36 × ln (CRP+1) + 0.014 × GH
+ 0.96 where:
The set of 28 joint count is based on evaluation of the shoulder, elbow, wrist,
metacarpophalangeal (MCP) 1, MCP2, MCP3, MCP4, MCP5, proximal interphalangeal
(PIP) 1, PIP2, PIP3, PIP4, PIP5 joints of both the upper right extremity and the upper left
extremity as well as the knee joints of lower right and lower left extremities
TEN28 is 28-joint count for tenderness
SQRT(TEN28) is square root of TEN28
SW28 is 28-joint count for swelling
SQRT(SW28) is square root of SW28
Ln (CRP+1) is natural logarithm of (CRP value [mg/L] + 1)
GH is PtGA of Disease Activity on a VAS of 100 mm
8.1.2.1.2. 
DAS28 Using Erythrocyte Sedimentation Rate
The DAS28-ESR is a statistically derived index combining tender joints (28 joints), swollen joints
(28 joints), ESR, and GH (Prevoo 1995). It is a continuous parameter and is defined as follows:
DAS28-ESR = 0.56 × SQRT(TEN28) + 0.28 × SQRT(SW28) + 0.70 × ln (ESR) + 0.014 × GH
The set of 28 joint count is based on evaluation of the shoulder, elbow, wrist, MCP1, MCP2,
MCP3, MCP4, MCP5, PIP1, PIP2, PIP3, PIP4, PIP5 joints of both the upper right extremity
and the upper left extremity as well as the knee joints of lower right and lower left extremities
TEN28 is 28-joint count for tenderness
SQRT(TEN28) is square root of TEN28
SW28 is 28-joint count for swelling
SQRT(SW28) is square root of SW28
Ln (ESR) is natural logarithm of ESR
GH is PtGA of Disease Activity on a VAS of 100 mm
8.1.2.1.3. 
DAS28 Response
DAS28 response is defined in Table 4 (van Riel 2000).
Table 4: DAS28 Response Criteria
Improvement from Baseline
DAS28 at the visit 
>1.2 
>0.6 and ≤1.2 
0.6
3.2 
Good response 
Moderate response 
No response
>3.2 and ≤5.1 
Moderate response 
Moderate response 
No response
>5.1 
Moderate response 
No response 
No response
Abbreviation: DAS28= Disease Activity Index Score 28

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8.1.2.1.4. 
DAS28 Low Disease Activity
DAS28 LDA is defined as a DAS28 value of≤3.2 at a visit.
8.1.2.1.5. 
DAS28 Remission
DAS28 remission is defined as a DAS28 value of <2.6 at a visit.
8.1.2.2. 
American College of Rheumatology Response
ACR responses are presented as the numeric measurement of improvement in multiple disease
assessment criteria. For example, an ACR20 response (Felson 1995) is defined as:
1. ≥20% improvement from baseline in both swollen joint count (66 joints) and tender joint count
(68 joints)
AND
2. ≥20% improvement from baseline in 3 of the following 5 assessments:
Patient’s Global Assessment of Disease Activity (VAS)
Patient’s assessment of pain (VAS)
Patient’s assessment of physical function as measured by HAQ-DI
Physician’s Global Assessment of Disease Activity (VAS)
CRP
ACR50, ACR70, and ACR90 are similarly defined except improvement threshold from baseline
is 50%, 70%, and 90%, respectively.
8.1.2.3. 
Clinical Disease Activity Index Score
The CDAI score is a derived score combining tender joints (28 joints), swollen joints (28 joints),
PtGA of Disease Activity, and PGA of Disease Activity (Aletaha 2006).
The CDAI score is defined as follows:
CDAI = TEN28 + SW28 + GH + PGH where:
TEN28 and SW28 were defined the same as in Section 8.1.2.1
GH is PtGA of Disease Activity (VAS)
PGH is PGA of Disease Activity (VAS)
CDAI Low Disease Activity
CDAI LDA is defined as a CDAI score of ≤10 at a visit.
CDAI Remission
CDAI remission is defined as a CDAI score of <2.8 at a visit.

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8.1.2.4. 
Simplified Disease Activity Index Score
The SDAI for RA score is a derived score combining tender joints (28 joints), swollen joints (28
joints), PtGA of Disease Activity, PGA of Disease Activity, and CRP (Aletaha 2006).
The SDAI score is defined as follows:
SDAI = TEN28 + SW28 + GH + PGH + CRP (mg/dL) where:
TEN28 and SW28 were defined the same as in Section 8.1.2.1
GH is Patient’s Global Assessment of Disease Activity (VAS)
PGH is Physician’s Global Assessment of Disease Activity (VAS)
Note: SDAI is the same as CDAI, except that CRP is included.
SDAI Low Disease Activity
SDAI LDA is defined as a SDAI score of ≤5.5 at a visit.
8.1.2.5. 
ACR/EULAR Remission
Simple Disease Activity Index-based ACR/EULAR Remission
SDAI based ACR/EULAR remission is defined as a SDAI value of ≤3.3 at a visit (Felson 2011).
Boolean-Based ACR/EULAR Remission
A participant is considered as having achieved the Boolean-based ACR/EULAR remission at a
visit if he/she meets all of the following 4 criteria at that visit (Felson 2011):
Tender joint count (68 joints) ≤1
Swollen joint count (66 joints) ≤1
CRP ≤1 mg/dL
PtGA of Disease Activity on VAS ≤1 (on a 0 to 10 scale)
8.2. 
Safety Assessments
Details regarding the Data Monitoring Committee are provided in Appendix 3
Adverse events will be reported and followed by the investigator as specified in Section 8.3, and
Appendix 4.
Any clinically relevant changes occurring during the study must be recorded on the Adverse Event
section of the CRF.
Adverse events must include the reporting of any observed effects on organ maturation and growth
and development, including fertility.
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 SoA.

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8.2.1. 
Physical Examinations
Physical examinations will be performed as indicated in the SoA. Clinically significant findings
should be reported as AEs.
Full physical examinations will include a review of the following body systems:
General appearance
Thorough skin and oral mucosa evaluation
Eyes, ears, nose, and throat
Cardiovascular
Respiratory
Abdomen
Peripheral pulsation
Lymph nodes
Neurologic
Musculoskeletal
Head, neck, and thyroid
8.2.2. 
Vital Signs
Temperature, pulse/heart rate, respiratory rate, blood pressure will be assessed.
Blood pressure and pulse/heart rate measurements will be assessed with a completely automated
device. Manual techniques will be used only if an automated device is not available.
Blood pressure and pulse/heart rate measurements should be preceded by at least 5 minutes of rest
in a quiet setting without distractions (eg, television, cell phones).
8.2.3. 
Electrocardiograms
A 12-lead ECG will be performed locally at screening. Additional ECGs can be performed locally
based on the investigator’s judgment.
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 Appendix 2: Clinical Laboratory Tests. The investigator must review the
laboratory results, document this review, and record any clinically relevant changes occurring

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during the study in the AE section of the CRF. The laboratory reports must be filed with the source
documents.
8.2.5. 
Pregnancy Testing
Additional serum or urine pregnancy tests (highly sensitive) may be performed, as determined
necessary by the investigator or required by local regulation, to establish the absence of pregnancy
at any time during the participation in the study.
8.2.6. 
Concomitant Medication Review
Concomitant medication will be reviewed at each visit.
8.2.7. 
Adverse Events Temporally Associated with Infusion
Any AE (except laboratory abnormalities) that occurs during or within the observation period after
the IV infusion of study intervention will be carefully evaluated. Participants will be observed for
safety duringand for 1-hour post-infusion after the first 3 infusions, if no clinically relevant AEs
related to the infusion are observed, participants will be observed for 30 minutes after subsequent
infusions.
8.2.8. 
Infusion Reactions
An infusion reaction is defined as any AE that occurs during the infusion or post-infusion and that
is reported by the investigator to represent an infusion reaction.
Minor infusion-related AEs may be managed by slowing the rate of the IV infusion and treating
with antihistamines and acetaminophen as clinically indicated. If an IV infusion of study
intervention is interrupted because of an AE that, in the opinion of the investigator, is not severe
or does not result in an SAE, the infusion may be restarted with caution.
8.2.9. 
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.
8.2.10. 
Hypersensitivity Reactions
Before any administration of study intervention, appropriately trained personnel and medications
(eg, antihistamines, injectable epinephrine) must be available to treat hypersensitivity reactions,
including anaphylaxis. All participants must be observed carefully for signs and symptoms of a
hypersensitivity reactions (eg, urticaria, pruritis, angioedema, wheezing, dyspnea, or hypotension).
Potential cases of anaphylaxis should be assessed according to Sampson’s criteria (Section 10.9)
In the case of severe allergic reaction (eg, anaphylaxis), SC aqueous epinephrine, corticosteroids,
respiratory assistance, and other proper resuscitative measures are essential and must be available
when study intervention is being administered. Participants who experience a severe infusion
reaction/allergic reaction, assessed by the investigator as being related to study intervention, must
be discontinued from further study intervention administrations.

