Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Nipocalimab Administered to Adults With Generalized Myasthenia Gravis
Phase: PHASE3
Conditions: Myasthenia Gravis
Sponsor: Janssen Research & Development, LLC

CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved, Date:  15 August 2024
Janssen Research & Development
Clinical Protocol
Protocol Title
Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the
Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Nipocalimab Administered to
Adults with Generalized Myasthenia Gravis
Short Title
Efficacy and Safety Study of Nipocalimab IV Infusions for Adults With Generalized Myasthenia
Gravis
Protocol MOM-M281-011; Phase 3
AMENDMENT 3
M281/ JNJ-80202135(nipocalimab)
Janssen Research & Development is a global organization that operates through different legal entities in
various countries/territories. Therefore, the legal entity acting as the sponsor for Janssen Research &
Development studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP;
Janssen Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen
Sciences Ireland UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term
“sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is
identified on the Contact Information page that accompanies the protocol.
United States (US) sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
Studies conducted at sites in the European Economic Area (EEA) will be conducted under Regulation
[EU] No 536/2014.
Regulatory Agency Identifier Number(s):
IND:  138975
EudraCT NUMBER:  2020-005732-29
EU TRIAL NUMBER:  2023-504152-97
Status: 
Approved
Date: 
15 August 2024
Prepared by: Janssen Research & Development, LLC.
EDMS number: 
EDMS-RIM-324706, 4.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory
requirements.
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or
otherwise.
NCT04951622

M281/ JNJ-80202135  (nipocalimab)
Clinical Protocol MOM-M281-011 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status: Approved, Date:  15 August 2024
TABLE OF CONTENTS
TABLE OF CONTENTS............................................................................................................................... 2
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 6
1. 
PROTOCOL SUMMARY..................................................................................................................... 8
1.1. 
Synopsis........................................................................................................................................... 8
1.2. 
Schema.......................................................................................................................................... 19
1.3. 
Schedule of Activities (SoA)........................................................................................................... 20
2. 
INTRODUCTION................................................................................................................................ 33
2.1. 
Study Rationale.............................................................................................................................. 35
2.2. 
Background.................................................................................................................................... 35
2.3. 
Benefit-Risk Assessment............................................................................................................... 37
2.3.1. 
Risks for Study Participation....................................................................................................... 38
2.3.2. 
Benefits for Study Participation .................................................................................................. 41
2.3.3. 
Benefit-Risk Assessment for Study Participation ....................................................................... 41
3. 
OBJECTIVES AND ENDPOINTS..................................................................................................... 41
4. 
STUDY DESIGN ................................................................................................................................ 45
4.1. 
Overall Design................................................................................................................................ 45
4.2. 
Scientific Rationale for Study Design............................................................................................. 48
4.2.1. 
Study-Specific Ethical Design Considerations ........................................................................... 51
4.3. 
Justification for Dose...................................................................................................................... 52
4.4. 
End of Study Definition................................................................................................................... 54
5. 
STUDY POPULATION ...................................................................................................................... 55
5.1. 
Inclusion Criteria............................................................................................................................ 56
5.1.1. 
Inclusion Criteria for Double-blind Placebo-Controlled Phase Entry.......................................... 56
5.1.2. 
Inclusion Criteria for Open-label Extension Phase Entry ........................................................... 59
5.2. 
Exclusion Criteria for Double-blind Placebo-Controlled Phase Entry and Open-label
Extension Phase Entry of Returning Phase 2 Participants............................................................ 60
5.3. 
Lifestyle Considerations................................................................................................................. 65
5.3.1. 
Meals and Dietary Restrictions................................................................................................... 66
5.3.2. 
Activity......................................................................................................................................... 66
5.4. 
Screen Failures.............................................................................................................................. 66
5.5. 
Criteria for Temporarily Delaying Administration of Study Intervention ......................................... 67
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY............................................................ 67
6.1. 
Study Intervention(s) Administered................................................................................................ 67
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 69
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 70
6.4. 
Study Intervention Compliance...................................................................................................... 72
6.5. 
Dose Modification........................................................................................................................... 72
6.6. 
Continued Access to Study Intervention After the End of the Study ............................................. 72
6.7. 
Treatment of Overdose .................................................................................................................. 73
6.8. 
Concomitant Therapy..................................................................................................................... 73
6.8.1. 
Prohibited Therapies................................................................................................................... 73
6.8.2. 
Rescue Medication/Therapy/Clinical Deterioration .................................................................... 74
6.8.3. 
Vaccinations (Including COVID-19)............................................................................................ 75
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 75
7.1. 
Discontinuation of Study Intervention ............................................................................................ 75
7.1.1. 
Liver Chemistry Stopping Criteria............................................................................................... 76

M281/ JNJ-80202135  (nipocalimab)
Clinical Protocol MOM-M281-011 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date:  15 August 2024
7.1.2. 
