A Multicenter, Randomized, Double-blind, Parallel-group, Placebo-controlled, Proof-of-concept Study Evaluating the Efficacy and Safety of Nipocalimab Administered Intravenously in Participants With Active Rheumatoid Arthritis Despite Standard Therapy
Phase: PHASE2
Conditions: Arthritis, Rheumatoid
Sponsor: Janssen Research & Development, LLC

CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved,  Date: 12 January 2022
Janssen Research & Development *
Clinical Protocol
Protocol Title
A Multicenter, Randomized, Double-blind, Parallel-group, Placebo-controlled,
Proof-of-concept Study Evaluating the Efficacy and Safety of Nipocalimab Administered
Intravenously in Participants with Active Rheumatoid Arthritis Despite Standard Therapy
Short Title
A Proof-of-concept Study of the Efficacy and Safety of Nipocalimab
in Participants with Active Rheumatoid Arthritis
Protocol 80202135ARA2001; Phase 2a
AMENDMENT 3
JNJ-80202135  nipocalimab
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen Biologics,
BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen Sciences Ireland
UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term “sponsor” is used
throughout the protocol to represent these various legal entities; the sponsor is identified on the Contact
Information page that accompanies the protocol.
United States (US)sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
Regulatory Agency Identifier Number(s):
IND: 154384
EudraCT Number: 2021-000510-42
Status: 
Approved
Date: 
12 January 2022
Prepared by: Janssen Research & Development, LLC
EDMS number:  EDMS-RIM-220499, 6.0
Global Amendment to EDMS-RIM-220499
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory
requirements.
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or
otherwise.
NCT04991753

JNJ-80202135 nipocalimab 
Clinical Protocol 80202135ARA2001 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status: Approved,  Date: 12 January 2022
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 3 
12 January 2022
Amendment 2 
30 June 2021
Amendment 1 
19 May 2021
Original Protocol 
07 April 2021
Amendment 3 (12 January 2022)
Overall Rationale for the Amendment:
Section Number
and Name
Description of Change 
Brief Rationale
NCT04991753
CCI
CCI

JNJ-80202135 nipocalimab 
Clinical Protocol 80202135ARA2001 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
3
Status: Approved,  Date: 12 January 2022
Section Number 
and Name
Description of Change 
Brief Rationale
NCT04991753
CCI

JNJ-80202135 nipocalimab 
Clinical Protocol 80202135ARA2001 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
4
Status: Approved,  Date: 12 January 2022
Section Number 
and Name
Description of Change 
Brief Rationale
NCT04991753
CCI

JNJ-80202135 nipocalimab 
Clinical Protocol 80202135ARA2001 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
5
Status: Approved,  Date: 12 January 2022
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 9
1. 
PROTOCOL SUMMARY................................................................................................................... 10
1.1. 
Synopsis......................................................................................................................................... 10
1.2. 
Schema.......................................................................................................................................... 17
1.3. 
Schedule of Activities (SoA)........................................................................................................... 18
2. 
INTRODUCTION................................................................................................................................ 22
2.1. 
Study Rationale.............................................................................................................................. 23
2.1.1. 
Unmet Need in Rheumatoid Arthritis.......................................................................................... 23
2.1.2. 
Rationale for Targeting FcRn in Rheumatoid Arthritis................................................................ 23
2.2. 
Background .................................................................................................................................... 24
2.3. 
Benefit-Risk Assessment............................................................................................................... 27
2.3.1. 
Risks for Study Participation....................................................................................................... 27
2.3.2. 
Benefits for Study Participation .................................................................................................. 30
2.3.3. 
Benefit-Risk Assessment for Study Participation ....................................................................... 31
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 31
4. 
STUDY DESIGN ................................................................................................................................ 33
4.1. 
Overall Design................................................................................................................................ 33
4.2. 
Scientific Rationale for Study Design............................................................................................. 35
4.2.1. 
Blinding, Control, Study Phase/Periods, Intervention Groups.................................................... 35
4.2.2. 
DNA and Biomarker Collection................................................................................................... 35
4.2.3. 
Actigraphy Measurements.......................................................................................................... 36
4.2.4. 
Participant Input into Design....................................................................................................... 36
4.2.5. 
Study-Specific Ethical Design Considerations ........................................................................... 36
4.3. 
Justification for Dose...................................................................................................................... 37
4.4. 
End of Study Definition................................................................................................................... 39
5. 
STUDY POPULATION ...................................................................................................................... 39
5.1. 
Inclusion Criteria............................................................................................................................ 39
5.2. 
Exclusion Criteria........................................................................................................................... 43
5.3. 
Lifestyle Considerations................................................................................................................. 48
5.4. 
Screen Failures.............................................................................................................................. 48
5.5. 
Criteria for Temporarily Delaying Administration of Study Intervention......................................... 49
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY............................................................ 49
6.1. 
Study Interventions Administered .................................................................................................. 49
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 50
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 51
6.4. 
Study Intervention Compliance...................................................................................................... 53
6.5. 
Dose Modification........................................................................................................................... 53
6.6. 
Continued Access to Study Intervention After the End of the Study ............................................. 53
6.7. 
Treatment of Overdose .................................................................................................................. 53
6.8. 
Concomitant Therapy..................................................................................................................... 53
6.8.1. 
Disease-Modifying Antirheumatic Drugs and Systemic Immunosuppressives .......................... 55
6.8.2. 
Corticosteroid Therapy ............................................................................................................... 55
6.8.3. 
Nonsteroidal Anti-inflammatory Drugs and Other Analgesics .................................................... 56
6.8.4. 
Vaccinations (Including COVID-19)............................................................................................ 56
6.8.5. 
Prohibited Therapies................................................................................................................... 56
NCT04991753

JNJ-80202135 nipocalimab 
Clinical Protocol 80202135ARA2001 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
6
Status: Approved,  Date: 12 January 2022
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 57
7.1. 
Discontinuation of Study Intervention ............................................................................................ 57
7.1.1. 
Liver Chemistry Stopping Criteria............................................................................................... 58
7.1.2. 
Study Stopping Rules ................................................................................................................. 58
7.2. 
Participant Discontinuation/Withdrawal From the Study................................................................ 58
7.2.1. 
Withdrawal from the Use of Research Samples......................................................................... 59
7.3. 
Lost to Follow-up............................................................................................................................ 60
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 61
8.1. 
Efficacy Assessments .................................................................................................................... 62
8.1.1. 
Evaluations ................................................................................................................................. 63
8.1.1.1. 
Patient’s and Physician’s Global Assessment of Disease Activity.......................................... 63
8.1.1.2. 
Pain Assessment..................................................................................................................... 63
8.1.1.3. 
Functional Assessment of Chronic Illness Therapy-Fatigue ................................................... 63
8.1.1.4. 
Joint Pain Severity NRS .......................................................................................................... 63
8.1.1.5. 
Health Assessment Questionnaire –Disability Index.............................................................. 63
8.1.1.6. 
36-item Short Form Health Survey (Standard)........................................................................ 64
8.1.1.7. 
Joint Assessments................................................................................................................... 64
8.1.1.8. 
Duration of Morning Stiffness .................................................................................................. 64
8.1.2. 
Definitions ................................................................................................................................... 65
8.1.2.1. 
Disease Activity Index Score 28.............................................................................................. 65
8.1.2.1.1. 
DAS28 Using C-reactive Protein.......................................................................................... 65
8.1.2.1.2. 
DAS28 Using Erythrocyte Sedimentation Rate.................................................................... 65
8.1.2.1.3. 
DAS28 Response................................................................................................................. 66
8.1.2.1.4. 
DAS28 Low Disease Activity................................................................................................ 66
8.1.2.1.5. 
DAS28 Remission................................................................................................................ 66
8.1.2.2. 
American College of Rheumatology Response....................................................................... 66
8.1.2.3. 
Clinical Disease Activity Index Score ...................................................................................... 66
8.1.2.4. 
Simplified Disease Activity Index Score .................................................................................. 67
8.1.2.5. 
ACR/EULAR Remission .......................................................................................................... 67
8.2. 
Safety Assessments....................................................................................................................... 68
8.2.1. 
Physical Examinations................................................................................................................ 68
8.2.2. 
Vital Signs................................................................................................................................... 69
8.2.3. 
Electrocardiograms..................................................................................................................... 69
8.2.4. 
Clinical Safety Laboratory Assessments .................................................................................... 69
8.2.5. 
Pregnancy Testing...................................................................................................................... 70
8.2.6. 
Concomitant Medication Review ................................................................................................ 70
8.2.7. 
Adverse Events Temporally Associated with Infusion................................................................ 70
8.2.8. 
Infusion Reactions ...................................................................................................................... 70
8.2.9. 
Hypersensitivity Reactions.......................................................................................................... 70
8.2.10. 
Infections .................................................................................................................................... 70
8.2.11. 
Increased Lipids.......................................................................................................................... 71
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting ....................................... 71
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information.................................................................................................................................. 71
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 72
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 72
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events and Anticipated
Events......................................................................................................................................... 72
8.3.5. 
Pregnancy................................................................................................................................... 73
8.3.6. 
Adverse Events of Special Interest............................................................................................. 73
8.4. 
Pharmacokinetics........................................................................................................................... 74
8.4.1. 
Evaluations ................................................................................................................................. 74
8.4.2. 
Analytical Procedures................................................................................................................. 74
8.4.3. 
Pharmacokinetic Parameters and Evaluations........................................................................... 75
8.5. 
Genetics and Pharmacogenomics................................................................................................. 75
8.6. 
Biomarkers..................................................................................................................................... 75
NCT04991753

JNJ-80202135 nipocalimab 
Clinical Protocol 80202135ARA2001 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
7
Status: Approved,  Date: 12 January 2022
8.6.1. 
Pharmacodynamics .................................................................................................................... 76
8.6.2. 
Serum and Plasma Biomarkers.................................................................................................. 76
8.6.3. 
Whole Blood Gene Expression Profile ....................................................................................... 76
8.6.4. 
Peripheral Blood Mononuclear Cells .......................................................................................... 76
8.6.5. 
Exploratory Biomarkers .............................................................................................................. 76
8.7. 
Immunogenicity Assessments ....................................................................................................... 77
8.8. 
Medical Resource Utilization and Health Economics .................................................................... 77
9. 
STATISTICAL CONSIDERATIONS.................................................................................................. 77
9.1. 
Statistical Hypotheses.................................................................................................................... 77
9.2. 
Sample Size Determination ........................................................................................................... 78
9.3. 
Populations for Analysis Sets ........................................................................................................ 78
9.4. 
Statistical Analyses ........................................................................................................................ 78
9.4.1. 
General Considerations.............................................................................................................. 79
9.4.2. 
Primary Endpoint ........................................................................................................................ 79
9.4.3. 
Secondary Endpoints.................................................................................................................. 80
9.4.4. 
Other Secondary Endpoints ....................................................................................................... 81
9.4.4.1. 
Pharmacokinetic Analyses ...................................................................................................... 81
9.4.4.2. 
Immunogenicity Analyses........................................................................................................ 81
9.4.5. 
Safety Analyses.......................................................................................................................... 81
9.4.6. 
Exploratory Endpoints................................................................................................................. 82
9.4.7. 
Other Analyses ........................................................................................................................... 82
9.5. 
Interim Analysis.............................................................................................................................. 83
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 84
10.1. 
Appendix 1: Abbreviations ............................................................................................................. 84
10.2. 
Appendix 2: Clinical Laboratory Tests ........................................................................................... 87
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations......................................... 89
10.3.1. 
Regulatory and Ethical Considerations ...................................................................................... 89
10.3.2. 
Financial Disclosure.................................................................................................................... 92
10.3.3. 
Informed Consent Process ......................................................................................................... 93
10.3.4. 
Data Protection........................................................................................................................... 94
10.3.5. 
Long-Term Retention of Samples for Additional Future Research ............................................ 94
10.3.6. 
Committees Structure................................................................................................................. 95
10.3.7. 
Publication Policy/Dissemination of Clinical Study Data............................................................ 95
10.3.8. 
Data Quality Assurance.............................................................................................................. 96
10.3.9. 
Case Report Form Completion................................................................................................... 97
10.3.10. Source Documents ..................................................................................................................... 97
10.3.11. Monitoring ................................................................................................................................... 98
10.3.12. On-Site Audits............................................................................................................................. 99
10.3.13. Record Retention........................................................................................................................ 99
10.3.14. Study and Site Start and Closure ............................................................................................. 100
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............................................................................................................................... 101
10.4.1. 
Adverse Event Definitions and Classifications ......................................................................... 101
10.4.2. 
Attribution Definitions................................................................................................................ 102
10.4.3. 
Severity Criteria........................................................................................................................ 102
10.4.4. 
Special Reporting Situations .................................................................................................... 102
10.4.5. 
Procedures ............................................................................................................................... 103
10.4.6. 
Product Quality Complaint Handling......................................................................................... 104
10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality........................................... 105
10.5. 
Appendix 5: Contraceptive and Barrier Guidance ....................................................................... 106
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments................................ 109
10.6.1. 
Stopping Algorithm ................................................................................................................... 109
10.6.2. 
Follow-up Assessments............................................................................................................ 110
10.6.2.1. 
Phase 2 Liver Chemistry Stopping Criteria and Follow-up Assessments............................. 110
NCT04991753

JNJ-80202135 nipocalimab 
Clinical Protocol 80202135ARA2001 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 12 January 2022
10.6.2.2. 
Phase 2 Liver Chemistry Increased Monitoring Criteria with Continued Study
Intervention............................................................................................................................ 112
10.7. 
Appendix 7: Hepatitis B Virus (HBV) Screening with HBV DNA Testing..................................... 113
10.8. 
Appendix 8: Guidance on Study Conduct During the COVID-19 Pandemic ............................... 114
10.9. 
Appendix 9: Criteria for Assessing Potential Cases of Anaphylaxis............................................ 116
10.10. Appendix 10: Protocol Amendment History................................................................................. 117
11. REFERENCES................................................................................................................................. 121
INVESTIGATOR AGREEMENT............................................................................................................... 123
NCT04991753

JNJ-80202135 nipocalimab 
Clinical Protocol 80202135ARA2001 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 12 January 2022
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Potential Risks of Nipocalimab for the Treatment of Rheumatoid Arthritis............................... 27
Table 2: 
Permitted Concomitant Medications for 80202135ARA2001, the Minimum
Stabilization Period before Randomization, and the Maximum Allowed Doses at Study
Randomization.......................................................................................................................... 55
Table 3: 
DAS28 Response Criteria......................................................................................................... 66
Table 4: 
Statistical Power for Treatment Difference in Change from Baseline in DAS28-CRP at
Week 12.................................................................................................................................... 78
FIGURES
Figure 1: Schematic Overview of 80202135ARA2001 ............................................................................ 17
NCT04991753