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8.2.11. 
Infections
Investigators are required to evaluate participants for any signs or symptoms of infection at
scheduled visits. Study intervention administration should not be given to a participant with a
clinically significant, active, chronic, or recurring infection. Study intervention must be
discontinued if a participant develops any serious infection (ie, that meets criteria for a SAE or
AESI), or develop a moderate or severe opportunistic infection or an infection that is unresponsive
or worsening while on anti-infective therapy (Section 7.1).
8.2.12. 
Increased Lipids
Lipids levels are routinely monitored in participants throughout the study.
In participants with elevated lipids at any time during the study, it is recommended that
investigators initiate or continue appropriate therapy for dyslipidemia per local health guidelines.
In participants with persistently elevated lipids (above LDL threshold of 190 mg/dL or the
triglyceride threshold of 1000 mg/dL), it is strongly recommended that investigator initiate
appropriate therapy or modify current therapy for dyslipidemia per local health guidelines.
8.2.13. 
Tuberculosis Evaluation
Initial Tuberculosis Evaluation
Participant 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 imaging results and responses to
tuberculin skin or other TB testing. Investigators have the option to use the tuberculin skin test in
addition to IGRA testing to screen for latent TB if preferred by local health authorities, or if they
believe based on their judgment that both tests are clinically indicated to evaluate a participant at
high risk for latent TB.
Participants with a negative IGRA test result are eligible to continue with prerandomization
procedures. Participants with a newly identified positive IGRA test result must undergo an
evaluation for active or latent TB, or suspected false-positive initial testing.
Participants with indeterminate/borderline IGRA test results should have the test repeated.
Participants with persistently indeterminate/borderline IGRA test results should be screening
failure or discontinued from the study treatment during the study.
Appropriate treatment for active or latent TB is defined according to local country guidelines for
immunocompromised patients. If no local country guidelines for immunocompromised patients
exist, US guidelines must be followed.
Ongoing Tuberculosis Evaluation
To aid in the early detection of TB infection or exposure during study participation, participants
must be evaluated for TB signs, symptoms, and close contacts at scheduled visits (refer to
Section 1.3). 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?”

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“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 for TB infection or the participant has had a close contact
exposure to TB, study intervention must be withheld and an immediate and thorough investigation
must be undertaken, including consultation with a physician specializing in TB to determine if
treatment is warranted.
Note: Investigators should be aware that TB reactivationin immunocompromised participants may
also present as extrapulmonary or disseminated disease.
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting
Timely, accurate, and complete reporting and analysis of safety information, including AEs,
serious AEs, and PQCs, from clinical studies are crucial for the protection of participants,
investigators, and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor
has established Standard Operating Procedures in conformity with regulatory requirements
worldwide to ensure appropriate reporting of safety information; all clinical studies conducted by
the sponsor or its affiliates will be conducted in accordance with those procedures.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate,
or the participant’s legally acceptable representative) for the duration of the study.
Further details on AEs, SAEs, and PQCs can be found in Appendix 4, Adverse Events, Serious
Adverse Events, Product Quality Complaints, and Other Safety Reporting: Definitions and
Procedures for Recording, Evaluating, Follow-up, and Reporting.
See Appendix 4, Adverse Events, Adverse Device Effects, Serious Adverse Events, Serious
Adverse Device Effects, Unanticipated Serious Adverse Device Effects, and Device Deficiencies:
Definition and Procedures for Recording, Evaluating, Follow-up, and Reporting in Medical Device
Studies, for details regarding AEs, product malfunctions, and deficiencies of a medical device
under evaluation in the study.
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.

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All AEs with an onset date after the signing of the ICF and up to 8 weeks after study treatment
discontinuation must be recorded on specific AE pages of the eCRF.
Serious Adverse Events
All SAEs occurring during the study must be reported to the appropriate sponsor contact person
by study site personnel immediately but no later than 24 hours of their knowledge of the event.
Serious adverse events, including those spontaneously reported to the investigator within 8 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.
All SAEs occurring after signature of the ICF up to 8 weeks after study treatment discontinuation
must be recorded on AE pages in the eCRF and on an SAE form, regardless of the investigator-
attributed causal relationship with study treatment or study mandated procedures.
A possible Hy’s law Case is defined by the occurrence of ALT/AST ≥3 x ULN, ALP <2 x ULN
together with Tbili ≥2 x ULN or INR >1.5 (if measured). Any possible Hy’s Law case is considered
an important medical event and must be reported to the sponsor in an expedited manner, even
before all other possible causes of liver injury have been excluded.
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event
Form and Safety Report Form of the CRF, which must be completed and reviewed by a
physician from the study site and transmitted to the sponsor immediately but no later than within
24 hours of their knowledge of the event. The initial and follow-up reports of an SAE should be
transmitted electronically or by facsimile (fax). Telephone reporting should be the exception and
the reporter should be asked to complete the appropriate form(s) first.
Selected events including potential MACE will undergo adjudication by an EAC. For such events
investigators will be asked to provide a specific package of information for evaluation. Further
details will be provided in a procedural manual. The EAC will assess such events according to the
committee’s charter and will independently classify the events while blinded to treatment
assignment.
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting adverse events or serious adverse events.
Open-ended and nonleading verbal questioning of the participant is the preferred method to inquire
about AE occurrence.
Solicited Adverse Events
Solicited AEs are predefined local and systemic events for which the participant is specifically
questioned and which are noted by participants in their diary (see Section 8, Study Assessments
and Procedures).

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Unsolicited Adverse Events
Unsolicited AEs are all AEs for which the participant is not specifically questioned in the
participant diary.
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events
The investigator is obligated to perform or arrange for the conduct of supplemental measurements
and evaluations as medically indicated to elucidate the nature and causality of the AE or SAE as
fully as possible. This may include additional laboratory tests or investigations, histopathological
examinations, or consultation with other health care professionals.
Adverse events and the special reporting situation of pregnancy will be followed by the
investigator as specified in 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 and
Anticipated Events
The sponsor assumes responsibility for appropriate reporting of safety information to Regulatory
Authorities/ IECs / IRBs in each respective country/territory, as applicable.
An anticipated event is an AE that commonly occurs in the study population independent of
exposure to the drug under investigation. For the purposes of this study the following SAE will be
considered anticipated events: worsening of RA.
These anticipated events will be periodically analyzed in aggregate by the sponsor during study
conduct. The sponsor will prepare a safety report in narrative format if the aggregate analysis
indicates that the anticipated event occurs more frequently in the treatment arm than in the control
arm and the sponsor concludes there is a reasonable possibility that the drug under investigation
caused the anticipated event.
The plan for monitoring and analyzing the anticipated events is specified in a separate Anticipated
Events Safety Monitoring Plan. The assessment of causality will be made by the sponsor’s
unblinded safety assessment committee.
The sponsor assumes responsibility for appropriate reporting of the listed anticipated events
according to the requirements of the countries/territories in which the studies are conducted.
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 the Serious Adverse Event form. Any participant
who becomes pregnant during the study must discontinue further study intervention.

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Follow-up information regarding the outcome of the pregnancy for female participants who
become pregnant, or where the pregnancy was the result of male participant and his partner, and
any postnatal sequelae in the infant will be required.
8.3.6. 
Adverse Events of Special Interest
Treatment-emergent AEs associated with the following situations are considered to be AESIs:
1. Infections that are severe or require IV anti-infective or operative/invasive intervention
2. Clinically significant opportunistic infection (eg, active TB, invasive fungal infections)
3. Hypoalbuminemia with albumin <20g/L (<2.0 g/dL)
4. Any newly identified malignancies
5. These AEs occurring after the first administration of study intervention in participants in
the clinical study must be reported by the investigator to the sponsor or designee within 24
hours after being made aware of the vent, according to the procedures in Appendix 4. These
events are to be considered serious only if they meet the definition of an SAE.
Observation Time After Each Infusion
Participants will be observed for safety 1-hour post infusion after the first 3 infusions; if no
clinically relevant AEs related to the infusion are observed in these first 3 infusions, participants
will be observed for 30 minutes after subsequent infusions.
8.4. 
Pharmacokinetics
Serum nipocalimab and certolizumab samples will be used to evaluate the PK of nipocalimab and
certolizumab, as well as the immunogenicity of nipocalimab (antibodies to nipocalimab). Serum
collected for PK and immunogenicity analyses may additionally be used to evaluate safety or
efficacy aspects that address concerns arising during or after the study period. Genetic analyses
will not be performed on these serum samples. Participant confidentiality will be maintained.
8.4.1. 
Evaluations
Venous blood samples will be collected at the time points shown in the SoA (Section 1.3) for
measurement of serum  concentrations ofnipocalimab and certolizumab and antibodies to
nipocalimab.
Serum samples will also be collected at the final visit from participants who terminate study
participation early.
At visits where PK and immunogenicity will be evaluated, 1 blood draw of sufficient volume can
be used. Each sample will be divided into 3 aliquots (1 aliquot for serum nipocalimab and
certolizumab concentration, antibodies to nipocalimab, and a backup).
Samples must be collected before study intervention administration at visits when a study
intervention administration is scheduled.

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For nipocalimab administrations, at Week 0, Week 2, Week 8 and Week 12, a blood sample before
study intervention and another blood sample 45 minutes (±15 minutes) after the end of infusion
will be collected. The sample should be drawn from the opposite arm than the IV line.
One random nipocalimab concentration sample will be collected from all participants any time
between days 3 to 7 after the Week 0 or Week 2 visit other than the scheduled samples.
One random certolizumab concentration sample will be collected from all participants any time
between Week 2 and Week 8 other than at the time of the Week 2, Week 4, Week 6 and Week 8
visits; this sample must be collected at least 24 hours prior to or after a study intervention
administration and must not be collected at a regularly scheduled visit.
The exact dates and times of blood sample collection must be recorded in the laboratory requisition
form.
Additional information about the collection, handling, and shipment of biological samples can be
found in the Laboratory Manual.
8.4.2. 
Analytical Procedures
Pharmacokinetics
Serum samples from participants who received at least one dose of certolizumab will be analyzed
to determine concentrations of certolizumab. Serum samples from participants who received at
least one dose of nipocalimab and certolizumab will be analyzed to determine concentration of
certolizumab and nipocalimab. Analysis will be performed using a validated, specific, and
sensitive Immunoassay method by or under the supervision of the sponsor. The sponsor or its
designee, under conditions in which the participants’ identity remains blinded, will assay these
samples.
8.4.3. 
Pharmacokinetic Parameters and Evaluations
Parameters
Based on the individual plasma concentration-time data, using the actual dose taken and the actual
sampling times, PK parameters and exposure information of nipocalimab and certolizumab will
be derived using population PK modeling. Baseline covariates (eg, body weight, age, sex, CrCL,
race) may be included in the model, if relevant.
8.5. 
Genetics and Pharmacogenomics
Pharmacogenomic blood samples may be collected from participants who consent separately to
this component of the study to allow for pharmacogenomic research, as necessary (where local
regulations permit). Participant participation in pharmacogenomic research is optional.
Genetic (DNA) variation may be an important contributory factor to interindividual variability in
drug response and associated clinical outcomes. Genetic and epigenetic factors may also serve as
markers for disease susceptibility and prognosis and may identify population subgroups that
respond differently to an intervention.