Temporary Discontinuation......................................................................................................... 76
7.2. 
Participant Discontinuation/Withdrawal From the Study................................................................ 76
7.2.1. 
Withdrawal From the Use of Research Samples ....................................................................... 77
7.3. 
Lost to Follow-up............................................................................................................................ 77
8. 
STUDY ASSESSMENTS AND PROCEDURES............................................................................... 78
8.1. 
Efficacy Assessments .................................................................................................................... 79
8.1.1. 
Myasthenia Gravis –Activities of Daily Living ............................................................................ 79
8.1.2. 
Quantitative Myasthenia Gravis.................................................................................................. 79
8.1.3. 
Revised MyastheniaGravis Quality of Life –15......................................................................... 80
8.1.4. 
Neuro-QoL-Fatigue..................................................................................................................... 80
8.1.5. 
Patient Global Impression of Severity ........................................................................................ 80
8.1.6. 
Patient Global Impression of Change......................................................................................... 81
8.1.7. 
EuroQol 5-Dimension 5-Level .................................................................................................... 81
8.1.8. 
Treatment Satisfaction Questionnaire for Medication ................................................................ 82
8.1.9. 
Digital Health –Actigraphy Measurements (at Selected Sites).................................................. 82
8.2. 
Safety Assessments....................................................................................................................... 82
8.2.1. 
Physical Examinations................................................................................................................ 83
8.2.2. 
Vital Signs................................................................................................................................... 83
8.2.3. 
Electrocardiograms..................................................................................................................... 83
8.2.4. 
Clinical Safety Laboratory Assessments .................................................................................... 84
8.2.5. 
Pregnancy................................................................................................................................... 84
8.2.6. 
Adverse Events Temporally Associated with Infusion................................................................ 84
8.2.7. 
Infusion-Reactions...................................................................................................................... 84
8.2.8. 
Hypersensitivity Reactions.......................................................................................................... 84
8.2.9. 
Suicidal Ideation and Behavior Risk Monitoring ......................................................................... 85
8.2.10. 
Benefit-Risk Balance .................................................................................................................. 85
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting ....................................... 85
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information.................................................................................................................................. 86
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 86
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 86
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events and Anticipated
Events......................................................................................................................................... 87
8.3.5. 
Pregnancy................................................................................................................................... 87
8.3.6. 
Adverse Events of Special Interest............................................................................................. 88
8.4. 
Pharmacokinetics........................................................................................................................... 88
8.4.1. 
Evaluations ................................................................................................................................. 88
8.4.2. 
Analytical Procedures................................................................................................................. 89
8.5. 
Genetics and Pharmacogenomics................................................................................................. 89
8.6. 
Biomarkers..................................................................................................................................... 89
8.6.1. 
Pharmacodynamics .................................................................................................................... 89
8.7. 
Immunogenicity Assessments ....................................................................................................... 90
8.8 
Medical Resource Utilization and Health Economics .................................................................... 90
9. 
STATISTICAL CONSIDERATIONS.................................................................................................. 90
9.1. 
Statistical Hypotheses.................................................................................................................... 91
9.2. 
Sample Size Determination ........................................................................................................... 91
9.3. 
Populations for Analysis Sets ........................................................................................................ 92
9.4. 
Statistical Analyses ........................................................................................................................ 93
9.4.1. 
General Considerations.............................................................................................................. 93
9.4.2. 
Double-blind Placebo-controlled Phase ..................................................................................... 93
9.4.2.1. 
Primary Endpoint..................................................................................................................... 93
9.4.2.2. 
Secondary Endpoint(s)............................................................................................................ 95
9.4.3. 
Testing Strategy for Japan.......................................................................................................... 98
9.4.4. 
Open-label Extension Phase...................................................................................................... 98
9.4.5. 
Safety Analyses.......................................................................................................................... 99
9.4.6. 
Other Analyses ......................................................................................................................... 100

M281/ JNJ-80202135  (nipocalimab)
Clinical Protocol MOM-M281-011 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
4
Status: Approved, Date:  15 August 2024
9.5. 
Interim Analysis............................................................................................................................ 101
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS.......................... 102
10.1. 
Appendix 1: Abbreviations ........................................................................................................... 102
10.2. 
Appendix 2: Clinical Laboratory Tests ......................................................................................... 104
10.3. 
Appendix 3: Hepatitis B Virus (HBV) Screening with HBV DNA Testing..................................... 106
10.4. 
Appendix 4: Regulatory, Ethical, and Study Oversight Considerations....................................... 107
10.4.1. 
Regulatory and Ethical Considerations .................................................................................... 107
10.4.2. 
Financial Disclosure.................................................................................................................. 109
10.4.3. 
Informed Consent Process ....................................................................................................... 110
10.4.4. 
Data Protection ......................................................................................................................... 110
10.4.5. 
Long-Term Retention of Samples for Additional Future Research .......................................... 111
10.4.6. 