JNJ-80202135 nipocalimab 
Clinical Protocol 80202135ARA2001 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
11
Status: Approved,  Date: 12 January 2022
 Change from baseline in DAS28-CRP (or DAS28-ESR) over time
 Proportion of participants achieving DAS28-CRP (or
DAS28-ESR) LDA over time
 Proportion of participants achieving DAS28-CRP (or
DAS28-ESR) remission over time
 Change from baseline in CDAI over time
 Proportion of participants achieving CDAI LDA over time
 Proportion of participants achieving CDAI remission over time
 Change from baseline in SDAI over time
 Proportion of participants achieving SDAI LDA over time
 Proportion of participants achieving SDAI-based ACR/EULAR
remission over time
 Proportion of participants achieving Boolean-based ACR/EULAR
remission over time
 Change from baseline in the Tender/Painful and Swollen Joint
Counts over time
 Change from baseline in duration of morning stiffness over time
To evaluate the impact of nipocalimab vs 
placebo on PROs in participants with 
moderate to severe active RA
 Change from baseline in the PtGA of Disease Activity score over
time
 Change from baseline in the Pain VAS score over time
 Change from baseline in FACIT-Fatigue score over time
 Change from baseline in Joint Pain Severity score over time
 Change from baseline in HAQ-DI score over time
 The proportion of participants achieving a decrease of
≥0.22 points from baseline in HAQ-DI score over time
 Change from baseline in SF-36 PCS, MCS, and domain scores
over time
To evaluate the effect of nipocalimab vs 
placebo on PD and disease biomarkers in 
participants with moderate to severe
active RA
 Change from baseline in serum total immunoglobulin and albumin
levels over time by treatment group
 Change from baseline in disease biomarkers (eg, autoantibodies,
circulating immune complexes) over time in participants with
abnormal levels at baseline
 Reduction of IgG level-clinical response relationship analysis
To evaluate changes in serological 
profiles in response to nipocalimab vs 
placebo treatment in participants with 
moderate to severe active RA
 Change from screening visit in serum ACPA and RF levels over
time by treatment group, in participants seropositive at screening
visit for ACPA and RF, respectively
Abbreviations: ACPA=anti-citrullinated protein antibodies; ACR=American College of Rheumatology; ADA=anti-drug antibody; AE=adverse
event; AESI=adverse event of special interest; CDAI=Clinical Disease Activity Index; DAS28-CRP=Disease Activity Index Score 28 using
C-reactive protein; DAS28-ESR=Disease Activity Index Score 28 using erythrocyte sedimentation rate; EULAR=European League Against
Rheumatism; FACIT-Fatigue=Functional Assessment of Chronic Illness Therapy Fatigue Scale; HAQ-DI=Health Assessment Questionnaire 
Disability Index; IgG=immunoglobulin G; LDA=low disease activity; MCS=mental component score; NAb=neutralizing antibody; PCS=physical
NCT04991753
CCI

JNJ-80202135 nipocalimab 
Clinical Protocol 80202135ARA2001 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
12
Status: Approved,  Date: 12 January 2022
component score; PK=pharmacokinetic(s); PRO=patient-reported outcome; PtGA=Patient Global Assessment of Disease Activity; RA=rheumatoid
arthritis; RF=rheumatoid factor; SAE=serious adverse event; SDAI=Simple Disease Activity Index (for Rheumatoid Arthritis); SF-36=36-item
Short Form Health Survey; VAS=visual analog scale
Hypothesis
The primary hypothesis is that treatment with nipocalimab 15 mg/kg intravenously (IV) every 2 weeks
(q2w) is superior to placebo in participants with moderate to severe active rheumatoid arthritis (RA) as
assessed by the mean change from baseline in the Disease Activity Index Score 28 using C-reactive Protein
(DAS28-CRP) at Week 12.
OVERALL DESIGN
This is a randomized, double-blind, parallel-group, placebo-controlled, proof-of-concept, multicenter study
in participants between the ages of 18 and 75, inclusive, with moderate to severe active RA despite standard
therapy, including anti-tumor necrosis factor (anti-TNF) agents.
The total duration of the study is up to 24 weeks, consisting of 3 study periods: a ≤6-week screening period
(rescreening is permitted once per participant), a 12-week double-blind treatment period, and a 6-week
safety follow-up period (8 weeks after the last administration of study intervention).
Participants who have had an inadequate response (IR) or were intolerant to at least one anti-TNF therapy
will be enrolled. Depending upon the enrollment rate, the study population may be expanded to also include
participants who have had an IR or intolerance to a conventional synthetic disease-modifying
anti-rheumatic drugs (csDMARD).
Participants will be randomly assigned into 1 of 2 treatment groups. A placebo comparator (in addition to
standard-of-care background therapy) will be used to allow for blinded, placebo-controlled evaluation of
the efficacy and safety of nipocalimab in participants with RA.
Efficacy, safety, pharmacokinetics (PK), immunogenicity, and biomarkers will be assessed according to
the Schedule of Activities (SoA). Pharmacogenomic blood samples will be collected from participants who
consent to the collection of these samples (where local regulations permit).
The primary endpoint (the change from baseline in DAS28-CRP compared with placebo at Week 12) will
be evaluated after all participants have completed the Week 12 visit (or discontinued). An interim analysis
is planned when 60% (30 participants) of the planned number of participants complete the Week 12
assessment. This analysis is for future planning purposes and will not impact the conduct of the current
study.
Every reasonable effort should be made to keep concomitant medications stable as defined in the protocol.
Beginning at the screening visit, all concomitant therapies and all changes in concomitant therapies should
be recorded throughout the study.
Key safety assessments include adverse events (AEs), serious adverse events (SAEs), adverse events of
special interest (AESIs), laboratory parameters (hematology, chemistry, lipid panel), vital signs, and
physical examination.
Serum samples will be used to evaluate PK and antibodies to nipocalimab. Blood-based biomarkers will be
evaluated for inflammation-associated proteins and other analytes and will be used to better understand the
biology of RA, to provide a biological assessment of the response of participants to treatment with
nipocalimab, to analyze differences between responders and nonresponders, to assess loss of response, and
to determine if the markers can be used to classify participants as potential responders prior to treatment.
Actigraphy data will utilize accelerometry measurements to assess physical activity, mobility, and sleep
parameters. These measurements will be captured via wrist-worn actigraph devices, which have been
validated against polysomnography to assess sleep-related variables.
NCT04991753

JNJ-80202135 nipocalimab 
Clinical Protocol 80202135ARA2001 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
13
Status: Approved,  Date: 12 January 2022
Database locks are planned at Week 12 and at the end of the study. The end of the study is defined as the
last follow-up assessment (8 weeks after the last infusion of study intervention) for the last participant.
A Data Monitoring Committee will be commissioned for this study.
NUMBER OF PARTICIPANTS
A target of 50 participants will be enrolled in this study.
INTERVENTION GROUPS AND DURATION
Participants will be randomly assigned into 1 of 2 treatment groups using a 2:3 randomization ratio,
respectively:
 
Group 1: Placebo IV q2w: Participants will receive placebo IV q2w through Week 10.
 
Group 2: Nipocalimab 15 mg/kg IV q2w: Participants will receive nipocalimab 15 mg/kg IV q2w
through Week 10.
Participants will remain on their assigned treatment through Week 10.
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
 
Functional Assessment of Chronic Illness Therapy –Fatigue Scale
 
Joint Pain Severity Numeric Rating Scale
 
Health Assessment Questionnaire –Disability Index
 
36-item Short Form Health Survey (Standard)
 
Clinician-reported outcomes
 
joint assessment
 
duration of morning stiffness
 
Physician’s Global Assessment of Disease Activity
PHARMACOKINETIC EVALUATIONS
Serum samples will be used to evaluate the PK of nipocalimab.
IMMUNOGENICITY EVALUATIONS
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.
PHARMACODYNAMIC AND BIOMARKER EVALUATIONS
Samples for the analysis of pharmacodynamic (PD) biomarkers will be collected from all participants as
specified in the SoA, where local regulations permit. Serum or plasma concentrations of immunoglobulin,
NCT04991753

JNJ-80202135 nipocalimab 
Clinical Protocol 80202135ARA2001 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
14
Status: Approved,  Date: 12 January 2022
albumin, and disease biomarkers (eg, autoantibodies, circulating immune complexes) will be measured to
assess the PD effect of nipocalimab.
Blood samples for serum and plasma biomarker analyses will be collected from all participants. Serum and
plasma will be analyzed for levels of specific proteins, and other inflammation-related molecules and/or
disease-associated serologies relevant to RA and treatment and response to nipocalimab.
PHARMACOGENOMIC (DNA) EVALUATIONS
Participation in pharmacogenomic research is optional. A pharmacogenomic blood sample will be collected
from participants who consent separately to this component of the study to allow for pharmacogenomic
research, where local regulations permit.
SAFETY EVALUATIONS
Key safety assessments include AEs, SAEs, AESIs, clinical laboratory parameters (ie, hematology,
chemistry, lipid panel), vital signs, and physical examination.
STATISTICAL METHODS
Sample Size Determination
Approximately 50 participants are planned to be randomized in a 2:3 ratio to the placebo and nipocalimab
intervention groups, respectively, in the study. The sample size selection was determined based on the
primary endpoint of the change from baseline in DAS28-CRP compared with placebo at Week 12. For this
study, assuming a difference of 1 in the change from baseline in DAS28-CRP between a nipocalimab group
and placebo, a sample size of 20 and 30 participants in the placebo group and nipocalimab 15 mg/kg group,
respectively, will provide a power of approximately 80% to detect a significant treatment difference at a
2-sided significance level of α=0.05 using a T-test.
Statistical Analyses
General Considerations
In general, descriptive statistics, such as mean, standard deviation, median, interquartile range, minimum,
and maximum for continuous variables, and counts and percentages for discrete variables will be used to
summarize most data.
For binary response efficacy endpoints, treatment comparisons will generally be performed using a
Chi-square test or a Cochran-Mantel-Haenszel test. For continuous efficacy endpoints, treatment
comparisons will be performed using an analysis of covariance, a Mixed-Effect Model Repeated Measure
(MMRM) model, or a constrained longitudinal data analysis model.
In general, all statistical tests will be performed using a 2-sided test at a significance level of 5%.
No multiplicity adjustment will be made for secondary endpoints; nominal p-values will be reported.
Primary Endpoint
The primary endpoint is the meanchange from baseline in DAS28-CRP compared with placebo atWeek 12.
In the primary efficacy analysis, data from all participants who were randomized in the study and received
at least 1 administration of study intervention (ie, the Full Analysis Set [FAS]) will be analyzed according
to randomized treatment group regardless of the treatment received. Missing data will be assumed as
Missing-At-Random. A MMRM will be used to test the difference between the nipocalimab group and the
placebo group at Week 12. The explanatory variables of the MMRM model will include treatment group,
and interaction terms of visit with treatment group, baseline score and randomization stratification factors.
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An unstructured covariance matrix for repeated measure within a participant will be used. Other structured
covariances matrix will be defined in the Statistical Analysis Plan (SAP) in case of lack of convergence.
The Least Square Mean difference and 95% confidence intervals between each nipocalimab group versus
the placebo group will be provided.
The comparison between the nipocalimab and placebo group for the primary endpoint will be tested at a
2-sided α level of 0.05.
Further details about the analysis of the primary endpoint, including sensitivity and subgroup analyses will
be included in the SAP.
Secondary Endpoints
The secondary endpoints are listed above.
Data from all participants in the FAS will be analyzed according to randomized treatment group regardless
of the treatment received.
Details of the analysis of the secondary endpoints will be included in SAP.
Safety Analyses
The following analyses will also be used to assess the safety of participants in the study:
 
Proportion of participants with treatment-emergent AE
 
Proportion of participants with treatment-emergent SAEs
 
Proportion of participants with treatment-emergent AEs leading to discontinuation of study
intervention
 
Proportion of participants with treatment-emergent AESIs
 
Laboratory parameters and change from baseline in laboratory parameters over time
 
Vital sign parameters and change from baseline in vital sign parameters over time
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those
participants who die, who discontinue intervention due to an AE, or who experience a severe or an SAE.
Listings of all participants with major adverse cardiovascular events (MACE; nonfatal myocardial
infarction, stroke, and cardiovascular death) will be provided.
Clinical Laboratory Tests: Laboratory data will be summarized by type of laboratory test. Descriptive
statistics will be calculated for selected laboratory analytes at baseline and for changes over time.
Vital Signs: Vital signs including temperature, pulse/heart rate, respiratory rate, and blood pressure (systolic
and diastolic) will be summarized over time, using descriptive statistics. The percentage of participants
with values beyond clinically important limits will be summarized.
Other Analyses
 
Pharmacokinetic Analyses: Serum nipocalimab concentrations over time will be summarized for
each treatment group 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. 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.
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 
Immunogenicity Analyses: The incidence and titers of antibodies to nipocalimab will be summarized
for all 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 neutralizing antibodies (NAbs) to nipocalimab will be
summarized for participants who are positive for antibodies to nipocalimab and have samples
evaluable for NAbs.
 
Biomarkers Analyses: Change in biomarkers over time may be summarized by treatment group.
Associations between baseline levels and changes from baseline in select biomarkers and clinical
response may be explored. Results of biomarker analyses will be summarized in a separate technical
report.
 
Pharmacokinetic/Pharmacodynamic Analyses: If data permit, the relationship between serum
concentrations of nipocalimab and the efficacy measures and/or relevant PD biomarkers/endpoints
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 (deoxyribonucleic acid) analyses may be conducted only in
participants who sign the consent form to participate in the pharmacogenomic sampling. These
analyses are considered exploratory and results will be summarized in a separate technical report.
 