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Pharmacogenomic blood samples will be collected to allow for identification of genetic and
epigenetic factors that may be associated with  the disease or the response to treatments. This
research may consist of the analysis of one or more candidate genes, or the analysis of genetic and
epigenetic markers throughout the genome, or analysis of the entire genome (as appropriate) in
relation to the disease and the treatments. Whole blood samples of approximately 6 mL will be
collected for the genetic and pharmacogenomic analyses.
8.6. 
Biomarkers
Biomarker assessments will be made to examine the biologic response to treatment and to identify
biomarkers that are relevant to certolizumab or certolizumab/nipocalimab combination  therapy
and RA, where local regulations permit. Assessments (detailed below) will include the evaluation
of relevant biomarkers in serum, plasma, whole, and urine collected as specified in the SoA
(Section 1.3), where local regulations permit.
Data collected from these samples will be used for exploratory research that will include the
following objectives:
1. To 
understand 
the 
molecular 
effects 
of certolizumab 
monotherapy  and
nipocalimab/certolizumab combination therapy
2. To understand RA pathogenesis
3. To understand why individual participants may respond differently to certolizumab
monotherapy and nipocalimab/certolizumab combination therapy
4. To understand the impact of certolizumab monotherapy and nipocalimab/certolizumab
combination therapy on RA or systemic inflammation
5. To develop diagnostic tests to identify RA populations that may be responsive or
nonresponsive to treatment with certolizumab monotherapy and nipocalimab/certolizumab
combination therapy
Stopping Analysis
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and
clinical response rates. Biomarker analysis may be deferred or not performed, if during or at the
end of the study, it becomes clear that the analysis will not have sufficient scientific value for
biomarker evaluation, or if there are not enough samples or responders to allow for adequate
biomarker evaluation. In the event the study is terminated early or shows poor clinical efficacy,
completion of biomarker assessments is based on justification and intended utility of the data.
8.6.1. 
Pharmacodynamics
Venous blood samples will be collected at time points shown in the SoA.
Serum concentrations of total IgG, IgM, IgE, and IgA will be measured to assess the PD effect.
IgG subclasses (IgG1, IgG2, IgG3, IgG4), albumin, CICs, and inflammatory markers (eg, CRP)
may also be evaluated using separate assays to assess the PD effect of nipocalimab and
certolizumab. The relationship between PD effects and clinical responses may be assessed.

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8.6.2. 
Serum and Plasma Biomarkers
Blood samples for serum and plasma biomarker analyses will be collected from all participants,
where local regulations permit. Serum and plasma may  be analyzed for levels of circulating
proteins, autoantibodies (eg, ACPA, RF), other inflammation-related molecules, and disease-
associated serologies relevant to RA and treatment and response to nipocalimab and certolizumab.
8.6.3. 
Whole Blood Gene Expression Profile
Whole blood will be collected by venipuncture from participants for RNA expression analysis,
where local regulations permit. Total RNA will be isolated and used for differential gene
expression analyses to identify gene expression patterns that are relevant to nipocalimab and
certolizumab treatment or RA and to evaluate markers that can predict clinical response.
Transcriptomic studies may be conducted using microarray or alternative equivalent technologies,
which facilitate the simultaneous measurement of the relative abundance of multiple RNA species
for each blood sample. The samples may also be used for targeted assessment of genes relevant to
RA and nipocalimab/certolizumab treatment. These analyses may be used to evaluate the changes
in gene expression profiles that may correlate with biologic response relating to RA and the action
of nipocalimab and certolizumab and may be used to identify population subtypes that respond
differently to an intervention.
8.6.4. 
Peripheral Blood Mononuclear Cells
If operationally feasible, whole blood may also be collected and processed for PBMC isolation
and cryopreserved for later analysis. Analysis may include but is not limited to flow cytometric
assessment of cell populations, single cell transcriptomics, or functional assessment of cells. The
samples may also be used to evaluate cellular and molecular changes in response to nipocalimab/
certolizumab treatment or related to RA pathogenesis. These analyses may not be performed if
cryopreserved PBMC samples do not meet the quality or quantity standards.
8.7. 
Immunogenicity Assessments
Antibodies to nipocalimab 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.
Serum samples will be screened for antibodies binding to nipocalimab and the titer of confirmed
positive samples will be reported. Other analyses may be performed to verify the stability of
antibodies to nipocalimab and/or further characterize the immunogenicity of nipocalimab.
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 nipocalimab will be performed using a
validated assay method by or under the supervision of the sponsor. All samples collected for

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detection of antibodies to nipocalimab will also be evaluated for nipocalimab serum concentration
to enable interpretation of the antibody data. Antibodies may be further characterized and/or
evaluated for their ability to neutralize the activity of the study intervention(s).
8.8. 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are not
evaluated in this study.

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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.
9.1. 
Statistical Hypotheses
The primary hypothesis is that treatment with nipocalimab in combination with certolizumab is
superior to certolizumab monotherapy in participants with moderately to severely active RA
despite treatment with ≥1 advanced therapy (bDMARDs or tsDMARDs) as assessed by the mean
change from baseline in DAS28-CRP at Week 12.
9.2. 
Sample Size Determination
Approximately 85 participants are planned to be randomized in a 2:3 ratio to the control arm and
experimental arm into the study. The sample size selection was determined based on the primary
endpoint of the change from baseline in DAS28-CRP at Week 12. For this study, assuming a
difference of 0.67 in the change from baseline in DAS28-CRP and a pooled standard deviation of
1.2 between control arm and experimental arm, a sample size of
• 
control arm: 34 participants receivingmonotherapy certolizumab + placebo
• 
experimental arm: 51 participants receivingcombination therapy ofnipocalimab +
certolizumab
will provide a power of approximately 80% to detect a significant treatment difference at a 1-sided
significance level of α=0.05 using a T-test. The difference of 0.67 is a meaningful improvement
over an effective treatment in RA.
Table 5 below shows the power to detect difference in the change from baseline in DAS28-CRP
between the control arm and experimental arm.
Table 5: 
Statistical Power for Treatment Difference in Change from Baseline in DAS28-CRP at Week 12
Sample Size 
Delta 
SD 
Power (%)
34:51 
0.6 
1.1 
79
0.6 
1.2 
72
0.6 
1.3 
66
0.67 
1.1 
86
0.67 
1.2 
80
0.67 
1.3 
75
0.7 
1.1 
89
0.7 
1.2 
83
0.7 
1.3 
79
0.8 
1.1 
95

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0.8 
1.2 
91
0.8 
1.3 
87
9.3. 
Participant Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Analysis Sets 
Description
Enrolled 
All participants who sign the ICF.
Full Analysis Set (FAS) 
All participants who were randomized in the study and received at least one
(complete or partial) administration of study intervention.
Safety Analysis Set (SAS) 
All participants who were randomized in the study and received at least one
(complete or partial) administration of study intervention.
Immunogenicity Analysis 
Set 
The immunogenicity analysis set is defined as all participants who received at least
one (partial or complete) administration of nipocalimab and have appropriate serum
samples for ADA detection.
Pharmacokinetics (PK) 
Analysis Set 
The PK analysis set is defined as all participants who received at least one (partial
or complete) administration of nipocalimab or certolizumab and have at least one
valid post-dose blood sample collection.
Pharmacodynamic (PD) 
Analysis Set 
The PD analysis set is defined as participants who received at least 1 dose (partial
or complete) of study intervention and have at least 1 valid post-dose blood sample
drawn for PD analysis.
9.4. 
Statistical Analyses
A DBL for primary efficacy analysis is planned at Week 12, when 100% of participants complete
their Week 12 assessments or terminate study prior to Week 12 (Week 12 DBL). A final DBL is
planned at Week 30, when all participants complete the study or have terminated the study prior
to Week 30 (final DBL). The end of the study is defined as the last follow-up assessment (6 weeks
after the last visit) for the last participant.
The primary endpoint is change from baseline in DAS28-CRP at Week 12, primary analysis will
be performed at Week 12 DBL.
The statistical analysis plan will be finalized prior to the Week 12 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
In general, descriptive statistics (eg, mean, median, SD, interquartile range, minimum, and
maximum) will be used to summarize continuous variables. Counts and percentages will be used
to summarize categorical variables. Graphical data displays (eg, line plots) may also be used to
summarize data.
Analyses suitable for categorical data (eg, chi-square tests, CMH tests or logistic regression, as
appropriate) will be used to compare the proportions of participants achieving selected endpoints
(eg, ACR response). In cases of rare events, the Fisher’s exact test will be used for treatment
comparisons. Continuous response parameters will be compared using ANCOVA, a MMRM or a
cLDA, as appropriate.