Committees Structure............................................................................................................... 111
10.4.7. 
Publication Policy/Dissemination of Clinical Study Data.......................................................... 112
10.4.8. 
Data Quality Assurance............................................................................................................ 113
10.4.9. 
Case Report Form Completion................................................................................................. 113
10.4.10. Source Documents ................................................................................................................... 114
10.4.11. Monitoring ................................................................................................................................. 115
10.4.12. On-Site Audits........................................................................................................................... 116
10.4.13. Record Retention...................................................................................................................... 116
10.4.14. Study and Site Start and Closure ............................................................................................. 117
10.5. 
Appendix 5: Adverse Events, Serious Adverse Events, Product Quality Complaints, and
Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up,
and Reporting............................................................................................................................... 118
10.5.1. 
Adverse Event Definitions and Classifications ......................................................................... 118
10.5.2. 
Attribution Definitions................................................................................................................ 119
10.5.3. 
Severity Criteria........................................................................................................................ 120
10.5.4. 
Special Reporting Situations .................................................................................................... 120
10.5.5. 
Procedures ............................................................................................................................... 120
10.5.6. 
Product Quality Complaint Handling......................................................................................... 122
10.5.7. 
Contacting Sponsor Regarding Safety, Including Product Quality........................................... 122
10.6. 
Appendix 6: Contraceptive and Barrier Guidance ....................................................................... 123
10.7. 
Appendix 7: Liver Safety: Suggested Actions and Follow-up Assessments................................ 126
10.7.1. 
STOPPING ALGORITHM......................................................................................................... 126
10.7.2. 
Follow-Up Assessments ........................................................................................................... 126
10.8. 
Appendix 8: Study Conduct During a Natural Disaster................................................................ 130
10.9. 
Appendix 9: Criteria for Assessing Potential Cases of Anaphylaxis............................................ 132
10.10. Appendix 10: Country/Territory-specific Requirements ............................................................... 133
10.10.1. Requirements for EU Region (EUR)......................................................................................... 133
10.10.2. Requirements for FRANCE (FRA)............................................................................................ 133
10.11. Appendix 11: Protocol Amendment History................................................................................. 135
11. REFERENCES................................................................................................................................. 147
INVESTIGATOR AGREEMENT............................................................................................................... 150

M281/ JNJ-80202135  (nipocalimab)
Clinical Protocol MOM-M281-011 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
5
Status: Approved, Date:  15 August 2024
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Schedule of Activities - Double-Blind Placebo-controlled Phase ............................................. 20
Table 2: 
Schedule of Activities - Open-label Extension Phase (Extension Week 1 through
Extension Week 24).................................................................................................................. 25
Table 3: 
Schedule of Activities - Open-label Extension Phase (Extension Week 26 through
Extension Week 240................................................................................................................. 29
Table 4: 
Safety Follow-up Phase............................................................................................................ 32
Table 5: 
Potential Risks for Study Participation...................................................................................... 38
Table 6: 
Between-group Differences in Proportions That can be Detected With at Least 90%
(80%) Power for the Key Secondary Endpoints ....................................................................... 91
FIGURES
Figure 1: Schematic Overview of the Study............................................................................................. 19
Figure 2: Model-Predicted IgG Reduction and MG-ADL Improvement with 15 mg/kg and 30
mg/kg  Q2W Maintenance Dosing............................................................................................ 53
Figure 3: Model-Predicted IgG Reduction and MG-ADL Improvement with a 30 mg/kg Loading
Dose.......................................................................................................................................... 54

M281/ JNJ-80202135  (nipocalimab)
Clinical Protocol MOM-M281-011 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
6
Status: Approved, Date:  15 August 2024
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Country/Territory Affected  
Date
Amendment 3 
All 
15 AUGUST 2024
Amendment 2 
All 
11 JANUARY 2023
Amendment 1 
All 
21 JULY 2022
Original Protocol 
All 
19 MARCH 2021
Amendment 3 (15August 2024)
Overall Rationale for the Amendment: To update the Study Intervention(s) Administered section of the
protocol to align with the other studies in the nipocalimab program, to extend the maximum duration of the
OLE in the EU region, and to align with standard language across the nipocalimab program. Additionally,
clarifying edits from the latest sponsor protocol template were made throughout the protocol.
The changes made to the clinical protocol MOM-M281-011  as part of Protocol Amendment 3 are listed
below, including the rationale of each change and a list of all applicable sections. Changes made in previous
protocol amendments are listed in Section 10.11 Appendix 11: Protocol Amendment History.
Section Number 
and Name
Description of Change 
Brief Rationale
Title page; 
1.1 Synopsis
Added EU Trial number. 
To align with EU CTR requirements.
1.3 SoA, Table 3 
Updated to clarify visits. 
Changes were made to clarify the
counting of weeks. No changes were
made to the frequency or scope of
visit assessments.