Actigraphy Analyses: Associations between actigraphy endpoints and primary and secondary
endpoints may be explored. All actigraphy-related analyses are considered exploratory and will be
summarized in a separate technical report.
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1.2. 
Schema
Figure 1: 
Schematic Overview of 80202135ARA2001
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b. 
Participants who discontinue study intervention administration but do not withdraw from study participation should be followed at all subsequent study visits
through Week 12. Week 12 may serve as the final safety follow-up visit if study intervention was stopped on or before Week 4, but a full physical examination
should be performed along with the other Week 12 assessments. Participants who discontinue study intervention administration and do not wish to continue in the
study should complete their Week 12 visit assessments at their next scheduled visit and should return 8 weeks after their last administration of study intervention
for the final safety visit.
c. 
Participants will be observed for safety 1 hour postinfusion 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.
d. 
(i.) 2X means 2 samples will be collected (1 sample will be collected prior to IV infusion and the other collected 45 minutes after the end of the infusion) for all
participants. The sample should be drawn from the opposite arm than the IV line. For all other visits, only a predose serum nipocalimab concentration sample will
be collected.
(ii.)For visits with study intervention administration, all blood samples for assessing predose nipocalimab concentration and antibodies to nipocalimab MUST be
collected BEFORE the administration of the study intervention.
(iv.)When samples for both PK (“nipocalimab concentration”) and ADA (“antibodies to nipocalimab”) are collected, 1 sample (instead of 2) will be collected for
both assays.
e. 
The sample should be collected at the specified time point, but it may be collected at a later time point without constituting a protocol deviation.
f. 
At screening at preselected sites, participants will be provided with an Actigraphy watch to be able to capture a baseline profile. Participants who will not prove
eligible will return their Actigraphy watch to the study site.
g. 
At the preselected sites where Actigraphy watches are distributed, participants will be asked to fill an exit survey when returning their Actigraphy watch to the
study site.
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2. 
INTRODUCTION
Nipocalimab (also referred to as JNJ-80202135 and M281) is a fully human aglycosylated
immunoglobulin (Ig)G1 monoclonal antibody (mAb) designed to selectively bind, saturate, and
block the IgG binding site on the endogenous neonatal Fc receptor (FcRn). The primary role of
FcRn in humans is to bind, salvage, and recycle IgG into circulation or transport IgG across the
placenta, following nonspecific pinocytosis into endothelial cells and cells of the
reticuloendothelial system. At homeostasis, FcRn recycles IgG to maintain serum IgG levels and
extend IgG half-life, and it also regulates immune cell inflammatory responses to IgG complexes.
By targeting the IgG binding site on FcRn, nipocalimab is expected to block the binding and,
hence, recycling of pathogenic IgG, resulting in a decrease in circulating IgG antibody levels,
including pathogenic IgG autoantibodies and alloantibodies, and potentially IgG immune
complexes (ICs). FcRn has also been shown to contribute to the protection of circulating immune
complexes (CICs) and the inhibition of FcRn results in  more rapid elimination of CICs
(Blumberg 2019). Clinical studies with other anti-FcRn mAbs or Fc fragments confirm that
blockade of IgG binding to FcRn rapidly decreases IgG to low but predictable steady-state levels
while also effectively decreasing circulating levels of pathogenic autoantibodies by increasing IgG
catabolism (Peter 2020). In addition, it has been shown that induction of inflammatory pathways
is dependent on FcRn and can be blocked by an FcRn inhibitor. Furthermore, this blockade of
FcRn-IgG binding may also directly inhibit inflammatory immune cell responses to IgG that
recruit and stimulate lymphocytes (Blumberg 2019; Hubbard 2020).
Administration of nipocalimab has not been observed to reduce levels of other immunoglobulins,
including IgA, IgM, or IgE, or impact other aspects of immune system response to infection,
considering FcRn blockage only affects IgG half-life and does not prevent IgG production.
To date, nipocalimab has not been approved in any therapeutic indication. Because of its
mechanism of action, nipocalimab is being evaluated for the treatment of patients with diseases
mediated by pathogenic IgG antibodies, including generalized myasthenia gravis (gMG) and warm
autoimmune hemolytic anemia (wAIHA), as well as diseases of the fetus and newborn caused by
maternofetal transfer of pathogenic IgG antibodies, such as early onset severe hemolytic disease
of the fetus and newborn (EOS-HDFN).
Immunoglobulin G antibodies cause inflammation and organ damage in autoimmune diseases such
as rheumatoid arthritis (RA). As nipocalimab use results in a decrease in circulating IgG antibody
concentrations, including pathogenic IgG antibody concentrations, and associated inflammatory
pathways, and considering that there remains unmet medical need in the treatment of RA,
exploring the use of nipocalimab in the treatment of RA is believed to be useful.
For the most comprehensive nonclinical and clinical information regarding nipocalimab, refer to
the latest version of the Investigator's Brochure (IB)for nipocalimab.
The term “study intervention” throughout the protocol, refers to study drug as defined in
Section 6.1, Study Interventions Administered.
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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.
The term “participant” throughout the protocol refers to the common term “subject.”
2.1. 
Study Rationale
Rheumatoid arthritis is a chronic autoimmune inflammatory disorder of unknown etiology that
occurs in approximately 1% of the population (Alamanos 2015). In all populations, RA is more
prevalent among women than men and usually develops in the fourth or fifth decades of life, with
80% of the total cases occurring between the ages of 35 and 50. Synovial inflammation underlies
the cardinal manifestations of this disease, which include pain, stiffness, swelling, and tenderness
in the joints followed by cartilage destruction, bone erosion, and subsequent deformities, resulting
in impaired physical function. There may also be associated morbidity from nonarticular
manifestations of RA, including fever, malaise, and pulmonary, ocular, and hematologic effects.
Patients with RA experience a shorter life expectancy than the general population, and the
increased mortality rates in RA are associated with clinical disease activity.
2.1.1. 
Unmet Need in Rheumatoid Arthritis
While there has been some success in treating patients with moderate to severe RA using various
targeted therapies, many patients continue to have refractory disease. In fact, between 20-50% of
patients fail to achieve low disease activity (LDA; Keystone 2004; Lipsky 2000; Weinblatt 2003).
Participants with  inadequate response (IR) to various disease-modifying anti-rheumatic drug
(DMARD) therapies including anti-tumor necrosis factor (anti-TNF) agents remain a top unmet
need in RA.
2.1.2. 
Rationale for Targeting FcRn in Rheumatoid Arthritis
Nipocalimab has a unique mechanism of action whereby it blocks the IgG binding site on
endogenous FcRn and is expected to decrease pathogenic IgG antibody concentrations.
A significant involvement of pathogenic IgG antibodies has been demonstrated in autoimmune
diseases including RA.
Autoantibody seropositivity is a defining characteristic of the majority of patients diagnosed with
RA, particularly for anti-citrullinated protein antibody  (ACPA) and rheumatoid factor (RF).
ACPAs have an IgG isotype in almost all seropositive patients, and seropositivity is associated
with more severe disease and predictive of progression of joint erosion (Jilani 2015). However,
about 70% of ACPA seropositive patients also have ACPA with  IgA and/or IgM isotypes
(Sieghart 2018). By definition, RF is autoreactive to the Fc domain of IgG, with pathogenicity
purported to be mediated by stabilizing IgG ICs, including IgG-ACPA ICs, to promote Fc-gamma
receptor- and complement-dependent effector functions (Anquetil 2015).
ACPAs are central to the development and propagation in RA, as they have been shown to bind
osteoclast precursor cells and directly promote their differentiation into bone-resorbing
osteoclasts. Other results have shown that in ACPA-positive individuals, bone loss starts even
before the onset of clinical disease; this is indicative of the independent effect of these antibodies
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in initiating skeletal damage. Additionally, once bone resorption occurs as a result of ACPA
binding generating osteoclasts, neoantigens can be generated by bone erosion that further augment
the inflammatory process in the articular tissues resulting is joint swelling and synovitis
(Kocijan 2013; Sun 2019). It is logical that by reducing levels of the pathologic antibodies with
nipocalimab, the severity and progression of RA should be abrogated.
Seropositivity for ACPA and/or RF is associated with clinical response to rituximab and abatacept
but not to TNF inhibitors (Courvoisier 2021). Given the IgG-lowering mechanism of action of
nipocalimab, it is presumed that autoantibody seropositivity and immune complex formation are
requisite for clinical impact. Although autoreactive antibodies and ICs are likely a feature of all
patients with RA, ACPA and/or RF seropositivity will be an inclusion criterion for this study to
provide the best opportunity for efficacy. In addition, the possible benefit of nipocalimab is
supported by data from the trials with Prosorba, a therapy in which patient’s serum is passed
through a Staphylococcal protein A column that absorbs IgG and ICs. The Prosorba Trial was a
randomized sham-controlled study demonstrating efficacy in American College of
Rheumatology 20 (ACR20) response with the Prosorba column (31.9%) compared with  sham
treatment (11.4%) (Felson 1999). A noninterventional prospective study  of refractory RA
demonstrated a response rate of 53.8% measured as ACR20 response (Roth 2004).
Nipocalimab is administered intravenously and, depending on the amount of IgG reduction
needed, may be administered every 2 weeks (q2w), which is supported by human pharmacokinetic
(PK)studies. This is the first study of an FcRn inhibitor in patients with RA so it is believed to be
prudent to study nipocalimab on top of standard-of-care (SOC) to achieve proof-of-concept and
collect basic efficacy and safety data in patients with RA who will be on SOC background
medications.
This Phase 2a, multicenter, randomized, double-blinded, placebo-controlled study is designed to
evaluate efficacy and safety of nipocalimab administrated intravenously in participants with
moderate to severe active RA.
2.2. 
Background
Nonclinical Studies
The nonclinical pharmacology, PK, and toxicity of nipocalimab have been adequately
characterized in appropriately designed nonclinical studies that support the potential efficacy,
safety, and mechanism of action. Pharmacologic studies showed that nipocalimab binds with high
affinity to the IgG binding site of FcRn preventing FcRn-mediated IgG recycling and promoting
IgG catabolism in vitro. In vivo, nipocalimab administered intravenously (IV) induced serum IgG
decreases in rodents or nonhuman primates and ameliorated disease pathology in animal models
of pathogenic IgG-driven autoimmune disease. Pharmacokinetic and pharmacodynamic (PD)
evaluation of IV nipocalimab in cynomolgus monkeys and mice established consistent dose-,
exposure-, and time-dependent relationships between PK, the PD effect on FcRn receptor
occupancy (RO) and the lowering of serum IgG concentrations.
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In repeat-dose toxicity studies of IV nipocalimab in the cynomolgus monkey, nipocalimab was
administered once-weekly at doses up to the maximum feasible dose of 300 mg/kg for up to
6 months in duration. Pharmacokinetic and PD assessment indicated target effects of
dose-dependent RO and reductions in serum IgG concentration occurred in a dose-dependent
manner. Chronic administration of nipocalimab was well tolerated without adverse effects,
including those associated with infection. Importantly, no immunotoxic effects were observed in
a comprehensive evaluation of innate and humoral immunity. In a reproductive toxicology study
in which pregnant cynomolgus monkeys received IV nipocalimab at doses of up to 300 mg/kg
from the early second trimester (ie, gestational day 45) through parturition, serum IgG in dams,
fetuses, and newborns was decreased with no evidence of nipocalimab-related developmental
toxicity or impact on fetal or infant survival.
These nonclinical pharmacology and toxicology results support the potential safety and efficacy
of nipocalimab and its clinical investigation in diseases caused by pathogenic IgG, including RA.
For the most comprehensive nonclinical information regarding nipocalimab, refer to the latest
version of the IB for nipocalimab.
Clinical Studies
Phase 1 Studies of IV Nipocalimab
Safety, PK, and PD data are available from 3 completed Phase 1 studies in healthy adult
participants: a first-in-human (FIH) study (MOM-M281-001) of single ascending doses (SAD) up
to 60 mg/kg and multiple ascending doses (MAD) study up to 30 mg/kg weekly; a single dose
infusion rate study (MOM-M281-007), and a single dose, dose escalating study conducted in
Japanese adults (MOM-M281-010).
Pharmacokinetic parameters for IV nipocalimab showed dose dependency and likely target
mediated disposition. Across the SAD dose groups (0.3-60 mg/kg), maximum concentration
increased in a dose-proportional manner, whereas area under the concentration-time curve
increased in a greater than dose-proportional manner. Serum clearance decreased nearly 50% from
10 to 60 mg/kg while half-life increased with increasing dose, from approximately 7.36 hours at
3 mg/kg to 32.2 hours at 60 mg/kg.
A close PK/PD relationship was observed, with the onset of PD effects (FcRn RO increases; IgG
and albumin mean decreases) occurring rapidly following all dose levels of nipocalimab. Recovery
of IgG and albumin toward baseline values following the last dose of nipocalimab was observed
to occur later at higher dose levels.
In healthy participants, IV nipocalimab was well tolerated with no deaths or serious adverse events
(SAEs)reported. The majority of the treatment-emergent adverse events (TEAEs) were transient,
mild, or moderate in severity, resolved without intervention, and were assessed as unrelated to
treatment. Infusions of IV nipocalimab were also well tolerated over infusion times from
15minutes to 2 hours.
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In the MAD portion of the MOM-M281-001 study, asymptomatic, dose dependent, reversible
elevations in non-fasting mean total cholesterol were observed up to 25% of baseline.
Retrospective analyses of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) data
could not be performed from this study.
In SAD and MAD healthy participants, there was no clear relationship between nipocalimab dose
and the presence of neutralizing antibodies (NAbs), anti-drug antibodies (ADA) or ADA titers.
Phase 2 Studies of IV Nipocalimab
In the Phase 2 study of nipocalimab in adults with gMG (Study MOM-M281-004), IV nipocalimab
was administered for 8 weeks in 4 nipocalimab groups (5 mg/kg every 4 weeks [q4w],
30 mg/kg q4w, 60 mg/kg q2w, and 60 mg/kg single dose) and the IV placebo group. Study conduct
has been completed and the final report is in preparation.
Consistent with its mechanism of action, nipocalimab produced dose-dependent, transient
decreases in mean serum IgG concentrations. Infusions of IV nipocalimab were generally safe and
well tolerated in this study with no deaths, discontinuations due to TEAEs, TEAEs of National
Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE)≥Grade 3, or
adverse events of special interest (AESIs; events of infection or hypoalbuminemia ≥Grade 3). The
overall incidence of TEAEs was similar between the combined nipocalimab group (83.3%) and
placebo group (78.6%). Three SAEs were reported during the study; an SAE of musculoskeletal
pain was reported for 1 nipocalimab-treated patient (30 mg/kg q4w) and 2 SAEs (ischemic stroke,
myasthenia gravis) were reported in placebo-treated patients; none of the SAEs were considered
by the investigator as related to study intervention.
In the MOM-M281-004 study, asymptomatic, dose dependent, reversible elevations in non-fasting
mean total cholesterol were observed up to 25% of baseline. The elevations in total cholesterol
appear to mirror the kinetics of the decreases in albumin observed with nipocalimab.
The Phase 2 study evaluating IV nipocalimab administered to pregnant women at high risk for
EOS-HDFN (MOM-M281-003) is ongoing.
A preliminary review of the ongoing study data suggested a possible treatment-emergent increase
in non-fasting 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.
Preliminary safety data on a limited number of patients with gMG in an ongoing long-term
extension study and in the wAIHA study have raised no safety concerns.
While a dose-dependent increase in the number of nipocalimab-treated patients with NAb was
observed in gMG participants, NAb titers were low throughout the studies. Overall,
IV administration of nipocalimab did not lead to a detectable clinically relevant immune response
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against nipocalimab. No definitive conclusions can be made regarding the impact of
immunogenicity on PK due to the low sample sizes.
For the most comprehensive information regarding nipocalimab, refer to the latest version of the
IB for nipocalimab.
2.3. 
Benefit-Risk Assessment
2.3.1. 
Risks for Study Participation
Table 1: Potential Risks of Nipocalimab for the Treatment of Rheumatoid Arthritis
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2.3.2. 
Benefits for Study Participation
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participants with moderate to severe active
RA
 Change from baseline in disease biomarkers (eg,
autoantibodies, CICs) over time in participants with
abnormal levels at baseline
 Reduction of IgG level-clinical response relationship
analysis
To evaluate changes in serological profiles
in response to nipocalimab vs placebo
treatment in participants with moderate to
severe active RA
 Change from screening visit in serum ACPA and RF
levels over time by treatment group, in participants
seropositive at screening visit for ACPA and RF,
respectively
Abbreviations: ACPA=anti-citrullinated protein antibodies; ACR=American College of Rheumatology; ADA=anti-drug antibody; AE=adverse
event; AESI=adverse event of special interest; CDAI=Clinical Disease Activity Index; CICs=circulating immune complexes; DAS28-CRP=Disease
Activity Index Score 28 using C-reactive protein; DAS28-ESR=Disease Activity Index Score 28 using erythrocyte sedimentation rate;
EULAR=European League Against Rheumatism; FACIT-Fatigue=Functional Assessment of Chronic Illness Therapy 
 Fatigue Scale;
HAQ-DI=Health Assessment Questionnaire
Disability Index; IgG=immunoglobulin G; IV=intravenous; LDA=low disease activity; MCS=mental
component score; NAb=neutralizing antibody; PCS=physical component score; PD=pharmacodynamics; PK=pharmacokinetic(s); PRO=patient-
reported outcome; PtGA=Patient Global Assessment of Disease Activity; RA=rheumatoid arthritis; RF=rheumatoid factor; SAE=serious adverse
event; SDAI=Simple Disease Activity Index (for Rheumatoid Arthritis); SF-36=36-item Short Form Health Survey; VAS=visual analog scale
Refer to Section 8, (Study Assessments and Procedures)for evaluations related to endpoints.
HYPOTHESIS
The primary hypothesis is that treatment with nipocalimab 15 mg/kg IV q2w is superior to placebo
in participants with moderate to severe active RA as assessed by the mean change from baseline
in the Disease Activity Index Score 28 using C-reactive Protein (DAS28-CRP)at Week 12.
4. 
STUDY DESIGN
4.1. 
Overall Design
This is a randomized, double-blind, parallel-group, placebo-controlled, proof-of-concept,
multicenter study in participants between the ages of 18 and 75, inclusive, with moderate to severe
active RA despite standard therapy, including anti-TNF agents.
The total duration of the study is up to 24 weeks, consisting of 3 study periods: a ≤6-week screening
period (rescreening is permitted once per participant), a 12-week double-blind treatment period,
and a 6-week safety follow-up period (8 weeks after the last administration of study intervention).
A target of 50 participants will be enrolled in this study. Participants who have had an IR or were
intolerant to at least one anti-TNF therapy will be enrolled. Depending upon the enrollment rate,
the study population may be expanded to also include participants who have had an IR  or
intolerance to a conventional synthetic DMARD (csDMARD; see Section 5.1).
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Participants will be randomly assigned into 1 of 2 treatment groups using a 2:3 randomization
ratio, respectively:
 
Group 1: Placebo IV q2w: Participants will receive placebo IV q2w through Week 10.
 