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The comparison for the primary endpoint will be tested at a 1-sided α level of 0.05. Nominal p-
values (1-sided) will be displayed for all other endpoint comparisons. Full details of the analysis
of the primary, secondary, and exploratory endpoints will be included in SAP.
9.4.2. 
Primary Endpoint(s)
Unless otherwise specified, efficacy analyses will be based on the FAS, defined as all randomized
participants who had at least one study intervention administration. Participants will be analyzed
according to the study treatment arm to which they were randomized regardless of the study
intervention they received.
The primary endpoint is the mean change from baseline in DAS28-CRP at Week 12. Analysis will
be based on the primary estimand, ie, a precise definition of the primary targeted treatment effect,
is defined by 5 attributes (treatment, population, variable, ICE, and population-level summary) for
the primary endpoint as stated below.
9.4.2.1. 
Primary Estimand of Change from Baseline in DAS28-CRP at Week 12
The composite estimand is defined by the following 5 components:
Treatment by Week 12:
Control arm: Certolizumab 400 mg at Week 0, 2, 4; then 200mg Q2W; Placebo IV q2w
Experimental arm: Certolizumab 400 mg at Week 0, 2, 4; then 200 mg Q2W; Nipocalimab 30
mg/kg IV q2w
Population:Participants between the ages 18 and 75, inclusive, with moderately to severely active
RA despite ≥1 advanced therapy (bDMARD or tsDMARD).
Variable (Endpoint):Change from baseline in DAS28-CRP at Week 12. A participant who initiates
or adjusts medication or discontinues or experiences an ICE in categories 1, 2, 3, or 4 (categories
defined below) during treatment prior to the Week 12 visit will be considered a treatment failure and
will be assigned a zero change from baseline in the DAS28-CRP score, regardless of the observed
change. The observed change from baseline in the DAS28-CRP score will not be used and will be
assumed to follow a MAR assumption.
ICE and Corresponding Strategies:
Event 
category
Definition 
Analysis Strategy
1 
Initiated protocol prohibited medications/therapies for RA  
Composite Strategy:A
participant with any of these
intercurrent events is
considered as to have no
change from baseline after this
event; the occurrence of this
ICE has been captured in the
variable definition.
2 
Initiation or dose increase of csDMARDs (such as MTX, 
SSZ, HCQ, CQ, or leflunomide) or oral corticosteroid 
therapy above the baseline dose for RA  
3 
Discontinuation of study intervention due to lack of efficacy 
or an AE of RA worsening 
4 
Discontinuation of study intervention due to COVID-19 
infection or for reasons other than those in ICE 3 
Note: If a participant experiences more than one ICE in ICEs 1-4 then the overall strategy will be based on the first
ICE to occur in ICEs 1-4 categories
Population- level summary:Differences in the mean change in DAS28-CRP score at Week 12 as
defined in the Variable attribute above between the combination therapy (certolizumab +
nipocalimab) group and the monotherapy (certolizumab + placebo) group.

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9.4.2.2. 
Estimator for the Primary Endpoint
In the primary efficacy analysis, data from all participants in the FAS will be analyzed according
to randomized treatment group regardless of the treatment received.
Participants who have protocol prohibited medications changes, or changed their baseline
medication, or had an intercurrent events before Week 12 visit will be considered as to have no
change from baseline in DAS28-CRP at Week 12, regardless of the observed changes.
After intercurrent event rules are applied, any remaining missing data will be imputed by using MI
assuming MAR assumption. Full details of imputation models will be provided in the SAP.
The treatment effect of the combination therapy (certolizumab+ nipocalimab) versus monotherapy
(certolizumab + placebo) will be compared using an ANCOVA model, including treatment group,
baseline DAS28-CRP and randomization stratification factors:
csDMARDs usage at baseline (yes or no)
Screening ACPA level (high ≥400 U/mL; low <400 U/mL)
DAS-28-CRP at baseline
Study country
Territory/Investigator site
The least Square Mean difference and 90% CIs (equivalent to the 1-sided 0.05 level test) between
the combination therapy group and monotherapy group will be presented. In addition, 95%
confidence interval will be reported. The comparison for the primary endpoint will be tested at a
1-sided α level of 0.05.
To evaluate the robustness of the primary analysis results, additional supplemental analyses (eg,
alternative estimands) and a sensitivity analysis using re-randomization test to evaluate the impact
of the dynamic randomization will be performed, details will be described in the SAP.
9.4.2.3. 
Subgroup Analysis
To evaluate the consistency of the primary analysis results, subgroup analyses based on
demographic characteristics, baseline disease characteristics, and baseline medications will be
performed if sufficient participant data is available in the subgroup. Further details will be provided
in the SAP.
9.4.3. 
Secondary Endpoint(s)
Secondary efficacy endpoints are:
ACR20, ACR50, ACR70, and ACR90 at Week 12
DAS28-CRP remission at Week 12
DAS28-CRP LDA at Week 12
Change from baseline in HAQ-DI score at Week 12
Change from baseline in CDAI at Week 12

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Analyses will compare between combination therapy (certolizumab + nipocalimab) and
monotherapy (certolizumab+ placebo). The methods of analysis, as well as the data handling rules,
will be provided in the SAP.
9.4.4. 
Safety Analyses
The primary safety analysis will use the on-study Safety Analysis-Set, ie, participants who
received at least one dose (complete or partial) of any study intervention.
Adverse Events
The verbatim terms used in the CRF by investigators to identify AEs will be coded using the
MedDRA. Any AE occurring at or after the initial administration of study intervention through the
day of last dose plus 8 weeks is considered to be treatment-emergent. All reported treatment-
emergent AEs will be included in the analysis. For each AE, the percentage of participants who
experience at least 1 occurrence of the given event will be summarized by treatment arm.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those
participants who die, who discontinue intervention due to an AE, or who experience a severe or a
SAE.
Listings of all participants with MACE (nonfatal MI, nonfatal stroke, and cardiovascular death)
will be provided.
In addition, an exposure-adjusted supplementary on-treatment analysis for treatment emergent
AEs: infection, SAE, and AE leading to treatment discontinuation based on primary safety analysis
will be performed. An exposure adjusted on-study safety analysis based on primary safety analysis
will only be performed when the rate of dropout from study is high. Full details will be provided
in the SAP.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Descriptive statistics will be
calculated for all selected laboratory analyte at baseline and change over time.
Vital Signs
Vital signs including temperature, pulse/heart rate, and blood pressure (systolic and diastolic) will
be summarized over time, using descriptive statics and/or graphically. The percentage of
participants with values beyond clinically important limits will be summarized.
9.4.5. 
Tertiary or Exploratory Efficacy Endpoints
Exploratory endpoints are provided in Section 3. They will be descriptively summarized either at
a single time point or over time (through Week 24) by treatment groups. The methods of analysis
and the data handling rules will be provided in the SAP.

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9.4.6. 
Other Analyses
9.4.6.1. 
Pharmacokinetic Analyses
Serum nipocalimab concentrations over time will be summarized for each treatment group using
descriptive statistics. All concentrations below the lowest quantifiable sample concentration of the
assay or the missing data will be labeled as such in the concentration data listing or statistical
analysis dataset. The lowest quantifiable sample concentration of the assay will be treated as zero
in the summary statistics. Participants will be excluded from the PK analysis if their data do not
allow for accurate assessment of the PK (eg, incomplete administration of the study intervention,
missing information of dosing and sampling times).
If sufficient data are available, a population PK analysis using a nonlinear mixed-effects modeling
approach will be used to characterize the disposition characteristics of nipocalimab and/or
certolizumab. The apparent total systemic clearance and apparent volume of distribution values
will be estimated. The influence of important variables (eg, body weight, antibodies to
nipocalimab, and concomitant medications if relevant) on the population PK parameter estimates
may be evaluated. Details will be given in a population PK analysis plan and the results of the
population PK analysis will be presented in a separate technical report.
9.4.6.2. 
Biomarkers Analyses
The biomarker analyses will be used to understand RA, characterize the effects of nipocalimab
and certolizumab to identify PD markers and biomarkers relevant to treatment, and to determine
if these markers can predict response to nipocalimab and certolizumab. The biomarkers may
include but are not limited to serum immunoglobulins, autoantibodies, inflammatory markers,
whole blood RNA profile, and other categories of biomarkers potentially involved in the
development and the progression of RA.
Changes in biomarkers over time will be summarized by treatment arm. Associations between
baseline levels and changes from baseline in select markers and clinical response maybe explored.
Results ofbiomarker analyses may be summarized in a separate technical report.
Planned biomarker analyses may be deferred if emerging study data show no likelihood of
providing useful scientific information or if an insufficient number of samples are available for
analysis. Any biomarker samples received by the contract vendor or sponsor after the cutoff date
will not be analyzed, and therefore, excluded from the biomarker analysis.
9.4.6.3. 
Pharmacokinetic/Pharmacodynamic Analyses
If data permit, the relationship between serum concentrations of nipocalimab  and certolizumab
and the efficacy measures and relevant PD biomarkers may be explored when appropriate. If any
visual pattern is observed, additional analysis may be conducted. Results of analyses will be
summarized in a separate technical report.
9.4.6.4. 
Pharmacogenomic Analyses
Genetic (DNA) analyses may be conducted only in participants who sign the consent form to
participate in the pharmacogenomic sampling. These analyses are considered exploratory.