1.3 SoA, Table 3; 
10.10.1 Requirements for EU 
Region (EUR) 
OLE extended from 192 to 240 
weeks. 
In the EUR, the maximum duration
of the OLE period has been extended
to Week 240. In non-EUR
countries/territories, the OLE will be
of variable duration as defined under
Section 4.4 End of Study Definition.
2.3.1 Risks for Study 
Participation 
Updated risk language in Table 5. 
No changes to risks were identified;
text was streamlined to better align
with the latest IB.
4.2.1 Study-Specific Ethical 
Design Considerations 
Blood volumes removed. 
Blood volume information is not
required in this section and is
included in Section 8.
5.3.2 Activity  
Removed “participants should not 
begin any new exercise program 
during the study.”
To clarify study expectations given
the duration of the OLE period.
6.1 Study Intervention(s) 
Administered; 
6.2 Preparation/Handling/Storage/ 
Accountability  
Removed table describing study 
interventions administered and 
revised text describing study 
interventions to align with other 
protocols across the nipocalimab
program.
To align across the nipocalimab
program. The most current
formulation information is
maintained within the IB.
6.3 Measures to Minimize Bias 
Modified text to allow unblinding of 
sites after completion of the primary 
analysis CSR. 
Blind linked to operational aspects of
the study no longer needs to be
maintained for sites during the OLE
period.
6.8.2 Rescue 
Medication/Therapy/Clinical 
Deterioration  
For participants who undergo rescue 
treatment, text was revised from  
‘must’ to ‘may’ complete an  
In some circumstances it is not
possible to have this unscheduled
visit.

M281/ JNJ-80202135  (nipocalimab)
Clinical Protocol MOM-M281-011 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
7
Status: Approved, Date:  15 August 2024
Section Number 
and Name
Description of Change 
Brief Rationale
unscheduled visit prior to
continuing in the OLE.
8 STUDY ASSESSMENTS AND 
PROCEDURES  
Blood volumes updated. 
To account for the extended duration
of the OLE period.
8.1.3 Revised Myasthenia Gravis 
Quality of Life –15
Repeated text removed. 
To remove repeated information.
8.6 Biomarkers 
Added “Sample collection and 
testing will comply with local 
regulations.”
To align with current sponsor
template.
9.5 Interim Analysis 
Added text regarding interim 
analyses. 
To allow periodic analysis of OLE
data.
10.4.3 Informed Consent Process 
Removed language informing 
participants who have received 
previous treatment with rituximab 
that they may be at an increased risk
of infection during the study.
To provide consistency for all
nipocalimab protocols. The risk
remains as stated in the ICF.
Removed standard protocol 
template language allowing an 
impartial witness to sign the ICF if 
the participant is unable to read or 
write.
Administrative correction to remove
template text as participants are
required to be able to read and write
per Inclusion Criterion 16.
10.4.13 Record Retention  
Added text regarding record 
retention under EU regulation.
To align with EU CTR requirements.
10.5.2 Attribution Definitions 
Listed factors to be considered in 
causality assessment and specified 
that a causal relationship to study
intervention should be documented
in the participant’s medical records.
To align with current sponsor
template.
Throughout the protocol 
Minor grammatical, formatting, or 
spelling changes were made.
Minor errors were noted

M281/ JNJ-80202135  (nipocalimab)
Clinical Protocol MOM-M281-011 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
8
Status: Approved, Date:  15 August 2024
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy,
Safety, Pharmacokinetics, and Pharmacodynamics of Nipocalimab Administered to Adults with
Generalized Myasthenia Gravis
EU Trial Number: 2023-504152-97
Short Title: Efficacy and Safety Study of Nipocalimab IV Infusions for Adults With Generalized
Myasthenia Gravis
DESCRIPTION OF COMPOUND
Nipocalimab is a fully human, aglycosylated, effectorless immunoglobulin G (IgG) 1 monoclonal antibody
that targets the neonatal Fc receptor (FcRn) IgG binding site with high affinity at both neutral and acidic
pH, thereby interfering with the binding, and hence recycling of native IgG. In endothelial cells,
monocytes, and granulocytes, FcRn binding of IgG protects it from degradation and contributes to its
long half-life. Interference with FcRn function results in a decrease in serum IgG concentrations. By
blocking FcRn-mediated recycling of IgG, nipocalimab is expected to reduce circulating levels of IgG
antibodies, including the pathogenic autoantibodies that cause generalized myasthenia gravis (gMG), thus
improving disease manifestations.