Group 2: Nipocalimab 15 mg/kg IV q2w: Participants will receive nipocalimab 15 mg/kg
IV q2w through Week 10.
A placebo comparator (in addition to SOC background therapy) will be used to allow for blinded,
placebo-controlled evaluation of the efficacy and safety of nipocalimab in participants with RA.
Efficacy, safety, PK, immunogenicity, and biomarkers will be assessed according to the Schedule
of Activities (SoA, Section  1.3). Pharmacogenomic blood samples will be collected from
participants who consent to the collection of these samples (where local regulations permit).
The primary endpoint (the change from baseline in DAS28-CRP compared with  placebo at
Week 12) will be evaluated after all participants have completed the Week 12 visit (or
discontinued). An interim analysis (IA) is planned when 60% (30 participants) of the planned
number of participants complete the Week 12 assessment. This analysis is for future planning
purposes and will not impact the conduct of the current study (Section 9.5).
Every reasonable effort should be made to keep concomitant medications stable as defined in the
protocol (Section 6.8). Beginning at the screening visit, all concomitant therapies and all changes
in concomitant therapies should be recorded throughout the study.
Key safety assessments include adverse events (AEs), SAEs, AESIs, clinical laboratory parameters
(eg, hematology, chemistry, lipid panel), vital signs, and physical examination.
Serum samples will be used to evaluate PK and antibodies to nipocalimab. Blood-based
biomarkers will be evaluated for inflammation-associated proteins and other analytes and will be
used to better understand the biology of RA, to provide a biological assessment of the response of
participants to treatment with nipocalimab, to analyze differences between responders and
nonresponders, to assess loss of response, and to determine if the markers can be used to classify
participants as potential responders prior to treatment.
Actigraphy data will utilize accelerometry measurements to assess physical activity, mobility, and
sleep parameters. These measurements will be captured via wrist-worn actigraph devices, which
have been validated against polysomnography to assess sleep-related variables.
Database locks (DBLs) are planned at Week 12 and at the end of the study. The end of the study
is defined as the last follow-up assessment (8 weeks after the last infusion of study intervention)
for the last participant.
A Data Monitoring Committee (DMC) will be commissioned for this study. Refer to
Section 10.3.6 for details on the DMC.
A diagram of the study design is provided in Section 1.2, Schema.
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4.2. 
Scientific Rationale for Study Design
This study is designed to examine the efficacy and safety of nipocalimab, the effects of
nipocalimab on physical function, patient-reported outcomes (PROs), and population PK  of
nipocalimab in participants with moderate to severe active RA who are refractory to standard
therapy.
A double-blind, placebo-controlled study design  (allowing background SOC therapy to be
continued) was selected, as a true placebo design (no treatment) would not be appropriate. The
background SOC therapy is defined as being treated with  any csDMARDs (eg, methotrexate
[MTX], sulfasalazine [SSZ], hydroxychloroquine [HCQ], chloroquine [CQ], and leflunomide).
4.2.1. 
Blinding, Control, Study Phase/Periods, Intervention Groups
4.2.2. 
DNA and Biomarker Collection
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4.2.3. 
Actigraphy Measurements
Digital health applications may help to objectively capture participant well-being. Wearable
devices equipped with biometric sensors and self-reporting mobile applications are able to
continuously track participant activities and may provide useful insights on disease progression,
clinical response, or complications.
Digital sensing technologies will provide valuable data that supplement clinical data streams such
as clinical endpoints, PROs, objective measures from clinical laboratory and biomarker
assessments to better characterize the disease status and well-being of participants with RA when
treated with nipocalimabcompared with placebo.
4.2.4. 
Participant Input into Design
Historical data were collected from a 30-60 minute internet survey which was administered to
6 sample groups of patients with RA in the United States. Mobility and fatigue were identified by
many as significant barriers to daily life. Actigraphy will be employed in this protocol (optional
participation) to track mobility and sleep data related to study intervention.
Additionally, the lack of new therapies has been identified as a recurrent cause of frustration among
patients with RA and rheumatologists. For this reason, the potential of nipocalimab to emerge as
a new treatment would be considered a valuable contribution to the RA suffering population.
4.2.5. 
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 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
patient preferences.
The primary ethical concern is that although targeting FcRn has shown promise of early efficacy
in humans in several diseases (eg, myasthenia gravis, primary immune thrombocytopenia
[Howard 2019, Kiessling 2017, Newland 2020]), efficacy has not been shown in RA, and response
to nipocalimab in RA is theoretical at this time.
The total blood volume to be collected is considered to be an acceptable amount of blood to be
collected over this time period from the population in this study based upon the standard of the
American Red Cross standard limit for whole blood donation (approximately 475 mL every
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8 weeks) and is, therefore, considered an acceptable amount of blood to be collected over this time.
For more details regarding blood collection, see Blood Sample Collection in Section 8.
4.3. 
Justification for Dose
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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.
Study Completion Definition
A participant will be considered to have completed the study if he or she has completed
assessments through Week 12 of the double-blind phase and the safety follow-up visit.
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 repeat of any screening
procedures are allowed.
The inclusion and exclusion criteria for enrolling participants in this study are described below. If
there is a question about these criteria, the investigator must consult with the appropriate sponsor
representative and resolve any issues before enrolling a participant in the study. Waivers are not
allowed.
For a discussion of the statistical considerations of participant selection, refer to Section 9.2.
5.1. 
Inclusion Criteria
Enrollment for this study will begin with participants who have demonstrated an IR or intolerance
to at least 1 anti-TNF therapy. Depending upon the enrollment rate, sites will be informed to
expand the participant population to also include those who are anti-TNF-therapy naïve and have
demonstrated an IR or intolerance to at least 1 csDMARD.
Each potential participant must satisfy the following criteria to be enrolled in the study:
Age
1. 
18 to 75 years of age (inclusive) at the time of consent. (In regions where the legal age of
consent is older than 18 years and the participant is under the legal age, signed informed
consent must be obtained from both the participant and his or her legally acceptable
representative.)
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Disease Characteristics
2. 
Diagnosis of RA and meeting the 2010 ACR / European League Against Rheumatism
(EULAR) Criteria for RA for at least 3 months before screening.
3. 
Has moderate to severe active RA as defined by persistent disease activity with at least
6 swollen and 6 tender joints out of the 66/68-swollen and tender joint count at the time of
screening and at baseline.
4. 
Is positive for ACPA and/or RF at screening.
5. 
Screening CRP ≥0.3 mg/dL by the central laboratory.
6. 
If has received prior anti-TNF agent (including biosimilars), has demonstrated IR or is
intolerant to the anti-TNF therapy based on 1 of the following:
a. IR to at least 1 anti-TNF agent including biosimilars, as assessed by the treating
physician, after at least 12 weeks of etanercept, adalimumab, golimumab, or
certolizumab pegol therapy and/or at least a 14-week dosage (ie, at least 4 doses)
of infliximab. Documented IR may include inadequate improvement in joint
counts or other parameters of disease activity.
b. Intolerance to an anti-TNF agent (as assessed by the treating physician)including
etanercept, adalimumab, golimumab, certolizumab pegol, or infliximab (including
biosimilars). Documented intolerance includes side effects and or
injection/infusion reactions.
7. 
If has not received prior anti-TNF agent (including biosimilars), has demonstrated IR or
intolerance to csDMARDs based on 1 of the following:
a. For participants receiving a csDMARD at the time of entry: has had regular use
of the csDMARD for at least 12 weeks prior to randomization, with a continuous
(nonchanging) dose for at least 8 weeks prior to randomization.
b. For participants not receiving a csDMARD at the time of entry: has failed, was
unable to tolerate, or had a contraindication to treatment with a csDMARD, as will
be documented by the investigator in the participant's history.
Concomitant or Previous Medical Therapies Received
8. 
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 csDMARD:
a. If using MTX: on a stable dosage of no more than 25 mg/week (intramuscular
[IM], subcutaneous [SC], or oral [PO])
b. If using SSZ: on a 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 a stable dosage of 10-20 mg/day
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9. 
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.
10. 
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.
11. 
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.
12. 
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.
Sex and Contraceptive/Barrier Requirements
13. 
Criterion deleted per Amendment 3.
14. 
A woman of childbearing potential must have a negative highly sensitive urine pregnancy
test (β-human chorionic gonadotropin [β-hCG]) at screening and a negative urine (β-hCG)
pregnancy test at Week 0 prior to administration of study intervention.
15. 
Criterion modified per Amendment 3.
15.1. A woman must be (as defined in Section 10.5):
a. Not of childbearing potential
OR
b. Of childbearing potential, and:
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 30 days 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 Section 10.5.
16. 
A woman must agree not to donate eggs (ova, oocytes) or freeze for future use for the
purposes of assisted reproduction during the study and for 30 days after the last
administration of study intervention.
17. 
A male participant who is sexually active with a woman of childbearing potential and who
has not had a vasectomy must agree to use a barrier method of birth control (eg, either a
condom [with spermicidal foam/gel/film/cream/suppository if available in their locale] or
a partner with an occlusive cap [diaphragm or cervical/vault caps] plus spermicidal
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foam/gel/film/cream/suppository if available in their local), during the study and for at
least 90 days after receiving the last administration of study intervention.
18. 
A male participant must agree not to donate sperm for the purpose of reproduction during
the study and for a minimum of 90 days after receiving the last administration of study
intervention.
Vaccination History
19. 
Criterion modified per Amendment 3.
19.1. 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 a locally-approved (or emergency use-authorized)
COVID-19 vaccination regimen at least 2 weeks prior to study-related visits or procedures.
Study participants should follow applicable local vaccine labeling, guidelines, and
standards-of-care for patients receiving immune-targeted therapy when determining an
appropriate interval between vaccination and study enrollment (see also Section 6.8.4).
General
20. 
Criterion modified per Amendment 3.
20.1. Must sign an ICF indicating that the participant understands the purpose of, and
procedures required for, the study and is willing to participate in the study. (In regions
where the legal age of consent is older than 18 years, those under the legal age, must obtain
signed informed consent from both the participant and his or her legally acceptable
representative.)
21. 
Criterion modified per Amendment 3.
21.1. Must sign a separate ICF if the participant agrees to provide optional DNA samples
for research where local regulations permit. In regions where the legal age of consent is
older than 18 years, those under the legal age must obtain signed informed consent from
both the participant and his or her legally acceptable representative.
Refusal to give consent for the optional DNA samples does not exclude a participant from
participation in the study.
22. 
Must be willing and able to adhere to all specified requirements, including but not limited
to completion of the required assessments, adherence to the visit schedule, and compliance
with the lifestyle restrictions as specified in this protocol.
23. 
Must be able to read and write.
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5.2. 
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from
participating in the study:
Coexisting Medical Conditions or Past Medical History
1. 
Has any confirmed or suspected clinical immunodeficiency syndrome not related to
treatment of his/her RA  or has a family history of congenital or hereditary
immunodeficiency unless confirmed absent in the participant.
2. 
Currently has a malignancy or has a history of malignancy within 3 years before screening
(with the exception of localized basal cell carcinoma and/or squamous cell carcinoma skin
cancer that has been adequately treated with no evidence of recurrence for at least
12 weeks before the first administration of study intervention or cervical carcinoma in situ
that has been treated with no evidence of recurrence for at least 3 months before the first
administration of study intervention).
3. 
Has known allergies, hypersensitivity, or intolerance to nipocalimab or its excipients (refer
to the IB).
4. 
Is (anatomically or functionally) asplenic.
5. 
Has experienced myocardial infarction (MI), unstable ischemic heart disease, or stroke
within 12 weeks of screening.
6. 
Has a history of severe, progressive, and/or uncontrolled liver, gastrointestinal, renal,
pulmonary, cardiovascular, psychiatric, neurologic, or musculoskeletal disorder (with the
exception of RA), hypertension, or any other medical disorder that, in the opinion of the
investigator, might interfere with the participant's full participation in the study, or might
jeopardize the safety of the participant or the validity of the study results.
7. 
Has other known inflammatory diseases that might confound the evaluations of benefit
from nipocalimab therapy, including but not limited to ankylosing spondylitis, psoriatic
arthritis, systemic lupus erythematosus, Lyme disease.
8. 
Has screening laboratory test result as follows:
a. Hemoglobin <8.0 g/dL (International system of Units [SI]: <80 g/L)
b. White blood cells (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
f. Liver function test (aspartate aminotransferase [AST], alanine aminotransferase
[ALT]) results that are ≥2 × the upper limit of normal (ULN)
g. 
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9. 
Poor tolerability of venipuncture or lacks adequate venous access for required blood
sample collections during the study period.
10. 
Has shown a previous severe immediate hypersensitivity reaction, such as anaphylaxis, to
therapeutic proteins (eg, mAbs).
Concomitant or Previous Medical Therapies Received
11. 
Is currently taking IgG Fc-related protein therapeutics.
12. 
Has received plasmapheresis, immunoadsorption therapy, or IVIg within 6 weeks prior to
screening.
13. 
Criterion modified per Amendment 3.
13.1. Has received a live vaccine within 3 months prior to screening or has a known need
to receive a live vaccine during the study, or within at least 3 months after the last
administration of study intervention in this study.
Has had a Bacille Calmette-Guérin (BCG) vaccination within 1 year of first administration
of study intervention.
14. 
Has taken any disallowed therapies (within the periods of time detailed in Section 6.8,
Concomitant Therapies) prior to the planned first administration of study intervention.
15. 
Has received anti-TNF agent (or its biosimilars)within 30 days or 5 half-lives, whichever
is greater, prior to the first administration of study intervention.
16. 
Has received biologic therapy or targeted synthetic DMARDs including but not limited to
the below  within  30 days or 5 half-lives, whichever is greater, prior to the first
administration of study intervention:
a. anti-interleukin (IL)-6 receptor mAb (eg, tocilizumab or sarilumab)
b. anti-IL-1 blockers (eg, anakinra)
c. Co-stimulatory inhibitors (eg, abatacept)
d. Janus kinase inhibitors (JAKi, eg, tofacitinib, baricitinib, upadacitinib)
17. 
Has received rituximab within 6 months prior to first administration of study intervention.
18. 
Currently using MTX and leflunomide combination therapy.
19. 
Has used oral cyclophosphamide within 3 months or IV cyclophosphamide within
6 months prior to the first administration of study intervention.
20. 
Has received cyclosporine A, azathioprine, tacrolimus, mycophenolate mofetil, oral or
parenteral gold, or D-penicillamine within 4 weeks prior to the first administration of study
intervention.
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21. 
Use of complementary therapies, including traditional/Chinese medicines, herbs,
ointments, or procedures (eg, acupuncture), that have the potential to activate
(eg, echinacea) or inhibit (eg, Tripterygium wilfordii Hook F) the immune system is
prohibited within 6 weeks of 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
22. 
Criterion modified per Amendment 3.
22.1. Has received an investigational intervention within 3 months or 5 half-lives
(whichever is longer) or used an invasive investigational medical device within 3 months
before the planned first administration of study intervention or is currently enrolled or
plans to enroll in an investigational study.
23. 
Is currently breastfeeding, pregnant, intends to become pregnant during the study, or is
planning egg donation during the study or within 30 days after the last administration of
study intervention.
24. 
Is planning to father a child while enrolled in this study or donate sperm within 90 days
after the last administration of study intervention.
Infections or Predisposition to Infections
25. 
Has a severe infection including opportunistic infections (eg, 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-week
exclusionary period has passed.
26. 
Has a chronic infection (eg, bronchiectasis, chronic osteomyelitis, chronic pyelonephritis)
or requires chronic treatment with anti-infectives (eg, antibiotics, antivirals).
27. 
Tests positive for hepatitis B virus (HBV) infection (see Section 10.7).
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28. 
Is seropositive for antibodies to hepatitis C virus (HCV), unless they satisfy 1 of the
following conditions:
a. Has a history of successful treatment, defined as being negative for HCV
ribonucleic acid (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.
29. 
Has a history of being HIV1 or HIV2 antibody-positive, or tests positive for HIV at
screening.
30. 
Criterion modified per Amendment 3.
30.1. COVID-19 infection:
During the 6 weeks prior to baseline, has had any  of the following (regardless of
vaccination status): (a) confirmed severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) infection (test positive) OR(b)suspected SARS-CoV-2 infection (clinical
features of COVID-19 without documented test results) OR(c) close contact with a person
with known or suspected SARS-CoV-2 infection
 Exception: may be included with a documented negative result for a validated
SARS-CoV-2 test
i) obtained at least 2 weeks after conditions (a), (b), (c) above (timed from resolution
of key clinical features if present, [eg, fever, cough, dyspnea])
AND
ii) with absence of all conditions (a), (b), (c) above during the period between the
negative test result and the baseline study visit
Note on COVID-related exclusion:
 The field of COVID-related testing (for presence of, and immunity to, the
SARS-CoV-2 virus) is rapidly evolving. Additional testing may be performed as part
of screening and/or during the study if deemed necessary by the investigator and in
accordance with current regulations/guidance from authorities/standards of care.
Precaution: for those who may carry a higher risk for severe COVID-19 illness, follow
guidance from local health authorities when weighing the potential benefits and risks of
enrolling in the study, and during participation in the study.
31. 
Criterion modified per Amendment 3.
31.1. Has a history of active granulomatous infection, including histoplasmosis or
coccidioidomycosis, before screening.
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32. 
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.
Diagnostic Assessments
33. 
Had major surgery (eg, requiring general anesthesia [although not all procedures requiring
general anesthesia would necessarily be major]) within 3 months before screening, or will
not have fully recovered from surgery, or has surgery planned during the time the
participant is expected to participate in the study.
Note:Participants with planned surgical procedures to be conducted under local anesthesia
may participate.
Other Exclusions
34. 
History of moderate or severe substance or alcohol use disorder according to Diagnostic
and Statistical Manual of Mental Disorders (5th edition) criteria, except nicotine or
caffeine, within 1 year before screening.
35. 
Has 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.
36. 
Lives in an institution on court or authority order.
37. 
Currently participating or intends to participate in any other study using an investigational
agent or procedure during the conduct of this study.
38. 
Is an employee of the investigator or study site, with direct involvement in the proposed
study or other studies under the direction of that investigator or study site, as well as family
members of the employees or the investigator.
NOTE: Investigators 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 (refer to Section 5.4). The required source documentation
to support meeting the enrollment criteria are noted in Section 10.3.10.
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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 Section 6.8, Concomitant Therapy for details regarding prohibited and restricted
therapy during the study.
2. 
Agree to follow all requirements that must be met during the study as noted in the Inclusion
and Exclusion Criteria.
3. 
Participants must follow contraceptive measures as outline in Section 5.1. Women should
continue using these contraceptive measures for 30 days after the last dose of study
intervention. Men should continue using these contraceptive measures for 90 days after the
last dose of study intervention.
4. 
Criterion modified per Amendment 3.
4.1. Must agree not to receive a live vaccine during the study and for 3 months after
receiving the last dose of study intervention.
Must agree not to receive a BCG vaccination during the study and for 1 year after receiving
the last dose of study intervention.
5. 
Must be willing and able to complete study-related questionnaires and document clinical
symptoms, AEs, and concomitant medications.
6. 
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.
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.
Retesting
Retesting of abnormal laboratory values for safetythat may lead to exclusion will be allowed once.
Retesting can occur at an unscheduled visit during the screening phase, as long as this is done
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within the specified screening window of up to 6 weeks. 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 tests 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(s)
analyzed by the central laboratory may be repeated more than once in the event of suspected error
in sample collection or analysis as long as the result is obtained within the 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 new participant numbers, 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  10.8. Criteria for temporary discontinuation of study intervention are described in
Section 7.1.2.
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY
6.1. 
Study Interventions Administered
Participants will be randomized in a 2:3 ratio to 1 of 2 treatment groups as described below:
 