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DNA samples will be used for research related to nipocalimab and certolizumab or RA. They may
also be used to develop tests/assays related to nipocalimab certolizumab and RA.
Pharmacogenomic research may consist of the analysis of one or more candidate genes or of the
analysis of genetic and epigenetic markers throughout the genome or analysis of the entire genome
(as appropriate) in relation to the disease and treatments.
Results of analyses may be presented in a separate technical report.
9.4.6.5. 
Immunogenicity Analysis
The incidence and titers of antibodies to nipocalimab will be summarized for all exposed
participants who received at least 1 administration of nipocalimab and have appropriate samples
for detection of antibodies to nipocalimab (ie, participants with at least 1 sample obtained after
their first dose of nipocalimab). The incidence of NAbs to nipocalimab will be summarized for
participants who are positive for antibodies to nipocalimab and have samples evaluable for NAbs.
A listing of participants who are positive for antibodies to nipocalimab will be provided. The
maximum titers of antibodies to nipocalimab will be summarized for participants who are positive
for antibodies to nipocalimab.
Other immunogenicity analyses may be performed to further characterize the generated immune
response.
9.5. 
DMC
An external independent DMC will be established and will meet periodically to review interim
unblinded safety data to ensure the continuing safety of the participants enrolled in the study. The
DMC will consist of 2 physicians and a statistician. The DMC responsibilities, authorities, and
procedures will be documented in a separate DMC Charter and DMC SAP.
The DMC’s initial responsibility will be careful review of the safety data from the first 15
participants randomized to any treatment arm and treated. Similar to conduct of a Phase 1 study,
the safety of these first 15 participants will be monitored weekly for any potential safety concerns.
Detailed guidance for the DMC regarding these reviews will be provided in the DMC charter.
Once the 15th participant is randomized, the DMC will perform a review of unblinded safety tables.
If no new safety concerns are identified during this initial review period, then the subsequent DMC
reviews will include monthly reports of all SAEs in enrolled participants as well as review of
unblinded safety tables at least every 3 months. After each safety review, the DMC will make
recommendations regarding the continuation of the study.
Details of the Committees Structure can be found in Appendix 3, Regulatory, Ethical, and Study
Oversight Considerations.

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Abbreviations and Definitions
ACPA  
Anti-citrullinated protein/peptide antibody
ACR  
American College of Rheumatology
ADA  
anti-drug antibody
AE 
adverse event
AESI 
adverse event of special interest
ALP  
alkaline phosphatase
ALT  
alanine aminotransferase
ANCOVA  
analysis of covariance
AST 
aspartate aminotransferase
AUC  
area under the curve
AxMP  
Auxiliary Medicinal Product (also known as NIMP)
BCG  
Bacilli Calmette Guerin
β-hCG  
β-human chorionic gonadotropin
BP 
blood pressure
CDAI 
Clinical Disease Activity Index
CHF  
Congestive heart failure
cLDA  
constrained longitudinal data analysis
CIC  
circulating immune complex
ClinRO  
clinician-reported outcome
CMH  
Cochran-Mantel-Haenszel
COVID-19 
Coronavirus disease of 2019
CrCL 
creatine clearance
CRO  
Contract research organization
CTM  
clinical trial manager
CPK  
Creatine phosphokinase
CQ  
chloroquine
CRP  
C-reactive protein
CRF  
case report form(s) (paper or electronic as appropriate for this study)
csDMARD  
conventional synthetic disease modifying antirheumatic drug
CSR  
clinical study report
DAS28-CRP  
Disease Activity Index Score 28 using C-reactive protein
DAS28-ESR  
Disease Activity Index Score 28 using erythrocyte sedimentation rate
DBL 
database lock
DDI 
drug-drug interaction
DILI 
drug induced liver injury
DMARD  
disease modifying antirheumatic drug
DMC  
Data Monitoring Committee
DNA  
desoxyribonucleic acid
EAC  
Event adjudication committee
ECG  
electrocardiogram
eCRF  
electronic case report form
eDC  
electronic data capture
EOS-HDFN  
early onset severe hemolytic disease of the fetus and newborn
ESR  
erythrocyte sedimentation rate
EULAR  
European League Against Rheumatism
FAS  
Full Analysis Set
FcRn  
neonatal Fc receptor
FIH  
first-in-human
FOIA  
Freedom of Information Act
FSH  
follicle stimulating hormone
GCP  
Good Clinical Practice
gMG  
generalized myasthenia gravis
HAQ-DI 
Health Assessment Questionnaire –Disability Index
HBsAg 
hepatitis B surface antigen

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HBV  
hepatitis B virus
HCQ  
hydroxychloroquine
HCV  
hepatitis C virus
HDL 
high-density lipoprotein
HIV  
human immunodeficiency virus
HRQOL 
Health-Related Quality of life
HRT  
Hormone replacement therapy
IB  
Investigator's Brochure
IC  
immune complex
ICE 
intercurrent event
ICF  
informed consent form
ICH  
International Council on Harmonisation
ICMJE 
International Committee of Medical Journal Editors
IEC  
Independent Ethics Committee
Ig 
immunoglobulin
IGRA  
Interferon-gamma release assay
IL 
interleukin
IM  
intramuscular
IMP  
Investigational Medicinal Product
IND  
Investigational New Drug
INR  
International Normalized Ratio
IPPI 
Investigational Product Preparation and Administration Instructions
IR  
inadequate response
IRB  
Institutional Review Board
IUGR  
Intra-uterine growth restriction
IV  
intravenous(ly)
IWRS  
interactive web response system
JAKi 
janus kinase inhibitors
LA  
Lupus anticoagulant
LDA  
low disease activity
LDH  
lactase dehydrogenase
LDL 
low-density lipoprotein
LEF  
leflunomide
LLOQ  
lower limit of quantification
LTM  
local trial manager
mAb 
monoclonal antibody
MACE  
major adverse cardiovascular event
MAD  
multiple ascending dose(s)
MAR  
Missing-at-Random
MCP  
metacarpophalangeal
MCS  
mental component score
MG-ADL 
Myasthenia Gravis –Activities of Daily Living
MI 
myocardial infarction
MMRM  
Mixed-Effect Model Repeated Measure
MoA  
mode-of-action
MTX  
methotrexate
NAb 
neutralizing antibody
NCI-CTCAE 
National Cancer Institute –Common Terminology Criteria for Adverse Events
NIMP  
Non-Investigational Medicinal Product
NRS  
Numeric Rating Scale
nr-axSpA  
Non-radiographic axial spondyloarthritis
NSAID  
nonsteroidal anti-inflammatory drug
PBMC  
peripheral blood mononuclear cell
PBO 
placebo
PCC  
protocol clarification communication
PCS  
physical component score
PD 
pharmacodynamic(s)
PEF  
peak expiratory flow

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PEG  
polyethylene glycol
PGA  
Physician’s Global Assessment (of Disease Activity)
PIP  
proximal interphalangeal
PK 
pharmacokinetic(s)
PO 
oral (by mouth)
PoC 
proof-of-concept
PQC  
Product Quality Complaint
PRO  
patient-reported outcome
PsO  
psoriasis
PT  
prothrombin time
PtGA  
Patient’s Global Assessment (of Disease Activity)
q2w  
every 2 weeks
q4w  
every 4 weeks
RA  
rheumatoid arthritis
RBC  
red blood cell
RF  
rheumatoid factor
RNA  
ribonucleic acid
RO  
receptor occupancy
SAD  
single ascending dose
SAE 
serious adverse event
SAP  
Statistical Analysis Plan
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2
SC 
subcutaneous
SDAI 
Simple Disease Activity Index (for Rheumatoid Arthritis)
SF-36 
36-item Short Form Health Survey
SI 
International System of Units
SIPPM  
Site Investigational Product Procedures Manual
SoA  
Schedule of Activities
SOC  
standard ofcare
SSG  
Statistical support group
SSZ 
sulfasalazine
SUSAR  
suspected unexpected serious adverse reaction
TB  
tuberculosis
TEAE 
treatment-emergent adverse event
TMDD  
Target-mediated drug disposition
TNF  
tumor necrosis factor
TT  
thrombin time
UC  
ulcerative colitis
ULN  
upper limit of normal
USPI 
United States prescribing information
VAS  
visual analog scale
wAIHA  
warm autoimmune hemolytic anemia
WBC  
white blood cell

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If dipstick result is abnormal, flow cytometry or microscopy will be used to measure
sediment. In case of discordance between the dipstick results and the flow cytometric
results, the sediment will be examined microscopically.
In the microscopic examination, observations other than the presence of WBC, RBC and
casts may also be reported by the laboratory.
Dipstick and flow cytometric analysis of the urine samples will be performed in parallel,
ie, in the same sample at the same time.
Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, and urobilinogen will be
determined using a dipstick. Red blood cells, WBCs, epithelial cells, crystals, casts, and
bacteria will be measured using flow cytometry or microscopy. If there is discordance
between the dipstick results and the flow cytometric results, the sediment will be
examined microscopically.
Dipstick and flow cytometric analysis of the urine samples will be performed in parallel,
in the same sample at the same time. Specific gravity, pH, glucose, protein, blood,
ketones, bilirubin, urobilinogen, nitrite, and leukocyte esterase will be determined using
dipstick. Red blood cells, WBCs, and epithelial cells will be measured using flow
cytometry.
In case of discordance between the dipstick results and the flow cytometric results, the
sediment will be examined microscopically. Crystals, casts, and bacteria will only be
reported if they are present.
Other
Screening
Tests
Urine Pregnancy Testing (highly sensitive) for female participants of childbearing
potential only (Participants of childbearing potential will be given urine pregnancy
tests to be self-administered at home until 5 months after their last dose of the
study intervention. The site is responsible for contacting these participants on a
monthly basis to confirm that the pregnancy test has been performed. If a
participant tests positive for pregnancy, the site is required to report this to the
sponsor within 24 hours of becoming aware of the event).
Serology (HIV antibody; hepatitis B surface antigen [HBsAg] and Hepatitis B
surface antibody [anti-HBs], Hepatitis B core antibody [anti-HBc] HBV DNA [if
applicable]; hepatitis C virus antibody, and HCV RNA [if applicable])
Coagulation (prothrombin time, activated partial thromboplastin time, INR)
CRP
ACPA
RF
CIC
Immunoglobulin isotype profile (total IgG, IgG1, IgG2, IgG3, IgG4, IgA, IgM,
and IgE)
Antibodies to nipocalimab- done by sponsor laboratory

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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 ICH guidelines on GCP, and applicable regulatory and country-or territory-
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 Clarification Communications
If text within a final approved protocol requires clarification (eg, current wording is unclear or
ambiguous) that does not change any aspect of the current study conduct, a PCC may be prepared.
The PCC Document will be communicated to the Investigational Site, Site Monitors, LTMs, CTMs,
and/or CROs who will ensure that the PCC explanations are followed by the investigators.
The PCC Document may be shared by the sites with Independent IECs/IRBs per local regulations.
The PCC Documents must NOT be used in place of protocol amendments, but the content of the
PCC Document must be included in any future protocol amendments.
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) involves only logistic or administrative aspects of the study, the IEC/IRB (where
required) only needs to be notified.
In situations where a departure from the protocol is unavoidable during the study, the investigator
or other physician in attendance will contact the appropriate sponsor representative listed in the
Contact Information page(s), which will be provided as a separate document. Except in emergency
situations, this contact must 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.