BENEFIT-RISK ASSESSMENT
A Phase 2 study (MOM-M281-004) of nipocalimab in gMG has shown that the majority of, but not all,
participants responded to nipocalimab. The potential risks of exposure to nipocalimab based on its
mechanism of action include the potential for increased risk for infection, reduced effectiveness of routine
vaccines, activation of latent virus, clinical manifestations of hypoalbuminemia, infusion reaction,
drug-drug interactions, and increased lipids. Mitigation strategies include the exclusion of participants at
high risk of serious complications, close monitoring of participant safety, and guidelines for participants'
management (including monitoring of clinical laboratory tests and treatment interruption/discontinuation
criteria), detailed review of permitted and prohibited concomitant medications, and comprehensive medical
monitoring of safety data by the sponsor during the conduct of the studies. Comprehensive medical
monitoring of safety data includes regular reviews and assessment of adverse events (AEs), adverse events
of special interest (AESIs) and serious adverse events (SAEs), and the evaluations of vital signs, physical
examination, and laboratory tests’ results.
OBJECTIVES AND ENDPOINTS
Objective 
Outcome Measures
Primary Objective
To evaluate the efficacy of nipocalimab
compared to placebo based on the
Myasthenia Gravis-Activities of Daily
Living (MG-ADL) scale, in seropositive
generalized myasthenia gravis (gMG)
participants when treatment is taken as
directed.
Average change from baseline in MG-ADL score over Weeks 22,
23, and 24 of the double-blind placebo-controlled phase.
Key Secondary Objectives
To evaluate the efficacy of nipocalimab
compared to placebo based on the
Quantitative Myasthenia Gravis (QMG)
Average change in QMG score over Weeks 22 and 24 of the
double-blind placebo-controlled phase.

M281/ JNJ-80202135  (nipocalimab)
Clinical Protocol MOM-M281-011 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date:  15 August 2024
Objective 
Outcome Measures
scale, in seropositive gMG participants
when treatment is taken as directed.
To evaluate the effect of nipocalimab  
compared to placebo in achieving the 
minimum clinically important 
difference (MCID) or better based on 
the MG-ADL scale, in seropositive
gMG participants when treatment is
taken as directed.
Percentage of participants whose average improvement in MG-
ADL total score over Weeks 22, 23, and 24 of the double-blind
placebo-controlled phase is at least a 2-point improvement
compared to baseline.
To evaluate the efficacy of nipocalimab 
loading dose compared to placebo based 
on the MG-ADL scale, in seropositive 
gMG participants when treatment is
taken as directed.
Percentage of participants with improvement in MG-ADL total
score ≥ 2 points at Week 1 and/or Week 2 of the double-blind
placebo-controlled phase.
To evaluate sustainability of therapeutic 
response of nipocalimab compared to 
placebo based on the MG-ADL scale, in 
seropositive gMG participants when 
treatment is taken as directed. 
Percentage of participants with improvement in MG-ADL total
score ≥ 2 points at Week 4 through Week 24 of the double-blind,
placebo-controlled phase with no more than 2 non-consecutive
excursions allowed between Week 6 through Week 23 (excursion
defined as loss of improvement in MG-ADL score ≥ 2 points
from baseline).
To evaluate the effect of nipocalimab 
compared to placebo on the percentage 
of participants achieving ≥50% 
symptom improvement based on the 
MG-ADL scale, in seropositive gMG
participants when treatment is taken as
directed.
Percentage of participants whose average improvement in
MG-ADL total score over Weeks 22, 23, and 24 of the
double-blind, placebo-controlled phase is at least a 50%
improvement from baseline.
Other Secondary Objectives
To evaluate safety and tolerability of 
treatment with nipocalimab. 
Proportion of participants with adverse events (AEs), serious AEs
(SAEs), AEs of special interest (AESIs: severe or serious
infections and hypoalbuminemia < 20g/L).
Change in vital signs and clinical laboratory values.
Change in Columbia-Suicide Severity Rating Scale (C-SSRS)
score.
To evaluate sustainability of therapeutic 
response of nipocalimab compared to 
placebo based on the QMG scale, in 
seropositive gMG participants, when 
treatment is taken as directed. 
Percentage of participants with improvement in QMG of
≥3 points from baseline at Week 2 through Week 24 of the
double-blind placebo-controlled phase with no more than 2
non-consecutive excursions allowed at Weeks 4 through 22
(excursions defined as loss of improvement in QMG score of ≥3
points from baseline).
To evaluate the effect of nipocalimab 
compared to placebo on fatigue based 
on the Quality of Life in Neurological 
Disorders (Neuro-QoL) Fatigue scale, in
seropositive gMG participants when
treatment is taken as directed.
Average change from baseline in the Neuro-QoL Fatigue total
score over Weeks 22 and 24 of the double-blind
placebo-controlled phase.
To evaluate the effect of nipocalimab 
compared to placebo on health-related 
quality of life based on the15-item
Myasthenia Gravis –Quality of Life
(revised) instrument (MG-QoL15r) and
the EuroQol 5-Dimension 5-Level
(EQ-5D-5L) scale, in seropositive gMG
Average change from baseline in the MG-QoL15r score over
Weeks 22 and 24 of the double-blind placebo-controlled phase.
Change from baseline in the visual analog scale and health status
index of the EQ-5D-5L over 24 weeks of the double-blind
placebo-controlled phase.