Group 1 –placebo IV q2w: Participants will receive placebo IV q2w from Week 0 through
Week 10.
 
Group 2 –nipocalimab 15 mg/kg IV q2w: Participants will receive nipocalimab 15mg/kg
IV q2w from Week 0 through Week 10.
Participants will remain on their assigned treatment through Week 10. All participants will receive
a planned total of 6 IV infusions over a 10-week period.
Intravenous study intervention should be prepared and administered according to the instructions
specified in the Investigational Product Preparation and Administration Instructions (IPPI).
Study intervention administration must be captured in the source documents and the electronic
case report form (eCRF).
Nipocalimab will be manufactured and provided under the responsibility of the sponsor. Refer to
the IB for a list of excipients. Placebo will be a commercially available saline solution. Placebo will
be centrally sourced and provided under the responsibility of the sponsor where required per local
regulations. Nipocalimab and the centrally-sourced and supplied placebo are designated as
Investigational Medicinal Product (IMP). In the United States of America, a site-sourced and
locally-sourced saline placebo option will be available in addition to the centrally-sourced placebo.
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These site and locally sourced commercial saline for placebo are designated as Non-Investigational
Medicinal Product (NIMP) per US Food and Drug Administration (FDA) regulations.
For a definition of study intervention overdose, refer to Section 6.7.
Guidelines for study intervention administration affected by the COVID-19 pandemic are found
in Section 10.8.
6.2. 
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
The nipocalimab solution in the vial should be clear to slightly opalescent and colorless to slightly
brown and may contain small translucent particles. Do not use nipocalimab if the liquid is cloudy
or discolored or has large particles. Protection from light is not required during the preparation and
administration of the study intervention material but direct exposure to sunlight should be avoided.
Aseptic techniques must be used during the preparation and administration of the study
intervention material.
Saline will be used as a placebo.
Refer to the site IPPI and Site Investigational Product Procedures Manual (SIPPM) for additional
guidance on study intervention preparation, handling, and storage.
Accountability
The investigator is responsible for ensuring that all study intervention received at the site is
inventoried and accounted for throughout the study.
The study intervention administered to the participant must be documented on the intervention
accountability form or in the interactive web response system (IWRS) intervention accountability
system as applicable. 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 except as noted in the IPPI.
Study intervention must be handled in strict accordance with the protocol and as indicated on the
container label and must be stored at the study site in a limited-access area or in a locked cabinet
under appropriate environmental conditions. Unused study intervention  must be available for
verification by the sponsor's study site monitor during on-site monitoring visits. The return to the
sponsor or sponsor-designated destruction facility of unused study intervention will be
documented on the intervention return form or in the IWRS intervention accountability system, as
applicable. When the study site is an authorized destruction unit and study intervention supplies
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are destroyed on site, this must also be documented on the intervention return form or in the IWRS
intervention accountability system as applicable.
Potentially hazardous materials (eg, used needles and syringes) must be disposed of immediately
in a safe manner and, therefore, will not be retained for intervention accountability purposes.
Study intervention must 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
administered 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 intervention 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 this study. Participants will be randomly
assigned to 1 of2 intervention groups based on biased-coin algorithm implemented in the IWRS
before the study. Dynamic central randomization targets to balance the distribution of participants
to achieve the randomization ratio (2:3) at the study level and within the levels of each individual
stratification factor: baseline MTX use, anti-TNF IR/intolerance, and swollen and tender joint
counts level.
The requestor must use his or her own user identification and personal identification number when
contacting the IWRS and will then give the relevant participant details to uniquely identify the
participant.
Blinding
The participant, investigator, and sponsor will be blinded to study intervention for the duration of
the study. The unblinded site pharmacist(s) or designee will be responsible for preparing the study
intervention for infusion while the remainder of site personnel will remain blinded. To preserve
blinding, the unblinded pharmacist(s) or designee will prepare the infusion material to be identical
in appearance for administration, in accordance with the IPPI. Administration of study intervention
to the participants will be performed by a blinded, qualified healthcare provider. Independent drug
monitors will be used to monitor drug accountability and all unblinded study data.
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.
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Selected data will be handled with special care to minimize any potential impact on blinding/bias
(see Section 4.2.1). This can include masking/segregating the data in question from view by the
investigators, clinical team, or others as appropriate until the time of DBL and unblinding. If there
is sufficient safety concern that local laboratory samples are drawn to check the level of any
masked laboratory assessments, the medical monitor or sponsor should be notified immediately.
The participant may be required to be discontinued from study intervention.
Under normal circumstances, the blind must 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 IWRS. While the responsibility to break the intervention code in
emergency situations resides solely with the investigator, it is recommended that the investigator
contact the sponsor or its designee if possible to discuss the particular situation, before breaking
the blind. Telephone contact with the sponsor or its designee will be available 24 hours per day,
7 days per week. In the event the blind is broken, the sponsor must be informed as soon as possible.
The date and reason for the unblinding must be documented in the appropriate section of the eCRF
and in the source document. The documentation received from the IWRS indicating the code break
must be retained with the participant's source documents in a secure manner.
Participants who have had their intervention assignment unblinded should continue to return for
scheduled evaluations and are not eligible to receive further study intervention.
Additionally, a given participant’s treatment assignment may be unblinded to the sponsor, the
Independent Ethics Committee/Institutional Review Board (IEC/IRB), and site personnel to fulfill
regulatory reporting requirements for suspected unexpected serious adverse reactions (SUSARs).
A separate code break procedure will be available for use by the sponsor’s Global Medical Safety
group to allow for unblinding of individual participants to comply with specific requests from
regulatory or health authorities.
In general, randomization codes will be disclosed fully only if the study is completed and the
clinical database is closed. However, for the IA, the randomization codes and, if required, the
translation of randomization codes into intervention and control groups will be disclosed to those
authorized and only for those participants included in the IA.
The blind will be maintained until the last participant completes the safety follow-up assessments
at Week 12 and the data are locked. At the Week 12 DBL, the 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 participant-level data will be documented
prior to unblinding. Investigative sites and participants will remain blinded to initial intervention
assignment until the final DBL (Week 18).
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6.4. 
Study Intervention Compliance
Study-site personnel will maintain a log of all study intervention administered. Study intervention
supplies for each participant will be inventoried and accounted for.
Study intervention will be administered as an IV infusion by qualified study-site personnel and the
details of each administration is to be conducted using the IPPI.
Additional details may be provided in the site SIPPM that is provided separately. Compliance with
the treatment schedule is strongly encouraged.
6.5. 
Dose Modification
No study intervention dose adjustment will be permitted through the study.
6.6. 
Continued Access to Study Intervention After the End of the Study
There are no provisions for continued access to study intervention after the end of this
proof-of-concept study.
6.7. 
Treatment of Overdose
For this study, any dose ofnipocalimabgreater than
above the highest dose at a single dosing
visit specified in this protocol will be considered an overdose. The sponsor does not recommend
specific intervention for an overdose.
In the event of an overdose, the investigator or treating physician should:
 
Contact the medical monitor immediately.
 
Closely monitor the participant for AEs and SAEs.
 
Discuss with the medical monitor if one or additional serum sample for PK analysis will be
required and at what timepoints.
 
Document the quantity of the excess dose.
6.8. 
Concomitant Therapy
Detailed information of pre-study RA therapies, including dosage and frequency of administration,
must be recorded for past history. Other pre-study therapies and any COVID-19 vaccinations,
including vaccinations authorized for emergency use, administered at the time of screening or up
to 60 days before first dose of study intervention, whichever is longer, must be recorded at
screening. For any therapies that were discontinued, the reason for discontinuation
(eg, non-response, loss of response, intolerance, safety concern) should be documented.
Concomitant therapies (including RA concomitant therapies, non-RA concomitant therapies, and
any  COVID-19 vaccinations [including vaccinations authorized for emergency use]) must be
recorded throughout the study, beginning with screening to the final safety follow-up visit after
the last dose of study intervention.
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All concomitant therapies (prescription or over-the-counter medications, including vaccines,
vitamins, herbal supplements) different from the study intervention must be recorded in the eCRF.
Recorded information will include a description of the type of therapy, duration of use, dosage,
route of administration, and indication. Modification of an effective preexisting therapy should not
be made for the explicit purpose of entering a participant into the study.
In participants with elevated lipids at any time during the study, it is recommended that the
investigator initiates or continues appropriate therapy for dyslipidemia as per local health
guidelines.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered.
Every reasonable effort should be made to keep concomitant medications stable to avoid
introducing non-protocol medications for RA disease activity through the final safety visit, or as
specified in the sections below. Dose stabilization of all concomitant medications is required prior
to randomization. All medications must meet study protocol guidelines (see Section 5.1,
Section 5.2). It is recommended that all other concomitant medications be maintained at stable
doses through the final safety visit, including for those discontinuing the study prematurely. If
necessary, a concomitant medication may be reduced or temporarily discontinued because of
abnormal laboratory values, safety and tolerability issues, concurrent illness, or the performance
of a surgical procedure, but the change and reason for the medication change should be clearly
documented in the participant’s medical record. Adjustments in concomitant therapies that do not
comply with the study protocol guidelines may cause a participant to be considered a treatment
failure for the primary and secondary endpoints through Week 12.
During the entire study, investigators should consider whether increases in permitted background
therapy due to increased RA disease activity warrant discontinuation of study intervention. If
protocol-prohibited medication  (detailed in Section  6.8.5) is needed, the participant should be
considered for discontinuation from study intervention (see Section 7.1). This should be discussed
with the medical monitor and/or sponsor.
Table 2 outlines permitted concomitant medication use and dose stabilization requirements prior
to randomization.
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Table 2: Permitted Concomitant Medications for 80202135ARA2001, 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. 
Disease-Modifying Antirheumatic Drugs and Systemic
Immunosuppressives
If using csDMARDs (eg, MTX, SSZ, HCQ, CQ, or leflunomide), the participant:
 
should have started treatment at least 12 weeks prior to the first administration of study
intervention,
 
should have no serious toxic side effects attributable to the DMARD,
 
must be on a stable dosage for at least 8 weeks prior to the first administration of study
intervention,
 
if using MTX: stable dosage of ≤25 mg/week (IM, SC, or PO)
 
if using SSZ: stable dosage of 1000-2000 mg/day
 
if using HCQ or CQ: stable dosage of 200-400 mg/day
 
if using leflunomide: stable dosage of 10-20 mg/day
 
and must remain on the dosage throughout the study unless reduction or interruption is
required for safety or tolerability reasons.
If not currently using MTX, SSZ, HCQ, CQ, or leflunomide, the participant must not have received
these csDMARDs for at least 4 weeks prior to the first administration of the study intervention and
must not initiate these csDMARDs during the study.
6.8.2. 
Corticosteroid Therapy
Oral Corticosteroids
Participants treated with oral corticosteroids should receive a stable dosage equivalent to 10 mg
prednisone per day for at least 2 weeks prior to their first administration of the study intervention
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and continue to receive this dosage through the end of the study. The dosage and the type of oral
corticosteroid may be changed at the discretion of the investigator if the participant develops
unacceptable side effects.
Initiation of oral corticosteroids is prohibited during the study for any indication.
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.
6.8.3. 
Nonsteroidal Anti-inflammatory Drugs and Other Analgesics
Participants treated with NSAIDs, including aspirin and selective cyclooxygenase-2 inhibitors, and
other analgesics should receive the usual marketed doses approved in the country where the study
is being conducted. In this study, aspirin is considered an NSAID, except for low-dose aspirin
prescribed for cardiovascular 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 intervention and through Week 12. The dose and the type of NSAIDs or other analgesics
may be changed at the discretion of the investigator if the participant develops unacceptable side
effects or a contraindication to their use. Nonsteroidal anti-inflammatory drugs should not be used
within 24 hours before a study visit involving joint counts and pain assessments.
6.8.4. 
Vaccinations (Including COVID-19)
When considering use of locallyapproved non-live vaccines (including emergency-use-authorized
COVID-19 vaccines) in study participants, follow applicable local vaccine labeling, guidelines,
and standards-of-care for participants receiving immune-targeted therapy.
For study participants receiving a locally-approved (including emergency use-authorized)
COVID-19 vaccine, in order to help identify acute reactions potentially related to COVID-19
vaccine, it is recommended where possible that vaccine and study intervention be administered on
different days, separated by as large an interval as is practical within the protocol.
6.8.5. 
Prohibited Therapies
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:
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 
Systemic immunosuppressives or DMARDs (other than MTX, SSZ, HCQ, CQ, and
leflunomide)including azathioprine, oral cyclosporine A, tacrolimus, mycophenolate mofetil,
oral or parenteral gold
 
Anti-TNF therapy such as: infliximab, golimumab, etanercept, adalimumab, certolizumab,
and biosimilars to those anti-TNFs
 
Anti-IL-6 receptor mAb (eg, tocilizumab or sarilumab)
 
IL-1 inhibitors (eg, anakinra)
 
B-cell depleting biologic therapy (eg, rituximab)
 
Co-stimulatory inhibitors (eg, abatacept)
 
JAKi (eg, tofacitinib, baricitinib, upadacitinib)
 
Cytotoxic drugs such as cyclophosphamide, chlorambucil, nitrogen mustard, or other
alkylating agents
 
Any other targeted biologic therapy
 
Any investigational intervention or use of an invasive investigational medical device
 
Live vaccinations
 
The use of complementary therapies (eg, herbs, ointments, traditional Chinese medicine,
acupuncture) that have the potential to activate or inhibit the immune system is prohibited (see
Section 5.2). In addition, use of complementary therapies that have the potential to interact
with antithrombotic agents is prohibited in those taking antithrombotic agents.
As these lists cannot be exhaustive, please consult the medical monitor to discuss prior to starting
any biologic or other advanced therapies.
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.
 