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Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities
in each respective country/territory, 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:
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
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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
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

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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
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).
Country/Territory Selection
This study will only be conducted in those countries/territories where the intent is to launch or
otherwise help ensure access to the developed product if the need for the product persists, unless
explicitly addressed as a specific ethical consideration in Section 4.2.1., Study-Specific Ethical
Design Considerations.
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 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 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
must be in accordance with principles that originated in the Declaration of Helsinki, current ICH
and GCP guidelines, applicable regulatory requirements, and sponsor policy.

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Before enrollment in the study, the investigator or an authorized member of the studysite 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 for the treatment of their disease. Participants will be
told that alternative treatments are available if they refuse to take part and that such refusal will
not prejudice future treatment. Finally, they will be told that the investigator will maintain a
participant identification register for the purposes of long-term follow-up if needed and that their
records may be accessed by health authorities and authorized sponsor personnel without violating
the confidentiality of the participant, to the extent permitted by the applicable law(s) or regulations.
By signing the ICF the participant is authorizing such access, which includes permission to obtain
information about their survival status. It also denotes that the participant agrees to allow his or
her study physician to recontact the participant for the purpose of obtaining consent for additional
safety evaluations, and subsequent disease-related treatments, if needed. The physician may also
recontact the participant for the purpose of obtaining consent to collect information about his or
her survival status.
The participant 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 must be appropriately recorded by
means of either 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 (where local
regulations permit). 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.
Where local regulations require, a separate ICF may be used for the required DNA component of
the study.
10.3.4. 
Recruitment Strategy
Each site will be asked to identify participants from their patient database and their community of
practice, the identified patient may be invited to participate in the study. Additionally, Janssen will
provide sites with participant thank you communication, a doctor-to-doctor communication, a
patient brochure, general study posters/flyer, a participant welcome message, a participant Study
Visit Guide Booklet, a participant inclusion/exclusion criteria booklet, participant appointment
card, and a branded study blanket. Sites are provided with reference materials to assist in study
conduct such as mini protocol, and study reference cards. Each country may also opt to use a
recruitment vendor, with sponsor approval.

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10.3.5. 
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 information about, and where
required per applicable regulations, 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.
The informed consent also provides information to address the lawful transfer of the data to other
entities and to other countries/territories.
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, or make requests
concerning his or her personal data in accordance with applicable data protection law. 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.
In the event of a data security breach, the sponsor will apply measures to adequately manage and
mitigate possible adverse effects taking into consideration the nature of the data security breach as
necessary to address other obligations such as notifying appropriate authorities in accordance with
applicable data protection law.
Exploratory biomarker 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.
10.3.6. 
Long-term Retention of Samples for Additional Future Research
No additional research on study participants, study samples, or data derived from the study will be
conducted by the institution(s) or by a third party, without the prior written consent of the Sponsor.
Samples collected in this study may be stored for up to 15 years (or according to local regulations)
for additional research. Samples will only be used to understand nipocalimab and certolizumab, to
understand RA, to understand differential intervention responders, and to develop tests/assays
related to nipocalimab and certolizumab and RA. The research may begin at any time during the
study or during the post study storage period.

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Stored samples will be coded throughout the sample storage and analysis process and will not be
labeled with personal identifiers. Participants may withdraw their consent for their samples to be
stored for research (refer to Section 7.2.1., Withdrawal from the Use of Research Samples in Future
Research).
10.3.7. 
Committees Structure
Data Monitoring Committee
A Data Monitoring Committee (DMC) will be established to monitor data on an ongoing basis to
ensure the continuing safety of the participants enrolled in this study. This committee will consist
of at least one medical expert in the relevant therapeutic area and at least one statistician;
committee membership responsibilities, authorities, and procedures will be documented in its
charter. The committee will meet periodically to review interim data. After the review, the DMC
will make recommendations regarding the continuation of the study.
10.3.8. 
Publication Policy/Dissemination of Clinical Study Data
All information, including but not limited to information regarding nipocalimab 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 exploratory 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 the
goals of 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 ofnipocalimab, 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 exploratory
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 the 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

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publish information from the study, a copy of the manuscript must be provided to the sponsor for
review at least 60 days before submission for publication or presentation. Expedited reviews will
be arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in
writing, the investigator will withhold such publication for up to an additional 60 days to allow for
filing of a patent application. In the event that issues arise regarding scientific integrity or
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will
not mandate modifications to scientific content and does not have the right to suppress information.
For multicenter study designs and 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 interim results of clinical studies as required by law. The
disclosure of the study results will be performed after the end of study in order to ensure the
statistical analyses are relevant. Study results will be uploaded to the CTIS database within one
year after end of trial in accordance with EU CTR Annex IV.
10.3.9. 
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, and 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 may review the 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.

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10.3.10. 
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 the CRF. All CRF entries, corrections,
and alterations must be made by the investigator or authorized study  site personnel. The
investigator must verify that all data entries in the 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 must be available for review at the next scheduled monitoring visit. All participative
measurements (eg, pain scale information or other questionnaires) will be completed by the same
individual who made the initial baseline determinations whenever possible.
If necessary, queries will be generated in the eDC tool. If corrections to 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.
10.3.11. 
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 must be identifiable. Given that patient-reported
outcomes (PROs) are reports of a patient’s health condition that come directly from the patient,
without interpretation by a clinician or anyone else, the responses to PRO measures entered by
study participants into source records cannot be overridden by site staff or investigators.
Specific details required as source data for the study and source data collection methods will be
reviewed with the investigator before the study and will be described in the monitoring guidelines
(or other equivalent document).
The following data will be recorded directly into the CRF and will be considered source data.
Race
History of smokingall nicotine use, eg, cigarettes (including e-cigarettes or the equivalent of
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Blood pressure and pulse/heart rate
Height and weight
Details of physical examination
Investigator-completed scales and assessments PRO Health Economics data
The minimum source documentation requirements for Section 5.1., Inclusion Criteria and
Section 5.2, Exclusion Criteria that specify a need for documented medical history are as follows:
Referral letter from treating physician
OR
Complete history of medical notes at the site
Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a
minimum by participant interview or other protocol required assessment (eg, physical examination,
laboratory assessment) and documented in the source documents.
An eSource system may be utilized, which contains data traditionally maintained in a hospital or
clinic record to document medical care (eg, electronic source documents) as well as the clinical
study-specific data fields as determined by the protocol. This data is electronically extracted for
use by the sponsor. If eSource is utilized, references made to the CRF in the protocol include the
eSource system, but information collected through eSource may not be limited to that found in the
CRF.
10.3.12. 
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 may  compare the data entered into the CRF with the source documents
(eg, hospital/clinic/physician’s office medical records). At these visits, the monitor will compare
data entered into the CRF with the source documents (eg, hospital/clinic/physician’s office medical
records); a sample may be reviewed. The nature and location of all source documents will be
identified to ensure that all sources of original data required to complete the 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

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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.
10.3.13. 
On-site Audits
Representatives of the sponsor’s clinical quality assurance department may visit the study site at
any time during or after completion of the study to conduct an audit of the study in compliance
with regulatory guidelines and company policy. These audits will require access to all study
records, including source documents, for inspection. Participant privacy must, however, be
respected. The investigator and studysite 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 must immediately notify the sponsor if he or she has been
contacted by a regulatory agency concerning an upcoming inspection.
10.3.14. 
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.

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10.3.15. 
Study and Site Start and Closure
First Act of Recruitment
The first subject screened is considered the first act of recruitment and it becomes the study start
date.
Study/Site Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been collected
and a study site closure visit has been performed.
The investigator may initiate study site closure at any time, provided there is reasonable cause and
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not
limited to:
Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or
local health authorities, the sponsor’s procedures, or GCP guidelines
Inadequate recruitment of participants by the investigator
Discontinuation of further study intervention development

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10.4. Appendix 4: Adverse Events, Serious Adverse Events, Product Quality
Complaints, and Other Safety Reporting: Definitions and Procedures for
Recording, Evaluating, Follow-up, and Reporting
Use International Organization for Standardization (ISO) definitions and procedures detailed in
Section 10.4.5: Adverse Events, Adverse Device Effects, Serious Adverse Events, Serious
Adverse Device Effects, Unanticipated Serious Adverse Device Effects, and Device Deficiencies:
Definition and Procedures for Recording, Evaluating, Follow-up, and Reporting in Medical Device
Studies
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 International Council on
Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the
baseline condition, or abnormal results of diagnostic procedures, including laboratory test
abnormalities.
Note: The sponsor collects AEs starting with the signing of the ICF (refer to All Adverse Events
under Section 8.3.1., Time Period and Frequency for Collecting Adverse Events and Serious
Adverse Events Information, for time of last AE recording).
For combination products with a device constituent, AEs include those resulting from insufficient
or inadequate instructions for use, deployment, implantation, installation, or operation, or any
malfunction of the device. It includes any AE resulting from use error or from intentional misuse
of the investigational device.
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

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Is a suspected transmission of any infectious agent via a medicinal product
Is Medically Important*
*Medical and scientific judgment must 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.
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).
For combination products with a device constituent, SAEs include adverse device effects that
resulted in any of the consequences characteristic of an SAE. An unanticipated serious adverse
device effect is a serious adverse device effect which by its nature, incidence, severity or outcome
has not been identified in the current version of the risk analysis report (see Section 2.3. Benefit-
Risk Assessment).
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 nipocalimab, the expectedness of an AE will be determined by
whether or not it is listed in the IB. For study drugs with a marketing authorization, the
expectedness of an AE will be determined by whether or not it is listed in the package insert.
10.4.2. 
Attribution Definitions
Assessment of Causality
The causal relationship to study intervention is assessed by the Investigator. The following
selection must 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.