M281/ JNJ-80202135  (nipocalimab)
Clinical Protocol MOM-M281-011 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
10
Status: Approved, Date:  15 August 2024
Objective 
Outcome Measures
participants when treatment is taken as
directed.
To evaluate the effect of nipocalimab 
compared to placebo on gMG minimum 
symptom expression based on the MG-
ADL scale, in seropositive gMG
participants when treatment is taken as
directed. 
Percentage of participants with MG-ADL score of 0 or 1 over
time in the double-blind, placebo-controlled phase.
Percentage of participants with MG-ADL score of 0 or 1 at any
time during the double-blind, placebo-controlled phase.
Percentage of participants with MG-ADL score of 0 or 1 at 50%
of timepoints during the double-blind, placebo-controlled phase.
Percentage of participants with MG-ADL score of 0 or 1 at 75%
of timepoints during the double-blind, placebo-controlled phase.
To evaluate pharmacokinetics (PK) and 
immunogenicity of nipocalimab.
Serum nipocalimab concentrations over time
Incidence and titers of anti-drug antibodies (ADA) to nipocalimab
and presence of neutralizing antibodies (NAb) to nipocalimab
To evaluate pharmacodynamic (PD) 
activity of nipocalimab. 
PD outcome measure:
Effects on total serum immunoglobulin G (IgG) concentrations
To explore the effects of nipocalimab 
treatment on biomarkers of MG disease
biology and response.
Effects on levels of autoantibodies associated with gMG.
Assessment of relationship between IgG lowering and MG-ADL
and QMG.
Evaluate the potential relationship between change in MG-ADL
and/or QMG score, and change in autoantibody levels in
seropositive participants (anti-AChR, anti-MuSK, anti-LRP4a)
treated with nipocalimab.
Exploratory Objectives
To further evaluate clinically relevant 
response to treatment with nipocalimab 
compared to placebo in seropositive 
gMG participants when treatment is
taken as directed.
Number of participants with a 2-, 3-, 4-, 5-, 6-, 7-, or ≥8 point
improvement in total MG-ADL score over time in the
double-blind placebo-controlled phase.
Number of participants with a 3-, 4-, 5-, 6-, 7-, 8-, or ≥9 point
improvement in total QMG score over time in the double-blind
placebo-controlled phase.
Time to first response (MG-ADL total score improvement of ≥2
points) in the double-blind placebo-controlled phase.
Time to treatment discontinuation during the double-blind
placebo-controlled phase for any reason.
Time to treatment discontinuation during the double-blind
placebo-controlled phase due to Clinical Deterioration requiring
hospitalization or rescue medication use.
Percentage of responders as measured by QMG (improvement on
QMG of ≥3 points) over time in the double-blind placebo-
controlled phase.
Number of participants with a total MG-ADL score of 0 or 1 over
time in the double-blind placebo-controlled phase.
Number of emergency room (ER) visits; number of
hospitalizations; average Length of Stay (LOS) from
hospitalization due to Clinical Deterioration over time in the
double-blind placebo-controlled phase.
a 
In China, anti-LRP4 autoantibody collection will only be tested at screening.

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Objective 
Outcome Measures
To evaluate the efficacy of nipocalimab 
compared to placebo in seronegative 
gMG participants when treatment is
taken as directed.
Average change from baseline in MG-ADL score over Weeks 22,
23, and 24 of the double-blind placebo-controlled phase.
Average change from baseline in QMG score over Weeks 22 and
24 of the double-blind placebo-controlled phase.
Percentage of participants whose average MG-ADL total score
over weeks 22, 23 and 24 of the double-blind, placebo-controlled
phase is at least a 2-point improvement compared to baseline.
To explore the effects of nipocalimab 
on biomarkers of MG disease biology in 
gMG participants when treatment is 
taken as directed. 
Evaluate exploratory biomarkersb (including but not limited to
IgG subtypes, IgM, IgA, IgE, MG-associated RNAs, complement
proteins. Analyses could use proteomic, glycoprotein, and
metabolomic markers).
To explore the changes in physical 
activity, mobility, and sleep, as 
measured by accelerometry, in 
nipocalimab compared to placebo in 
seropositive gMG participants when 
treatment is taken as directed (at
selected sites).
Change in Actigraphy watch-collected continuous data on physical
activity, mobility, and sleep (including but not limited to step
count, activity count, sleep time, sleep efficiency, and percent
mobile time) during the double-blind placebo-controlled phase (at
selected sites).
To explore the effects of nipocalimab 
compared to placebo on fatigue based 
on the meaningful change threshold
(MCT) of the Neuro-QoL Fatigue scale,
in seropositive gMG participants when
treatment is taken as directed. 
Estimation of MCT threshold using anchor-based, and
distribution- based approaches.
Cumulative Distribution Function curves of change from baseline
in Neuro-QoL Fatigue over time.