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 moderate or severe opportunistic infection.
 
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]).
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 
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 investigator believes that, for safety or tolerability reasons (eg, AE), it is in the best
interest of the participant to discontinue study intervention.
 
 
The participant initiates a prohibited therapy as described in Section 6.8.5.
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, they may continue in the study. Participants who permanently discontinue study
intervention but do not withdraw from study participation should be followed at all subsequent
study visits through Week 12. Study intervention assigned to the participant who discontinued
study intervention may not be assigned to another participant.
If the participant wishes to discontinue the study, then the Final Efficacy and Safety Follow-up
Visit assessments should be obtained as specified in the SoA (Section 1.3).
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 Section 10.6 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 cause of death is assessed by the investigator to be
related to study intervention and the DMC and sponsor believe that participants would
incur undue risk by continuing the study
 Three or more participants report serious infections assessed by the investigator to be
related to study intervention and the DMC and sponsor believe that participants would
incur undue risk by continuing the study.
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
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 
Death
When a participant withdraws before study  completion, the reason for withdrawal is to be
documented in the eCRF and in the source document. If the reason for withdrawal from the study
is withdrawal ofconsent, 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 as local regulations permit.
Prior to a participant withdrawing consent for follow-up, the investigator must offer the participant
an opportunity for one of the alternative reduced follow-up mechanisms described below.
Participants will not be allowed to continue to receive study intervention if reduced follow-up is
in place, but other study evaluations should continue as much as possible. 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:
 
participant
 
relatives of the participant
 
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
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destruction process, the investigator must notify the sponsor study site contact of withdrawal
of consent for the optional research samples and to request sample destruction. The sponsor
study site contact will, in turn, contact the biomarker representative to execute sample
destruction. If requested, the investigator will receive written confirmation from the sponsor
that the sample 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 Section 10.3.5). 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
site.
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8. 
STUDY ASSESSMENTS AND PROCEDURES
Overview
The SoA (Section 1.3) summarizes the frequency and timing of efficacy, PK, immunogenicity,
PD, biomarker, pharmacogenomic, and safety measurements applicable to this study.
All visit-specific PRO assessments must be conducted/completed before any tests, procedures, or
other consultations to prevent influencing participant responses. When multiple assessments are
scheduled for the same timepoint, it is recommended that PROs be completed in the following
sequence: Patient’s Global Assessment (PtGA) of Disease Activity, Pain visual analog scale
(VAS), Functional Assessment of Chronic Illness Therapy –Fatigue (FACIT-Fatigue)assessment,
Joint Pain Severity Numeric Rating Scale (NRS), Health Assessment Questionnaire –Disability
Index (HAQ-DI), and 36-item Short Form Health Survey (SF-36).
It is recommended that clinician-reported outcome (ClinRO) assessments be performed in the
following sequence: joint assessment, duration of morning stiffness, and Physician’s Global
Assessment (PGA) of Disease Activity. ClinRO  assessments should be performed by an
adequately trained assessor (see Section 8.1 for details).
Additional urine pregnancy tests may be performed (as determined necessary by the investigator
or required by local regulation) to establish the absence of pregnancy at any time during the
participation in the study.
Screening Phase
The screening phase is up to 6 weeks duration before randomization. After written informed
consent 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. Participants who meet all of the inclusion and none of the
exclusion criteria can be enrolled in the study. Every effort should be made to adhere to the SoA
(Section 1.3) for each participant. The collection of AEs will start at the time informed consent is
obtained.
Women of childbearing potential must have a negative urine pregnancy test result at screening and
at each visit and before any study intervention administration. Participants must be reminded that
they are required to use a highly effective method of contraception during the study and must
continue taking such precautions for 30 days after receiving the last dose of study intervention (as
described in Section  5.1 and Section  10.5). The method(s) of contraception used by each
participant must be documented.
All screening evaluations establishing participant eligibility will be performed and reviewed by
the investigator before a participant can be randomized. Participants must have received approval
for study randomization following assessment of inclusion and exclusion criteria.
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Blood Sample Collection
The total blood volume to be collected from each participant over 12 weeks will be approximately
300 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 eCRF or laboratory
requisition form.
Refer to the SoA for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the
Laboratory Manual that will be provided. Collection, handling, storage, and shipment of samples
must be under the specified, and where applicable, controlled temperature conditions as indicated
in the Laboratory Manual.
Study-Specific Materials
The investigator will be provided with the following supplies:
 
Investigator Site File (includes protocol and nipocalimab IB)
 
Study SIPPM and IPPI
 
Sample ICFs
 
Laboratory Manual(s) and laboratory kits
 
IWRS Manual
 
eCRF completion instructions
 
Electronic ClinRO and/or PRO equipment (tablet device questionnaires, completion
instructions)
 
Actigraphy device and instruction for use
 
Patient recruitment materials
 
Procedural Manual for major adverse cardiovascular events (MACE)Adjudication
8.1. 
Efficacy Assessments
Patient-reported outcomes and investigator assessments of efficacy are included in this section.
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.
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 
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 one another.
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. 
Functional Assessment of Chronic Illness Therapy-Fatigue
The FACIT-Fatigue assessment (version 4.0) is a 13-item questionnaire formatted for participant
self-administration that assesses patient-reported fatigue and its impact upon daily activities and
function over the past 7 days. Participants will be asked to answer each question using a 5-point
Likert-type scale (0=Not at all; 1=A little bit; 2=Somewhat; 3=Quite a bit; and 4=Very Much).
The interpretation of FACIT-Fatigue score is such that a higher score indicates less fatigue, with
a range of possible scores of 0-52, with 0 being the worst possible score and 52 the best. The
FACIT-Fatigue can generally be completed in 5 minutes (Cella 2002; Yellen 1997).
FACIT-Fatigue has been used in clinical trials of participants with RA and has demonstrated
sensitivity to change in these participants (Smolen 2008; Yount 2007).
8.1.1.4. 
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).
8.1.1.5. 
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,
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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).
8.1.1.6. 
36-item Short Form Health Survey (Standard)
The SF-36 version 2 Standard health survey is a self-administered, 36-item questionnaire
measuring health-related quality of life, with a recall period of the past 4 weeks. It includes
8 domains that measure physical functioning, role limitations due to physical health problems,
bodily pain, general health, vitality, social functioning, role limitations due to emotional problems
and mental health. The 8 domains can be aggregated into 2 summary scales that reflect physical
and mental health: a physical component scale (PCS) and a mental component score (MCS).
Responses to all items are rated on a 3-, 5- or 6-point Likert scale. The SF-36 version 2 Standard
survey can generally be completed in 5 to 10 minutes (Quality Metric 2011).
8.1.1.7. 
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 “non-evaluable” 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).
8.1.1.8. 
Duration of Morning Stiffness
The average duration of morning stiffness during the previous week in minutes will be assessed.
If a participant has stiffness that lasts the entire day, this should be recorded as 1440 minutes of
morning stiffness.
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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 combining tender 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:
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 Disease Activity Index Score 28 using erythrocyte sedimentation rate (DAS28-ESR) is a
statistically derived index combining tender joints (28 joints), swollen joints (28 joints),
erythrocyte sedimentation rate (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
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8.1.2.1.3. 
DAS28 Response
DAS28 response is defined in Table 3 (van Riel 2000).
Table 3: 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
8.1.2.1.4. 
DAS28 Low Disease Activity
DAS28 LDA is defined as a DAS28 value of ≥2.6 and ≤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 Clinical Disease Activity Index (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).
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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.
8.1.2.4. 
Simplified Disease Activity Index Score
The Simplified Disease Activity Index (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
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 
CRP ≤1 mg/dL
 
PtGA of Disease Activity on VAS ≤1 (on a 0 to 10 scale)
8.2. 
Safety Assessments
Details regarding the DMC are provided in Section 10.3.6.
Adverse events will be reported and followed by the investigator as specified in Section 8.3 and
Section 10.4.
Any clinically relevant changes occurring during the study must be recorded on the Adverse Event
section of the eCRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will be
followed by the investigator until resolution or until a clinically stable condition is reached.
The study will include the following evaluations of safety and tolerability according to the time
points provided in the SoA (Section 1.3).
8.2.1. 
Physical Examinations
Physical examinations will be performed by the investigator or designated physician, nurse
practitioner or physician assistant as specified in the SoA (Section 1.3). Any new, clinically
significant finding (in the opinion of the investigator) must be captured as an AE. In addition,
resolution of any abnormal findings during the study will be noted in the source document and in
the eCRF.
The full physical examination will be performed including: the head and neck, chest, abdomen,
and extremities, as well as including examinations based on the individual’s medical history and
manifestations of RA.
The targeted physical examination (performed at visits not specified for full physical exams) based
on a participant’s RA history and manifestations should also include evaluation of signs or
symptoms of infection.
Specific assessment of RA-related signs and symptoms will be performed by a clinical assessor as
described in Section 8.1 and at timepoints specified in the SoA (Section 1.3).
Assessment of the participants for safety may require some physical examination by an
investigator.
Height and Weight
Height and weight will be measured as specified in the SoA (Section 1.3). Participants will be
instructed to remove shoes and outdoor apparel and gear prior to this measurement.
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8.2.2. 
Vital Signs
Temperature, pulse/heart rate, respiratory rate, and blood pressure (BP) will be assessed at each
visit.
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.
If feasible, BP 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).
At a study intervention administration visit, vital signs should be obtained before and 30 minutes
after completion of the IV infusions, or if the participant reports any symptoms.
8.2.3. 
Electrocardiograms
A 12-lead electrocardiogram (ECG) will be performed at screening. Subsequent ECGs can be
performed locally based on 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, hematology, coagulation, serology, lipid panel, and other
safety laboratory assessments will be collected as noted in Section 1.3. The investigator must
review the laboratory results, document this review, and record any clinically relevant changes
occurring during the study in the AE section of the eCRF. The laboratory reports must be filed
with the source documents.
The following tests will be performed by the central laboratory unless otherwise specified or
approved by the medical monitor or designee:
 
Hematology assessments
 
Blood chemistry assessments
 
Urine assessments
 
Coagulation assessment
 
Serology assessments
 
Lipid panel assessments
A medical monitor or designee and the clinical site will be notified if pre-specified abnormal
laboratory values defined in the Laboratory Manual are identified in any participant during the
conduct of the study.
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8.2.5. 
Pregnancy Testing
Urine pregnancy testing will be done for women of childbearing potential only (performed
locally), see definition in Section 10.5. Additional urine pregnancy tests may be performed, if
applicable, 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 medications 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 for 1 hour postinfusion after the first 3 infusions; if no clinically relevant AEs related to the
infusion are observed with these first 3 infusions, participants will be observed for 30 minutes after
subsequent infusions.
8.2.8. 
Infusion Reactions
An infusion reaction is defined as any AE that is reported by investigator to represent an infusion
reaction.
Minor infusion-related AEs may be managed by slowing the rate of the IV infusion and/or treating
with antihistamines and/or acetaminophen (paracetamol) as clinically indicated. If an IV infusion
of study intervention is 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. 
Hypersensitivity Reactions
Before any administration of study intervention at the study site, 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 reaction (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 a 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.
8.2.10. 
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 infection. Study intervention must be discontinued if a participant
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develops any serious infection (ie, that meets criteria for a serious AE), or develops a moderate or
severe opportunistic infection or develops an infection that is unresponsive or worsening while on
anti-infective therapy (Section 7.1).
8.2.11. 
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 investigators initiate
appropriate therapy or modify current therapy for dyslipidemia per local health guidelines.
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting
Timely, accurate, and complete reporting and analysis of safety information, including AEs, SAEs,
and Product Quality Complaints (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 Section 10.4.
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 nonserious, 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.
All AEs with an onset date after the signing of the ICF and up to 30 days 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 within 24 hours of their knowledge of the
event.
Serious adverse events, including those spontaneously reported to the investigator within by the
final safety visit after the last dose of study intervention, must be reported. The sponsor will
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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 30 days after study treatment discontinuation
must be reported 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×ULN, alkaline
phosphatase <2×ULN together with total bilirubin ≥2×ULN or International Normalized Ratio
(INR) >1.5 (if measured). Any possible Hy’s Law case is considered an important medical event
and should be reported to the sponsor within 24 hours, 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 eCRF, which must be completed and signed by a physician
from the study site and transmitted to the sponsor immediately, but no later than within 24 hours.
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 Event Adjudication
Committee (EAC). For such events, Investigators will be asked to provide 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 AEs or SAEs. Open-ended and nonleading
verbal questioning of the participant is the preferred method to inquire about AE occurrence.
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events
The investigator is obligated to perform or arrange for the conduct of supplemental measurements
and evaluations as medically indicated to elucidate the nature and causality of the AE, SAE, or
PQC as fully as possible. This may include additional laboratory tests or investigations,
histopathological examinations, or consultation with other health care professionals.
Adverse events and the special reporting situation of pregnancy, will be followed by the
investigator as specified in Section 10.4.
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events and
Anticipated Events
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities.
The sponsor will also report to the investigator (and the head of the investigational institute where
required) all SUSARs. The investigator (or sponsor where required) must report SUSARs to the
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appropriate IEC/IRB that approved the protocol unless otherwise required and documented by the
IEC/IRB. A SUSAR will be reported to regulatory authorities unblinded. Participating
investigators and IEC/IRB will receive a blinded SUSAR summary, unless otherwise specified.
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 an anticipated event: worsening of RA.
This anticipated event will be periodically analyzed by the sponsor during study conduct. The
sponsor will prepare a safety report in narrative format if the analysis indicates that the anticipated
event occurs more frequently in the intervention group than in the control group, 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 event 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 event
according to the requirements of the countries 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 an SAE reporting form. Any participant who becomes
pregnant during the study must discontinue further study intervention.
Follow-up information regarding the outcome of the pregnancy for female participants who
become pregnant, or where the pregnancy was the result of a male participant and his partner, and
any postnatal sequelae in the infant will be required (see Section 10.5and Section 10.4).
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. 
These AEs occurring after the first administration(s) of study intervention in participants in this
clinical study must be reported by the investigator to the sponsor or designee within 24 hours after
being made aware of the event, according to the procedures in Section 10.4. These events are to
be considered serious only if they meet the definition of an SAE.
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Observation Time After Each Infusion
Participants will be observed for safety 1-hour postinfusion  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 samples will be used to evaluate the PK ofnipocalimabas 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 nipocalimabconcentrations 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 split into 3 aliquots (1 aliquot for serum
nipocalimab concentration, 1 aliquot for antibodies to study intervention, and 1 aliquot as a
backup). Samples must be collected before study intervention administration at visits when a study
intervention administration is scheduled. At Week 0, Week 2, and Week 8, a blood sample before
study intervention administration and another blood sample 45 minutes after the end of infusion
will be collected. The sample should be drawn from the opposite arm than the IV line.
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 will be analyzed to determine serum nipocalimab concentrations using a validated,
specific, and sensitive immunoassay method by the sponsor’s bioanalytical facility 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.
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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 will be derived using
population PK modeling. Baseline covariates (eg, body weight, age, sex, creatinine clearance,
race) may be included in the model, if relevant.
8.5. 
Genetics and Pharmacogenomics
Participation in pharmacogenomic research is optional. A pharmacogenomic blood sample may
be collected from participants who consent separately to this component of the study to allow for
pharmacogenomic research, where local regulations permit.
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.
The optional pharmacogenomic samples may be analyzed for identification of genetic and
epigenetic factors that may be associated with the disease and/or the response to the 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.
8.6. 
Biomarkers
Biomarker assessments will be made to examine the biologic response to treatment and to identify
biomarkers that are relevant to nipocalimab treatment and/or RA, where local regulations permit.
Assessments (detailed below) will include the evaluation of relevant biomarkers in serum, plasma,
whole blood, 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 nipocalimab.
2. To understand RA pathogenesis.
3. To understand why individual participants may respond differently to nipocalimab.
4. To understand the impact of treatment with nipocalimab on RA or systemic inflammation.
5. To develop diagnostic tests to identify RA populations that may be responsive or
nonresponsive to treatment with nipocalimab.
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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
Samples for the analysis of PD biomarkers will be collected from all participants, where local
regulations permit. Serum concentrations of total IgG, IgG1, IgG2, IgG3, IgG4, albumin, ACPA,
RF, and CICs will be measured to assess the PD effect of nipocalimab.
8.6.2. 
Serum and PlasmaBiomarkers
Blood samples for serum and plasma biomarker analyses will be collected from all participants.
Serum and plasma will be analyzed for levels of specific proteins, and other inflammation-related
molecules and/or disease-associated serologies relevant to RA and treatment and response to
nipocalimab.
8.6.3. 
Whole Blood Gene Expression Profile
8.6.4. 
Peripheral Blood Mononuclear Cells
8.6.5. 
Exploratory Biomarkers
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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 nipocalimaband the titer of confirmed
positive samples will be reported. Other analyses may be performed to verify the stability of
antibodies to nipocalimaband/or further characterize the immunogenicity of nipocalimab(such as
for the incidence of NAbs).
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
detection of antibodies to nipocalimabwill also be evaluated for serum nipocalimabconcentrations
to enable interpretation of the antibody data. Antibodies may be further characterized and/or
evaluated for their ability to neutralize the activity of the study intervention(s). Samples may be
stored up to 1 month after approval of the final Clinical Study Report (CSR) (or according to local
regulations) following the last participant’s last visit for the study at a facility selected by the
sponsor to enable further analysis of immune responses to nipocalimab.
8.8. 
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics parameters are not evaluated in this study.
9. 
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general
description of the statistical methods to be used to analyze the efficacy and safety data is outlined
below. Specific details will be provided in the Statistical Analysis Plan (SAP).
9.1. 
Statistical Hypotheses
Treatment with nipocalimab 15 mg/kg q2w is superior to placebo in participants with moderate to
severe active RA as measured by the mean change from baseline in DAS28-CRP at Week 12.
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9.2. 
Sample Size Determination
Table 4: 
Statistical Power for Treatment Difference in Change from Baseline in DAS28-CRP at
Week 12
9.3. 
Populations for Analysis Sets
9.4. 
Statistical Analyses
The SAP 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
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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, such as mean, standard deviation, median, interquartile range,
minimum, and maximum for continuous variables, and counts and percentages for discrete
variables will be used to summarize most data.
For binary response efficacy endpoints, treatment comparisons will generally be performed using
a Chi-square test or a Cochran-Mantel-Haenszel test. For continuous efficacy endpoints, treatment
comparisons will be performed using an analysis of covariance, a Mixed-Effect Model Repeated
Measure (MMRM) model, or a constrained longitudinal data analysis model.
In general, all statistical tests will be performed using a 2-sided test at a significance level of 5%.
No multiplicity adjustment will be made for secondary endpoints; nominal p-values will be
reported.
9.4.2. 
Primary Endpoint
Definition of the Primary Endpoint
The primary endpoint is the mean change from baseline in DAS28-CRP compared with placebo
at Week 12.
Primary Estimand
The primary endpoint will be analyzed based on the composite estimand defined by the following
5components:
 