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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 must 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 interventionin an interventional study that may require
expedited reporting or safety evaluation include, but are not limited to:
Overdose of a sponsor study intervention
Suspected abuse/misuse of a sponsor study intervention
Accidental or occupational exposure to 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
Reporting of participant pregnancy or participant partner(s) pregnancy
Participant-specific special reporting situations mustbe recorded in the CRF. Any special reporting
situation that meets the criteria of an SAE must 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)

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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
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 CRF).
Note: Hospitalizations that were planned before the signing of the ICF, and where the
underlying condition for which the hospitalization was planned has not worsened, will not be
considered SAEs. Any AE that results in a prolongation of the originally planned
hospitalization is to be reported as a new SAE
For convenience the investigator may choose to hospitalize the participant for the duration of
the intervention period
The cause of death of a participant in a study within 8 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 and
safety report form of the CRF, which must be completed and reviewed by a physician from the
study site, and transmitted in a secure manner to the sponsor immediately, but no later than within
24 hours of their knowledge of the event. The initial and follow-up reports of an SAE should be
transmitted in a secure manner electronically or by facsimile (fax). Telephone reporting should be
the exception and the reporter should be asked to complete the appropriate form(s) first.

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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.
All complaints related to ANY part of the Combination Product must be reported within 1 business
day. In the event of public holiday, measures must be taken to ensure reporting no later than
calendar day 3.
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 must be contacted
regarding safetyissues, PQC, or questions regarding the studyare listed in the Contact Information
page(s), 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
Female Participants of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal unless
permanently sterile (see below).
Female Participants 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 FSH level (>40 IU/L or mIU/mL) in the postmenopausal range may be used to
confirm a postmenopausal state in female participants 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 female participants on HRT, the female
participant will be required to use one of the non-estrogen-containing hormonal highly
effective contraceptive methods if they wish to continue HRT during the study
permanently sterile (for the purpose of this study)
Permanent sterilization methods include hysterectomy, or bilateral salpingectomy, or
bilateral oophorectomy.
Has congenital abnormalities resulting in sterility.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal female
participant experiences menarche) or the risk of pregnancy changes (eg, a female participant who
is not heterosexually active becomes active), a female participant must begin a highly effective
method of contraception, as described throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
Contraceptive (birth control) use by male participants or female participants must 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. Use must be
consistent with local regulations regarding the use of contraceptive methods for participants in
clinical studies.

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Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED FOR FEMALE PARTICIPANTS
DURING THE STUDY INCLUDE:
USER INDEPENDENT
Highly Effective Methods That Are User Independent Failure rate of <1% per year when used
consistently and correctly.
Implantable progestogen-only hormone contraception associated with inhibition of ovulation
Intrauterine device (IUD)
Intrauterine hormone-releasing system (IUS)
Tubal closure (eg, bilateral tubal occlusion, bilateral tubal ligation)
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 female participant ofchildbearing potential and the absence of sperm
has been confirmed. If not, additional highly effective method of contraception must 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 ovulation
oral
intravaginal
transdermal
injectable
Progestogen-only hormone contraception associated with inhibition of ovulation
oral
injectable
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 or female condom with or without spermicide
Cap, diaphragm, or sponge with spermicide
A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-
barrier methods)
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
Withdrawal (coitus-interruptus)
Spermicides alone
Lactational amenorrhea method (LAM)

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a) Typical use failure rates may differ from those when used consistently and correctly. Use must be
consistent with local regulations regarding the use of contraceptive methods for participants in
clinical studies.

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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments
10.6.1. 
Stopping Algorithm
10.6.2. 
Follow-up Assessments
10.6.2.1. 
Phase 2 Liver Chemistry Stopping Criteria and Follow-up
Assessments
Phase 2 liver chemistry stopping criteria are designed to assure participant safety and to evaluate
liver event etiology.
CCI

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Liver Chemistry Stopping Criteria
ALT /AST  
absolute
ALT or AST  5xULN
ALT /AST  
Increase 
If cannot monitor:
ALT or AST  3 x ULN and cannot be monitored weekly for 4 weeks
Or if able to monitor:
ALT or AST  3xULN persists for 4 weeks
Total 
bilirubin1, 2 
ALT or AST  3xULN and total bilirubin 2xULN (or at least a doubling
of direct bilirubin in known Gilbert’s syndrome)
INR2 
ALT or AST 3xULN and INR >1.5, if INR measured
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 stop study intervention  
Report the event to the sponsor within 
24 hours 
Complete the CRF according to CRF 
completion guidelines, and complete a SAE 
data collection tool 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 (see MONITORING)
MONITORING:
If ALP <2 x ULN,ALT or AST  3xULN AND
total bilirubin 2xULN (or at least a doubling
of direct bilirubin in known Gilbert’s
syndrome) or INR >1.5 (if measured): 
Repeat liver chemistry tests (include ALT,
aspartate transaminase [AST], alkaline
phosphatase, total and direct 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
Viral hepatitis serology4
Obtain INR and recheck with each
liver chemistry assessment until the
transaminases values show downward
trend
Obtain blood sample for PK analysis
45 minutes (±15 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
Obtain complete blood count with
differential to assess eosinophilia
Record the appearance or worsening
of clinical symptoms of liver injury,
or hypersensitivity, on the CRF as per
CRF completion guidelines
Record use of concomitant
medications (including
acetaminophen, herbal remedies,
recreational drugs and other over-the-
counter medications)

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A specialist or hepatology consultation is
recommended
If ALT or AST  3xULN AND total bilirubin
<2xULN and INR 1.5:
Repeat liver chemistry tests (include ALT,
AST, alkaline phosphatase, total and direct
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
RESTART/RECHALLENGE
If liver event causality is determined to be
“not related”, restart may be permitted
upon written approval of the sponsor. See
restart guidelines
Record alcohol use on the [CRF as per
CRF completion guidelines].
If ALT or AST  3xULN AND total
bilirubin 2xULN or INR >1.5 (if
measured) obtain the following in
addition to the assessments listed above:
Antinuclear 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) and/or liver biopsy to
evaluate liver disease; complete CRF
as per CRF completion guidelines
Liver biopsy may be considered and
discussed with local specialist if
available:
o In participants when serology
raises the possibility of
autoimmune hepatitis (AIH)
o In participants when suspected
DILI progresses or fails to resolve
on withdrawal of study
intervention
o In participants with acute or
chronic atypical presentation
If liver biopsy conducted complete
CRF as per CRF completion
guidelines
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin
fractionation is not immediately available, discontinue study intervention if ALT 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 ofALP <2 x ULN, ALT or AST  3 x ULN and total bilirubin 2xULN (or at least a
doubling of direct bilirubin in known Gilbert’s sydnrome) or ALP <2 x ULN, ALT or AST  3 x
ULN and INR >1.5 (if measured) 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 are met

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(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: hepatitis A immunoglobulin M (IgM) antibody; HBsAgG and HBcAB; hepatitis C RNA;
cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable,
heterophile antibody or monospot testing); and hepatitis E IgM antibody.
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 Study Reference Manual.

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10.7. Appendix 7: Study Conduct During a Pandemic
GUIDANCE ON STUDY CONDUCT DURING COVID-19 PANDEMIC
It is recognized that the COVID-19 pandemic may have an impact on the conduct of this clinical
study due to, for example, isolation or quarantine of participants and study site personnel; travel
restrictions/limited access to public places, including hospitals; study site personnel being
unavailable, isolated, or reassigned to critical tasks.
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 judgment of the investigator to protect the health and well-being of
participants and site staff. If, at any time, a participant’s travel to the study site is considered to be
dangerous, study participation may be interrupted, and study follow-up conducted. If it becomes
necessary to discontinue participation in the study, the procedures outlined in the protocol for
discontinuing study intervention will be followed.
If, as a result of the COVID-19 pandemic scheduled visits cannot be conducted in person at the
study site, they will be performed to the extent possible remotely/virtually or delayed until such
time that on-site visits can be resumed. At each contact, participants will be interviewed to collect
safety data. Key efficacy endpoint assessments should be performed if required and as feasible.
Participants will also be questioned regarding general health status to fulfill any physical
examination requirement.
Every effort should be made to adhere to protocol-specified assessments for participants on study
intervention, including follow-up. Modifications to protocol required assessments may be
permitted after consultation 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 pandemic-related” in the CRF.
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.
Modifications made to the study conduct as a result of the COVID-19 pandemic should be
summarized in the clinical study report.
If the participant has tested positive for SARS-CoV-2, the investigator should contact the sponsor’s
responsible medical officer to discuss plans for administration of study intervention, performing
study assessments, 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.