Patient Global Impression of Change (PGI-C) and Patient Global
Impression of Severity (PGI-S) frequency distribution of
responses over time (anchoring for Neuro-QoL Fatigue) during
the double-blind placebo-controlled phase.
To explore the long-term efficacy of 
nipocalimab 15 mg/kg q2w during the 
open-label extension phase.
Change from baseline in the total MG-ADL score over time
during the open-label extension phase.
Number of participants with a 2-, 3-, 4-, 5-, 6-, 7-, or ≥8 point
improvement in total MG-ADL score over time during the open-
label extension phase.
Change from baseline in total QMG score over time during the
open-label extension phase.
Percentage of responders as measured by QMG (improvement on
QMG of ≥3 points) over time during the open-label extension
phase.
Change from baseline in Neuro-QoL Fatigue scores over time
during the open-label extension phase.
Number of participants with a total MG-ADL score of 0 or 1 over
time during the open-label extension phase.
Change from baseline in the MG-QoL15r score over time during
the open-label extension phase.
Change from baseline in the visual analog scale and health status
index of the EQ-5D-5L over time during the open-label extension
phase.
b 
Exploratory biomarkers (including but not limited to IgG subtypes, IgM, IgA, and IgE) are not applicable for
collection in China

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Objective 
Outcome Measures
Number of participants having Clinical Deterioration requiring
hospitalization or rescue therapy during the open-label extension
phase.
PGI-C and PGI-S frequency distribution of responses over time
(anchoring for Neuro-QoL Fatigue) during the open-label
extension phase.
Changes in individualized concomitant medications for gMG over
time during the open-label extension phase.
Hypothesis
The primary hypothesis of this study is that IV nipocalimab is superior to placebo as measured by average
change from baseline in the MG-ADL score over Weeks 22, 23 and 24 for seropositive participants
(consisting of anti-AChR positive, anti-MuSK positive, and/or anti-LRP4 positive).
OVERALL DESIGN
This is a multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety
of nipocalimab compared to placebo in participants with gMG who are inadequately controlled with
standard of care therapy. Participants who have completed the double-blind placebo-controlled phase of the
study have an option to receive open-label treatment of nipocalimab to evaluate long-term safety and
efficacy of nipocalimab.
The study will consist ofa screening phase of up to 4 weeks, a 24-week double-blind placebo-controlled
phase and an open-label extension (OLE) phase. The OLE will be of variable duration per participating
country/territory depending on the timing of market authorization and commercial availability of
nipocalimab. For EU region (EUR)-specific information, please refer to Appendix 10. Efficacy, safety, PK,
PD, and immunogenicity will be assessed according to the Schedule of Activities. Participants who
discontinue study intervention during the double-blind placebo-controlled phase for any reason other than
Clinical Deterioration requiring hospitalization or rescue therapy will be required to complete study
procedures per the Schedule of Activities until the completion of the 24-week period. Rollover into the
OLE of such participants will not be permitted unless the 24 weeks of study procedures have been
completed. Participants who discontinue study intervention administration or withdraw at any point during
the study will be requested to complete a follow-up assessment 8 weeks after their last infusion of study
intervention.
An independent Data Monitoring Committee (DMC) and Major Adverse Cardiovascular Events (MACE)
Event Adjudication Committee (EAC) will be commissioned for this study. The responsibilities,
authorities, and procedures of each committee will be documented in separate DMC and EAC charters.
Double-blind Placebo-controlled Phase
Approximately 190 participants will be enrolled into the double-blind placebo-controlled phase of the
study, including approximately 150 seropositive participants (anti-AChR positive, anti-MuSK positive,
and/or anti-LRP4 positive). Seronegative participants will also be enrolledc. Participants will be randomly
assigned in a 1:1 ratio to receive either placebo or nipocalimab (30 mg/kg for the first infusion followed by
15 mg/kg every 2 weeks [q2w]) during the first 24 weeks. Randomization will be stratified by autoantibody
c 
Seronegative participants are no longer being recruited; all participants must have a positive serologic test for a
gMG related pathogenic autoantibody (anti-AChR, anti-MuSK and/or anti-LRP4 autoantibodies), confirmed prior
to randomization.

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status (anti-AChR and/or anti-MuSK positive, anti-AChR negative and anti-MuSK negative), Day 1
MG-ADL total score (≤9, >9), and region (East Asia, United States [US], rest of world).
Open-label Extension Phase
Participants who complete the double-blind placebo-controlled phase will continue to the OLE phase where
treatment with nipocalimab will continue until 2 years after marketing authorization in a participant’s local
country/territory or until nipocalimab becomes available commercially or via other continued access
program, whichever comes first. For EUR-specific information, please refer to Appendix 10. All
participants entering the OLE phase will receive open label nipocalimab treatment of 15 mg/kg q2w.