Population:
Participants between the ages of 18 and 75, inclusive, with moderate to severe active RA
despite standard therapy, including anti-TNF agents.
 
Treatment:
 
Control: Placebo IV q2w
 
Nipocalimab (experimental treatment/intervention) 15 mg/kg IV q2w
 
Variable:
Change from baseline in DAS28-CRP at Week 12. A participant who initiates or adjusts
medication or discontinues or experiences an intercurrent event (ICE) in categories 1, 2, or 3
(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. For a participant who experiences an ICE in category 4 (defined
below), the observed change from baseline in the DAS28-CRP score will not be used and will
be assumed to follow a Missing-at-Random (MAR) assumption.
 
Intercurrent Events and Corresponding Strategies:
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1. Initiated protocol-prohibited medications/therapies for RA
2. Initiation or increased the dose of csDMARDs (such as MTX, SSZ, HCQ, CQ or
leflunomide) or oral corticosteroid therapy above the baseline dose for RA
3. Discontinued study intervention infusion due to any reason, including COVID-19
infection but excluding other COVID-19 reasons
4. Treatment discontinuation due to study conduct affected by other COVID-19 reasons
such as site closure/restricted access
ICEs in categories 1, 2, and 3 will be considered treatment failures and will be handled with
the composite strategy to be include in the variable. ICE category 4 will be handled with the
hypothetical strategy as if the ICE would not have occurred. For participants experiencing
multiple ICEs, an ICE in category 1, 2, or 3 will supersede an ICE in category 4. For
participants experiencing multiple ICEs, an ICE in category 1 will supersede an ICE in
category 4.
 
Population-level summary:
Difference in mean between the nipocalimab group and the placebo group.
Primary Efficacy Analysis
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. Missing data will be assumed
as MAR. A MMRM model will be used to test the difference between the nipocalimab group and
the placebo group at Week 12. The explanatory variables of the MMRM model will include
treatment group, and interaction terms of visit with treatment group, baseline score and
randomization stratification factors. An unstructured covariance matrix for repeated measure
within a participant will be used. Other structured covariances matrix will be defined in the SAP
in case of lack of convergence. The Least Square Mean difference and 95% confidence intervals
between each nipocalimab group versus the placebo group will be provided.
The comparison between the nipocalimab and placebo group for the primary endpoint will be
tested at a 2-sided α level of 0.05.
To evaluate the robustness of the primary endpoint analysis, sensitivity/supplementary analyses
will be conducted. Details will be specified in SAP.
Subgroup analysis will be performed to evaluate consistency in the primary efficacy endpoint by
demographic characteristics, baseline disease characteristics, and prior and baseline medications.
Interaction test between the subgroups and treatment group will also be provided if appropriate.
9.4.3. 
Secondary Endpoints
The secondary endpoints are listed in Section 3.
Data from all participants in the FAS will be analyzed according to randomized treatment group
regardless of the treatment received.
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Details of the analysis of the secondary endpoints will be included in SAP.
9.4.4. 
Other Secondary Endpoints
9.4.4.1. 
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 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. 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.
9.4.4.2. 
Immunogenicity Analyses
The incidence and titers of antibodies to nipocalimab will be summarized for all 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 nipocalimabwill be summarized for participants who are positive
for antibodies to nipocalimab.
Other immunogenicity analyses may be performed to further characterize the immune responses
that are generated.
9.4.5. 
Safety Analyses
All safety analyses will be made on the Safety Analysis Set population (Section 9.3). Participants
will be summarized by the treatment they actually received.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the
Medical Dictionary for Regulatory Activities. Any AE occurring at or after the initial
administration of study intervention  through the safety follow-up visit is considered to be
treatment-emergent. All reported TEAEs will be included in the analysis. For each AE, the
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percentage of participants who experience at least 1 occurrence of the given event will be
summarized by intervention group. In addition, comparison between intervention groups will be
provided if appropriate.
The following analyses will also be used to assess the safety of participants in the study:
 
Proportion of participants with treatment-emergent AEs
 
Proportion of participants with treatment-emergent SAEs
 
Proportion of participants with treatment-emergent AEs leading to discontinuation of study
intervention
 
Proportion of participants with treatment-emergent AESIs
 
Laboratory parameters and change from baseline in laboratory parameters over time
 
Vital sign parameters and change from baseline in vital sign parameters over time
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those
participants who die, who discontinue intervention due to an AE, or who experience a severe or
an SAE. Listings of all participants with MACE (nonfatal MI, stroke, and cardiovascular death)
will be provided.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Descriptive statistics will be
calculated for selected laboratory analytes at baseline and for changes over time.
Vital Signs
Vital signs including temperature, pulse/heart rate, respiratory rate, and BP (systolic and diastolic)
will be summarized over time, using descriptive statistics. The percentage of participants with
values beyond clinically important limits will be summarized.
9.4.6. 
Exploratory Endpoints
All exploratory endpoints are listed in Section 3.
9.4.7. 
Other Analyses
Biomarkers Analyses
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9.5. 
Interim Analysis
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Abbreviations
ACPA  
anti-citrullinated protein antibodies
ACR  
American College of Rheumatology
ADA  
anti-drug antibody
AE 
adverse event
AESI 
adverse event of special interest
ALP  
alkaline phosphatase
ALT  
alanine aminotransferase
AST  
aspartate aminotransferase
β-hCG  
β-human chorionic gonadotropin
BP 
blood pressure
CDAI 
Clinical Disease Activity Index
CIC  
circulating immune complex
ClinRO  
clinician-reported outcome
COVID-19 
Coronavirus (Disease) 2019
CPK  
creatine phosphokinase
CQ  
chloroquine
CRP  
C-reactive protein
csDMARD  
conventional synthetic disease-modifying anti-rheumatic 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
DMARD  
disease-modifying anti-rheumatic drug
DMC  
Data Monitoring Committee
DNA  
deoxyribonucleic acid
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
FACIT-Fatigue 
Functional Assessment of Chronic Illness Therapy –Fatigue Scale
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
HBV  
hepatitis B virus
HCQ  
hydroxychloroquine
HCV  
hepatitis C virus
HDL 
high-density lipoprotein
HRT  
hormone replacement therapy
IA  
interim analysis
IAC  
Interim Analysis Committee
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
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Ig 
immunoglobulin
IL 
interleukin
IM  
intramuscular
IMP  
Investigational Medicinal Product
INR  
International Normalized Ratio
IPPI 
Investigational Product Preparation and Administration Instructions
IR  
inadequate response
IRB  
Institutional Review Board
IV  
intravenous(ly)
IWRS  
interactive web response system
JAKi 
janus kinase inhibitors
LDA  
low disease activity
LDL 
low-density lipoprotein
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
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
NSAID  
nonsteroidal anti-inflammatory drug
PCC  
protocol clarification communication
PCS  
physical component score
PD 
pharmacodynamic(s)
PEF  
peak expiratory flow
PGA  
Physician’s Global Assessment (of Disease Activity)
PIP  
proximal interphalangeal
PK 
pharmacokinetic(s)
PO 
oral (by mouth)
PQC  
Product Quality Complaint
PRO  
patient-reported outcome
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(ly)
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-of-care
SSZ 
sulfasalazine
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SUSAR  
suspected unexpected serious adverse reaction
TEAE 
treatment-emergent adverse event
TNF  
tumor necrosis factor
ULN  
upper limit of normal
VAS  
visual analog scale
wAIHA  
warm autoimmune hemolytic anemia
WBC  
white blood cell
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10.2. Appendix 2: Clinical Laboratory Tests
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10.3. Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
10.3.1. 
Regulatory and Ethical Considerations
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the
protocol, current International Council for Harmonisation (ICH) guidelines on Good Clinical
Practice (GCP), and applicable regulatory and country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing,
conducting, recording, and reporting studies that involve the participation of human participants.
Compliance with this standard provides public assurance that the rights, safety, and well-being of
study participants are protected, consistent with the principles that originated in the Declaration of
Helsinki, and that the study data are credible.
Protocol 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 protocol clarification
communication (PCC) may be prepared. The PCC Document will be communicated to the
Investigational Site, Site Monitors, Local Trial Managers (LTMs), Clinical Trial Managers
(CTMs), and/or Contract Research Organizations (CROs) who will ensure that the PCC
explanations are followed by the investigators.
The PCC Document may be shared by the sites with Independent Ethics Committees/Institutional
Review Boards (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 nonacceptance, except when
necessary to eliminate immediate hazards to the participants, in which case the amendment must
be promptly submitted to the IEC/IRB and relevant competent authority. Documentation of
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the
change(s) involve only logistic or administrative aspects of the study, the IEC/IRB (where
required) only needs to be notified.
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
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on an appropriate course of action. The data recorded in the eCRF and source documents will
reflect any departure from the protocol, and the source documents will describe this departure and
the circumstances requiring it.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities
in each respective country, if applicable. A study may not be initiated until all local regulatory
requirements are met.
Required Pre-study 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
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 
Local laboratory documentation demonstrating competence and test reliability
(eg, accreditation/license), if applicable
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB
with current and complete copies of the following documents (as required by local regulations):
 
Final protocol and, if applicable, amendments
 
Sponsor-approved ICF (and any other written materials to be provided to the participants)
 
IB (or equivalent information) and amendments/addenda
 
Sponsor-approved participant recruiting materials
 
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
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 
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at
least annually)
 
Reports of AEs that are serious, unlisted/unexpected, and associated with the study
intervention
 
New information that may adversely affect the safety of the participants or the conduct of the
study
 
Deviations from or changes to the protocol to eliminate immediate hazards to the participants
 