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10.9. Appendix 9: Criteria for Assessing Potential Cases of Anaphylaxis
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled (Sampson 2006):
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal
tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING:
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak
expiratory flow [PEF], hypoxemia)
b. 
Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia
[collapse], syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that
participant (minutes to several hours):
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen
lips-tongue-uvula)
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF,
hypoxemia)
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence)
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3. Reduced BP after exposure to known allergen for that participant (minutes to several hours):
a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in
systolic BP*
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that
person's baseline
*Low systolic BP for children is defined as less than 70 mm Hg from 1 month to 1 year, less than (70 mm Hg +
[2 x age]) from 1 to 10 years, and less than 90 mm Hg from 11 to 17 years.

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10.10. Appendix 10: Definition of Inadequate Initial Response, and Loss of
Response to Advanced Therapies (bDMARD or tsDMARD) in RA
The criteria for (I) inadequate initial response, and (II) loss of response to Advanced Therapies
(bDMARD or tsDMARD) are described below.
I. Inadequate initial response (primary nonresponse) to prior therapy with Advanced
Therapies (bDMARD or tsDMARD).
Eligible participants must satisfy criteria A and B.
A. Have received adequate dosing (including induction doses) of Advanced Therapies
(bDMARD or tsDMARD) see protocol section 5.1 for required adequate dosing period.
AND
Did not improve with at least 50% reduction in disease activity to these doses within
3 months and/or did not achieve target (ie, remission or low disease activity) within
6 months as assessed by a treating physician.
B. Have documentation available to the investigator that meets the following 2 requirements:
1) Provide the dates and doses of the failed Advanced Therapies (bDMARD or
tsDMARD).
2) Documents that the participant had persistence of disease activity following
Advanced Therapies (bDMARD or tsDMARD).
Examples of acceptable documents include medical records, letter provided by a referring
physician, or other “reason for referral” documents (eg, insurance authorization form).
II. Initial response followed by loss of response (secondary nonresponse) to current or prior
Advanced Therapies (bDMARD or tsDMARD).
Eligible participants must satisfy criteria A, B, and C.
A. Have received adequate dosing (including induction doses). see protocol section 5.1 for
required adequate dosing period:
AND
Initially responded, that is improved with at least 50% reduction in disease activity within
3 months and achieved target (remission or low disease activity) within the first 6 months
to therapy (including induction therapy).
B. Have or had at least 1 of the following signs or symptoms related to recurrence of
rheumatoid arthritis, as assessed by a treating physician:
3) Worsening in tender joint count
4) Worsening in swollen joint count
5) Worsening in physical function
6) Worsening in disease activity

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These signs and symptoms of rheumatoid arthritis offered only as a benchmark of the
minimally acceptable criteria required to designate a participant as having a loss of
response to Advanced Therapies (bDMARD or tsDMARD). It is acknowledged that
previous treatment decisions could have been made based on evaluation of other measures
that may be indicative of worsening disease (eg, elevations of inflammatory markers
including but not limited to CRP and/or evidence of disease flare based on clinical imaging
modalities including but not limited to CT and MRI). Under these circumstances,
documentation of these specified measures of worsening disease activity can be accepted
as evidence of IR to prior Advanced Therapies (bDMARD or tsDMARD). However,
investigators should note that participants must meet protocol-specified criteria for active
disease during the current screening period as described in Section 5.1 to be eligible for
enrollment.
C. Have documentation available to the investigator that meets the following 2 requirements:
7) Provide the dates and doses of the failed Advanced Therapies (bDMARD or
tsDMARD).
8) Documents that the participant had recurrence of disease activity despite Advanced
Therapies (bDMARD or tsDMARD). Examples of acceptable documents include
medical records, letter provided by a referring physician, or other “reason for
referral” documents (eg, insurance authorization form).

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10.11. Appendix 11: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents (TOC).
DOCUMENT HISTORY
Document 
Country/Territory Affected  
Date
Amendment 3 
All 
xx October 2023
Amendment 2 
All 
27 September 2023
Amendment 1 
All 
7 September 2023
Original Protocol 
All 
28 March 2023
Amendment 2 (27 September 2023)
Overall Rationale for the Amendment:  To address comments from EU CTR review.
The changes made to the clinical protocol 80202135ARA2002 as part of Protocol Amendment 2 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
1.3. SoA; 8.2.5
Pregnancy Testing;
Appendix 2:
Clinical Laboratory
Tests
Added the fact that pregnancy tests will be highly
sensitive.
To address the comments from
EU-CTR RFI.
5.1. Inclusion
Criteria;
Appendix 2:
Clinical Laboratory
Tests
Appendix 2, IC#17, IC#18, and IC#19 have been
modified to increase the time of using a
contraceptive (5 months instead of 70 days) after
the end of treatment.
To address the comments from
EU-CTR RFI.
5.2. Exclusion
Criteria
EC#24 has been modified to update the exclusion
criteria of participants with latent TB.
To address the comments from
EU-CTR RFI.
Amendment 1 (7 September 2023)
Overall Rationale for the Amendment:  To address comments from EU CTR review.
The changes made to the clinical protocol 80202135ARA2002 as part of Protocol Amendment 1 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
1.3. SoA  
A note was added to the SoA specifying that the
chest X-ray is only needed if no chest radiograph
done within the last 90 days before first
administration of study intervention, and required
for tuberculosis screening as per local standard
procedures.
Further clarification in the SoA
2.1 Study Rationale 
Updated a sentence describing the mechanism of
action of anti-TNFα agents.
To correct an inadvertently
incorrect description of the
mechanism of action of anti-TNFα
agents
1.1 Synopsis;
3. Objectives and
Added/updated tertiary or exploratory endpoints
through Week 24.
To clarify the tertiary or
exploratory endpoints.

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Section Number 
and Name
Description of Change 
Brief Rationale
Endpoints;
9.4.5.Tertiary or
Exploratory
Endpoints
1.1 Synopsis; 4.1 
Overall Design;  
6.3 Measures to
Minimize Bias:
Randomization and
Blinding; 9.5
Interim Analysis;
10.3.7 Committee
Structure
Updated text to remove the optional interim 
analysis. 
To remove the optional interim
analysis.
4.3 Justification for 
Dose 
Added further information from the completed 
Phase 2 RA study to support the proposed 
nipocalimab dosing.
To further clarify the selection of
the dose.
5.1 Inclusion 
Criteria 
Added a clarification that male participants should 
use an acceptable methods of contraception per 
local regulations during this study and for 90 days
after the last dose of study intervention.
To clarify the contraceptive
requirements.
5.1 Inclusion 
Criteria; 10.3.3. 
Informed Consent
Process
Removed the option for a legally acceptable 
representative to sign the ICF. 
To clarify the informed consent
process.
5.1 Inclusion 
Criteria; 
Added a requirement for male participants to use 
contraception during the study and for a period of 
90 days after the last administration of study 
intervention.
To clarify the duration of time that
male participants must use
contraception.
5.2 Exclusion 
Criteria 
Exclusion criteria 14 and 24 concerning 
malignancy and TB were updated. 
To minimize the risks of
immunosuppression with
combination therapy.
7.1 Discontinuation 
off Study 
Intervention
Removed the exception for basal cell carcinoma 
To further clarify the
discontinuation criteria.
8.3.4. Regulatory 
Reporting 
Requirements for
Serious Adverse
Events and
Anticipated Events
Added information on the appropriate reporting of 
safety information. 
To clarify the sponsor
responsibilities for safety reporting.
Appendix 2 
Added text explaining that urine pregnancy kits 
will be provided for female participants to allow 
for monthly home testing after Week 24 until
70 days after the last dose of study intervention.
To allow for pregnancy testing after
the last study visit.
Appendix 3 
Added Section 10.3.4 
To add a description of the
recruitment process.
Appendix 3 
Added a sentence to Section 10.3.8 to describe 
registration and disclosure of study results in 
accordance with EU CTR Annex IV. 
To update the protocol with the
publication policy of the trial data
being uploaded to the
CTIS database.
Appendix 5 
Removed footnote (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 
This footnote was removed as the
potential of DDI between
nipocalimab or certolizumab and
contraceptives is low.

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Section Number 
and Name
Description of Change 
Brief Rationale
hormonal contraception may interact with the
study intervention.
Appendix 10 
Appendix 10 was added. 
To define of inadequate response to
previous DMARDs.

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11. 
REFERENCES
Aletaha D, Smolen JS. The definition and measurement ofdisease modification in inflammatory rheumatic diseases.
Rheum Dis Clin North Am. 2006;32(1):9-44, vii.
Anderson JK, Zimmerman L, Caplan L, Michaud K. Measures of rheumatoid arthritis disease activity: Patient
(PtGA) and Provider (PrGA) Global Assessment of Disease Activity, Disease Activity Score (DAS) and Disease
Activity Score With 28-Joint Counts (DAS28), Simplified Disease Activity Index (SDAI), Cl. Arthritis Care Res.
2011;63(S11):S14–36.
Boleto G, Kanagaratnam L, Dramé M, Salmon JH. Safety of combination therapy with two bDMARDs in patients
with rheumatoid arthritis: A systematic review and meta-analysis. 2019; Seminars in arthritis and rheumatism;49(1),
35–42.
Felson DT, Anderson JJ, Boers M, et al. The American College of Rheumatology preliminary core set of disease
activity measures for rheumatoid arthritis clinical trials. The Committee on Outcome Measures in Rheumatoid
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JNJ-80202135 (nipocalimab)
Clinical Protocol 80202135ARA2002 Amendment-3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
127
Status: Approved, Date: 05 October 2023
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): 
 MD
Institution: 
Janssen Research & Development
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 study, written notification will be
provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD

Signature
User 
Date 
Reason
 
05-Oct-2023
20:31:06
(GMT)
Document Approval
PPD