Report of deaths of participants under the investigator's care
 
Notification if a new investigator is responsible for the study at the site
 
Development Safety Update Report and Line Listings, where applicable
 
Any other requirements of the IEC/IRB
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.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise help
ensure access to the developed product if the need for the product persists, unless explicitly
addressed as a specific ethical consideration in Section 4.2.5, Study-Specific Ethical Design
Considerations.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.5.
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 Pre-study Documentation (above) for details on financial disclosure.
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10.3.3. 
Informed Consent Process
Each participant (or a legally acceptable representative) 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.
Before enrollment in the study, the investigator or an authorized member of the study site personnel
must explain to potential participants or their legally acceptable representatives the aims, methods,
reasonably anticipated benefits, and potential hazards of the study, and any discomfort
participation in the study may entail. Participants will be informed that their participation is
voluntary and that they may withdraw consent to participate at any time. They will be informed
that choosing not to participate will not affect the care the participant will receive. Finally, they
will be told that the investigator will maintain a participant identification register for the purposes
of long-term follow-up if needed and that their records may be accessed by health authorities and
authorized sponsor personnel without violating the confidentiality of the participant, to the extent
permitted by the applicable law(s) or regulations. By signing the ICF the participant or legally
acceptable representative is authorizing such access, which includes permission to obtain
information about his or her survival status. It also denotes that the participant agrees to allow his
or her study physician to recontact the participant for the purpose of obtaining consent for
additional safety evaluations, and subsequent disease-related treatments, if needed.
The participant or legally acceptable representative will be given sufficient time to read the ICF
and the opportunity to ask questions. After this explanation and before entry into the study, consent
must be appropriately recorded by means of either the participant's or his or her legally acceptable
representative's personally dated signature. After having obtained the consent, a copy of the ICF
must be given to the participant.
Participants who are rescreened are required to sign a new ICF.
Participants will be asked for consent to provide optional samples for research where local
regulations permit. After informed consent for the study is appropriately obtained, the participant
or his or her legally acceptable representative will be asked to sign and personally date a separate
ICF indicating agreement to participate in the optional research component. Refusal to participate
in the optional research will not result in ineligibility for the study. A copy of this signed ICF will
be given to the participant.
Where local regulations require, a separate ICF will be used for the required DNA component of
the study.
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10.3.4. 
Data Protection
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality
and compliance with applicable data privacy protection laws and regulations. Appropriate
technical and organizational measures to protect the personal data against unauthorized disclosures
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place.
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity
of participants confidential.
The informed consent obtained from the participant (or his or her legally acceptable representative)
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.
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 DNA, PD, biomarker, PK, and immunogenicity] research is not conducted under
standards appropriate for the return of data to participants. In addition, the sponsor cannot make
decisions as to the significance of any findings resulting from exploratory research. Therefore,
exploratory research data will not be returned to participants or investigators, unless required by
law or local regulations. Privacy and confidentiality of data generated in the future on stored
samples will be protected by the same standards applicable to all other clinical data.
10.3.5. 
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local regulations)
for additional research. Samples will only be used to understand nipocalimab to understand RA,
to understand differential intervention responders, and to develop tests/assays related to
nipocalimaband RA. The research may begin at any time during the study or the poststudy 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).
10.3.6. 
Committees Structure
Interim Analysis Committee
An internal unblinded IAC will be established to review IA data, as specified in Section 9.5. This
committee will consist of physicians, statisticians, clinical pharmacologists, and
pharmacometricians unaffiliated with the study; committee membership responsibilities,
authorities, and procedures will be documented in its charter.
Further details of the interim analysis will be provided in the IAC SAP/Charter.
Data Monitoring Committee
An external DMC will be established to monitor data on an ongoing basis. This committee will
consist of at least 2 medical experts in the relevant therapeutic area and at least 1 statistician;
committee membership responsibilities, authorities, and procedures will be documented in the
combined DMC charter. The committee will meet periodically to review interim data through the
Week 18 DBL. For the scheduled safety reviews, the DMC will make a recommendation to the
sponsor whether the study should continue, be modified, or stopped for safety concerns.
Further details of the safety reviews will be provided in the DMC SAP/Charter.
10.3.7. 
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 biomarker research data, generated as a
result of this study, are considered confidential and remain the sole property of the sponsor. The
investigator agrees to maintain this information in confidence and use this information only to
accomplish this study and will not use it for other purposes without the sponsor's prior written
consent.
The investigator understands that the information developed in the study will be used by the
sponsor in connection with the continued development 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 CSR generated by the sponsor and will contain data
from all study sites that participated in the study 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 biomarker analyses
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performed after the CSR has been issued will be reported in a separate report and will not require
a revision of the CSR.
Study participant identifiers will not be used in publication of results. Any work created in
connection with performance of the study and contained in the data that can benefit from copyright
protection (except any publication by the investigator as provided for below) shall be the property
of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary (multicenter)
data and information without approval from the investigator. The investigator has the right to
publish study site-specific data after the primary data are published. If an investigator wishes to
publish information from the study, a copy of the manuscript must be provided to the sponsor for
review at least 60 days before submission for publication or presentation. Expedited reviews will
be arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in
writing, the investigator will withhold such publication for up to an additional 60 days to allow for
filing of a patent application. In the event that issues arise regarding scientific integrity or
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will
not mandate modifications to scientific content and does not have the right to suppress information.
For multicenter study designs and substudy approaches, secondary results generally should not be
published before the primary endpoints of a study have been published. Similarly, investigators
will recognize the integrity of a multicenter study by not submitting for publication data derived
from the individual study site until the combined results from the completed study have been
submitted for publication, within 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 interim results of clinical studies as required by law. The
disclosure of the study results will be performed after the end of the study to ensure the statistical
analyses are relevant.
10.3.8. 
Data Quality Assurance
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified
investigators and appropriate study sites, review of protocol procedures with the investigator and
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study site personnel before the study, periodic monitoring visits by the sponsor, and direct
transmission of clinical laboratory data from a central laboratory into the sponsor's database.
Written instructions will be provided for collection, handling, storage, and shipment of samples.
Guidelines for eCRF completion will be provided and reviewed with study site personnel before
the start of the study. The sponsor may review the eCRF for accuracy and completeness during
on-site monitoring visits and after transmission to the sponsor; any discrepancies will be resolved
with the investigator or designee, as appropriate. After upload of the data into the study database
they will be verified for accuracy and consistency with the data sources.
10.3.9. 
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each participant in electronic
format. All data relating to the study must be recorded in the eCRF. All eCRF entries, corrections,
and alterations must be made by the investigator or authorized study site personnel. The
investigator must verify that all data entries in the eCRF are accurate and correct.
The study data will be transcribed by study site personnel from the source documents onto an
eCRF, if applicable. Study-specific data will be transmitted in a secure manner to the sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any
such worksheets will become part of the participant's source documents. Data must be entered into
the eCRF in English. The eCRF 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 electronic data capture (eDC) tool. If corrections to
a eCRF are needed after the initial entry into the eCRF, this can be done in either of the following
ways:
 
Investigator and study site personnel can make corrections in the eDC tool at their own
initiative or as a response to an auto query (generated by the eDC tool).
 
Sponsor or sponsor delegate can generate a query for resolution by the investigator and study
site personnel.
10.3.10. 
Source Documents
At a minimum, source documents consistent in the type and level of detail with that commonly
recorded at the study site as a basis for standard medical care must be available for the following:
participant identification, eligibility, and study identification; study discussion and date of signed
informed consent; dates of visits; results of safety and efficacy parameters as required by the
protocol; record of all AEs and follow-up of AEs; concomitant medication; intervention
receipt/dispensing/return records; study intervention administration information; and date of study
completion and reason for early discontinuation of study intervention or withdrawal from the
study, if applicable.
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The author of an entry in the source documents must be identifiable. Given that PROs are reports
of a participant’s health condition that come directly from the participant, 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).
Information collected at unscheduled visits should be documented as described for scheduled
visits.
The minimum source documentation requirements for Section 5.1 and Section 5.2 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. These data are electronically extracted for
use by the sponsor. If eSource is utilized, references made to the eCRF in the protocol include the
eSource system but information collected through eSource may not be limited to that found in the
eCRF.
10.3.11. 
Monitoring
The sponsor will use a combination of monitoring techniques central, remote, or on-site monitoring
to monitor this study.
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will
record dates of the visits in a study site visit log that will be kept at the study site. The first
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits,
the monitor may  compare the data entered into the eCRF with the source documents
(eg, hospital/clinic/physician’s office medical records). The nature and location of all source
documents will be identified to ensure that all sources of original data required to complete the
eCRF are known to the sponsor and study site personnel and are accessible for verification by the
sponsor study site contact. If electronic records are maintained at the study site, the method of
verification must be discussed with the study site personnel.
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Direct access to source documents (medical records) must be allowed for the purpose of verifying
that the recorded data are consistent with the original source data. Findings from this review will
be discussed with the study site personnel. The sponsor expects that, during monitoring visits, the
relevant study site personnel will be available, the source documents will be accessible, and a
suitable environment will be provided for review of study-related documents. The monitor will
meet with the investigator on a regular basis during the study to provide feedback on the study
conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these
remote contacts, study site personnel will be available to provide an update on the progress of the
study at the site.
Central monitoring will take place for data identified by the sponsor as requiring central review.
10.3.12. 
On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at
any time during or after completion of the study to conduct an audit of the study in compliance
with regulatory guidelines and company policy. These audits will require access to all study
records, including source documents, for inspection. Participant privacy must, however, be
respected. The investigator and study site personnel are responsible for being present and available
for consultation during routinely scheduled study site audit visits conducted by the sponsor or its
designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part
of a national GCP compliance program or to review the results of this study in support of a
regulatory submission. The investigator must immediately notify the sponsor if he or she has been
contacted by a regulatory agency concerning an upcoming inspection.
10.3.13. 
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF
and all source documents that support the data collected from each participant, as well as all study
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical
Trial, and all study documents as specified by  the applicable regulatory requirement(s). The
investigator/institution will take measures to prevent accidental or premature destruction of these
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing
application in an ICH region and until there are no pending or contemplated marketing applications
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical
development of the investigational product. These documents will be retained for a longer period
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the
responsibility of the sponsor to inform the investigator/institution as to when these documents no
longer need to be retained.
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If the responsible investigator retires, relocates, or for other reasons withdraws from the
responsibility of keeping the study records, custody must be transferred to a person who will accept
the responsibility. The sponsor must be notified in writing of the name and address of the new
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any
documentation relating to this study, the investigator/institution must permit access to such reports.
10.3.14. 
Study and Site Start and Closure
First Act of Recruitment
The first participant 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
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 product (IMP or NIMP), whether or not related to that medicinal product (IMP or
NIMP). (Definition per ICH)
This includes any occurrence that is new in onset or aggravated in severity or frequency from the
baseline condition, or abnormal results of diagnostic procedures, including laboratory test
abnormalities.
Note: The sponsor collects AEs starting with the signing of the ICF (refer to All Adverse Events
under Section  8.3.1, Time Period and Frequency for Collecting Adverse Events and Serious
Adverse Events Information, for time of last AE recording).
Serious Adverse Event
An  SAE based on ICH and European Union Guidelines on Pharmacovigilance for Medicinal
Products for Human Use is any untoward medical occurrence that at any dose:
 
Results in death
 
Is life-threatening
(The participant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.)
 
Requires inpatient hospitalization or prolongation of existing hospitalization
 
Results in persistent or significant disability/incapacity
 
Is a congenital anomaly/birth defect
 
Is a suspected transmission of any infectious agent via a medicinal product
 
Is Medically Important*
*Medical and scientific judgment 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.
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If a serious and unexpected AE occurs for which there is evidence suggesting a causal relationship
between the study intervention and the event (eg, death from anaphylaxis), the event must be
reported as a serious and unexpected suspected adverse reaction even if it is a component of the
study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable product
reference safety information. For nipocalimab, the expectedness of an AE will be determined by
whether or not it is listed in the IB. For SOC background therapies with a marketing authorization,
the expectedness of an AE will be determined by whether or not it is listed in the package
insert/summary of product characteristics.
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.
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 intervention in an interventional studythat may require
expedited reporting or safety evaluation include, but are not limited to:
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 
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
Special reporting situations must be recorded in the eCRF. Any special reporting situation that
meets the criteria of an SAE must be recorded on the SAE page of the eCRF.
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 eCRF. Whenever possible,
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough,
runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory
infection"). Investigators must record in the eCRF their opinion concerning the relationship of the
AE to study therapy. All measures required for AE management must be recorded in the source
document and reported according to sponsor instructions.
For all studies with an outpatient phase, including open-label studies, the participant must be
provided with a "wallet (study) card" and instructed to carry this card with them for the duration
of the study indicating the following:
 
Study number
 
Statement, in the local language(s), that the participant is participating in a clinical study
 
Investigator's name and 24-hour contact telephone number
 
Local sponsor's name and 24-hour contact telephone number (for medical personnel only)
 
Site number
 
Participant number
 
Any other information that is required to do an emergency breaking of the blind
Serious Adverse Events
All SAEs that have not resolved by the end of the study, or that have not resolved upon  the
participant's discontinuation from the study, must be followed until any of the following occurs:
 
The event resolves
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 
The event stabilizes
 
The event returns to baseline, if a baseline value/status is available
 
The event can be attributed to agents other than the study intervention or to factors unrelated
to study conduct
 
It becomes unlikely that any additional information can be obtained (participant or health care
practitioner refusal to provide additional information, lost to follow-up after demonstration of
due diligence with follow-up efforts)
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during
participation in the study must be reported as an SAE, except hospitalizations for the following:
 
Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as pending
placement in long-term care facility).
 
Surgery or procedure planned before entry into the study (must be documented in the eCRF).
Note: Hospitalizations that were planned before the signing of the ICF, and where the
underlying condition for which the hospitalization was planned has not worsened, will not be
considered SAEs. Any AE that results in a prolongation of the originally planned
hospitalization is to be reported as a new SAE.
 
For convenience, the investigator may choose to hospitalize the participant for the duration of
the intervention period.
The cause of death of a participant in a study within 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, which
must be completed and signed by a physician from the study site, and transmitted in a secure
manner to the sponsor within 24 hours. The initial and follow-up reports of an SAE should be
made by facsimile (fax). Telephone reporting should be the exception and the reporter should be
asked to complete the appropriate form(s) first.
10.4.6. 
Product Quality Complaint Handling
Definition
A 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.
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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 safety issues, PQCs, or questions regarding the study are 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
Section 10.4.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless
permanently sterile (see below).
Woman Not of Childbearing Potential
 
premenarchal
A premenarchal state is one in which menarche has not yet occurred.
 
postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical
cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the
postmenopausal range may be used to confirm a postmenopausal state in women not using
hormonal contraception or hormone replacement therapy (HRT), however in the absence of
12 months 
of 
amenorrhea, 
a 
single 
FSH 
measurement 
is 
insufficient.
If there is a question about menopausal status in women on HRT, the woman will be required
to use one of the non-estrogen-containing hormonal highly effective contraceptive methods if
she wishes to continue HRT during the study.
 
permanently sterile (for the purpose of this study)
 
Permanent sterilization methods include hysterectomy, 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 woman
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually
active becomes active), a woman must begin a highly effective method of contraception, as
described throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
Contraceptive (birth control) use by men or women 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 STUDYINCLUDE:
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 ovulationb
 Intrauterine device
 Intrauterine hormone-releasing system
 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 woman of childbearing potential and the absence of sperm has been
confirmed. If not, additional highly effective method of contraception must be used.
Spermatogenesis cycle is approximately 74days.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used
consistently and correctly.
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with
inhibition of ovulationb
 oral
 intravaginal
 transdermal
 injectable
 Progestogen-only hormone contraception associated with inhibition of ovulationb
 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 spermicidec
 Cap, diaphragm, or sponge with spermicide
 A combination of male condom with either cap, diaphragm, or sponge with spermicide
(double-barrier methods)c
 Periodic abstinence (calendar, symptothermal, post-ovulation methods)
 Withdrawal (coitus-interruptus)
 Spermicides alone
 Lactational amenorrhea method
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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.
b)Hormonal contraception may be susceptible to interaction with the study intervention, which may
reduce the efficacy of the contraceptive method. In addition, consider if the hormonal contraception
may interact with the study intervention.
c)Male condom and female condom must not be used together (due to risk of failure with friction).
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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments
10.6.1. 
Stopping Algorithm
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10.6.2. 
Follow-up Assessments
10.6.2.1. 
Phase 2 Liver Chemistry Stopping Criteria and Follow-up
Assessments
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10.6.2.2. 
Phase 2 Liver Chemistry Increased Monitoring Criteria with
Continued Study Intervention
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10.8. Appendix 8: Guidance on Study Conduct During the COVID-19 Pandemic
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on
the conduct of this clinical study due to, for example, self-isolation 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
guidelines or 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 safety is considered to be at
unacceptable risk, study intervention will be discontinued, and study follow-up will be conducted.
If, as a result of the COVID-19 pandemic, 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.
The sponsor will continue to monitor the conduct and progress of the clinical study, and any
changes will be communicated to the sites and to the health authorities according to local guidance.
If a participant has tested positive for COVID-19, the investigator should contact the sponsor’s
medical officer or designee to discuss plans for 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 CSR.
ADDITIONAL ELEMENTS, WHERE APPLICABLE:
 
Certain protocol-mandated visits to the study site may not be possible during the COVID-19
outbreak. Therefore, temporary measures may be implemented if considered appropriate by
the sponsor and investigator to maintain continuity of patient care and study integrity. Certain
measures, such as those listed below, may be necessary and should be instituted in accordance
with applicable (including local) laws, regulations, guidelines, and procedures:
 
remote (eg, by phone / telemedicine) or in-person, off-site (eg, in-home) interactions
between site staff (or designees) and patients for study procedures (eg, those related to
safety monitoring / efficacy evaluation / study intervention storage and administration
[including training where pertinent])
 
procurement of study intervention by patients (or designee) or shipment of study
intervention from the study site directly to patients for at home administration
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 
laboratory assessments using a suitably accredited local laboratory; for selected measures
(eg, urine pregnancy), home testing may be employed
 
other procedures may be conducted at an appropriate facility
 
Missed assessments/visits will be captured in the clinical trial management system for
protocol deviations. Discontinuations of study interventions and withdrawal from the study
should be documented with the prefix “COVID-19-related” in the eCRF.
 
other relevant study data elements impacted by the pandemic should also be documented
/ labeled as “COVID-19-related” in eCRFs and / or other study systems, as directed by
detailed sponsor guidance. These may include missed / delayed / modified study visits /
assessments / dosing, and instances where temporary measures such as those above are
implemented.
 
The sponsor will evaluate the totality of impact of COVID-19 on collection of key study data
and additional data analyses will be outlined in study SAP(s).
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10.9. Appendix 9: Criteriafor 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: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents.
Amendment 2 (30 June 2021)
Overall Rationale for the Amendment: To include additional stopping criteria for the study and for
individual participants. Additionally, minor updates of a clarifying nature were made throughout the
protocol.
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Section Number 
and Name
Description of Change 
Brief Rationale
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Amendment 1 (19May 2021)
Overall Rationale for the Amendment: 
 
 
 
 
 
 
Section Number 
and Name
Description of Change 
Brief Rationale
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11. 
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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
 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.
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PPD

Signature
User 
Date 
Reason
 
12-Jan-2022 
18:14:42
(GMT)
Document Approval
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