Due to the COVID-19 pandemic, the MOM-M281-005 study, an open-label extension study to evaluate the
safety, tolerability, and efficacy of nipocalimab administered to participants with gMG, was placed on hold
and subsequently terminated. As a result, some participants from the MOM-281-004 study, a Phase 2,
multicenter, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability,
efficacy, pharmacokinetics and pharmacodynamics of nipocalimab administered to adults with gMG, were
unable to enroll into the MOM-M281-005 study. Participants affected by this study termination (either
those who were ongoing in the MOM-M281-005 study at the time of the hold or those who were unable to
enroll from MOM-M281-004) will have the opportunity to directly enter the OLE phase of the present study
(bypassing the double-blind placebo-controlled phase). These return participants will undergo a screening
assessment to confirm eligibility for entry into the OLE phase of the study.
NUMBER OF PARTICIPANTS
Approximately 190 participants will be enrolled in the double-blind placebo-controlled phase of this study
with approximately 95 participants planned in each treatment group. At least 150 eligible seropositive
participants will be enrolled. Seronegative participants will also be enrolled.d
It is expected that approximately 30 participants who previously participated in the Phase 2
MOM-M281-004 study may directly enter the OLE phase of the MOM-M281-011 study.
INTERVENTION GROUPS AND DURATION
Double-blind Placebo-controlled Phase
Participants will be randomized to 1 of 2 treatment groups as described below:
Nipocalimab: participants will receive infusion once every 2 weeks (30 mg/kg at first infusion and
15 mg/kg thereafter) for 24 weeks.
Placebo: participants will receive infusion once every 2 weeks for 24 weeks.
Recalculation of dose during the double-blind placebo-controlled phase for weight gained or lost will be
based on the weight measured for each participant every 4 weeks.
Open-label Extension Phase
Participants who completed the Phase 3 double-blind placebo-controlled phase or participants impacted by
the study hold and subsequent termination of the MOM-M281-005 study will receive open label treatment
d 
Seronegative participants are no longer being recruited; all participants must have a positive serologic test for a
gMG related pathogenic autoantibody (anti-AChR, anti-MuSK and/or anti-LRP4 autoantibodies), confirmed prior
to randomization.
CCI

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of nipocalimab 15 mg/kg administered by IV infusion q2w. 
Recalculation of dose during the OLE phase for weight gained or lost will be based on the weight measured
for each participant every 4 weeks through Extension Week 24 and every 12 weeks thereafter.
EFFICACY EVALUATIONS
Efficacy will be assessed in the following order: the patient-reported assessments of Neuro-QoL Fatigue,
PGI-S, PGI-C, MG-QoL15r, EQ-5D-5L questionnaire, followed by the rater administered MG-ADL and
then the QMG. Exploratory efficacy assessments will include Clinical Deterioration requiring
hospitalization or rescue therapy, Myasthenia Gravis Foundation of America (MGFA) classification, and
assessment of physical activity using an actigraphy watch (in selected countries/territories and sites).
PHARMACOKINETIC EVALUATIONS
Blood samples will be taken as described in the Schedule of Activities for measurement of serum
nipocalimab concentrations to assess nipocalimab PK.
IMMUNOGENICITY EVALUATIONS
Serum samples will be evaluated for the presence and titers of ADA to nipocalimab. Serum samples that
test positive for ADA will be further evaluated to determine the presence of NAb to nipocalimab.
PHARMACODYNAMIC AND BIOMARKER EVALUATIONS
Blood samples will be obtained as outlined in the Schedule of Activities for measurement of total IgG, IgG
subtypes, IgM, IgA, IgE, MG-associated RNAs, complement proteins, proteomic, glycoprotein, and
metabolomic markers.
SAFETY EVALUATIONS
Safety assessments include collection of AEs and SAEs, use of concomitant medications, clinical laboratory
testing (including chemistry, hematology, lipid profiles, and urinalysis), ECGs, vital signs, and physical
examinations. A serum or urine pregnancy tests will be performed only for women of childbearing potential
(WOCBP). In addition, the emergence of suicidal ideation will be assessed using the C-SSRS. Severe or
serious infections and events of hypoalbuminemia (<20 g/L) will be considered adverse events of special
interest (AESI).
For participants affected by interruption of the MOM-M281-005 study due to the COVID-19 pandemic:
Adverse events that occurred during the COVID-19 pandemic treatment interruption will be recorded as
medical history. Recording of new AEs (ie, any new clinically relevant finding or worsening of a pre-
existing condition) will start at the time of the ICF is signed for the OLE phase.
STATISTICAL METHODS
Double-blind Placebo-controlled Phase
Participant Information
The primary efficacy analysis set for the double-blind placebo-controlled phase will include all seropositive
participants (anti-AChR positive, anti-MuSK positive, and/or anti-LRP4 positive) who received at least 1
dose (partial or complete) of any study intervention in the double-blind phase.
The full analysis set for the double-blind placebo-controlled phase will include all randomized participants
who received at least 1 dose (partial or complete) of any study intervention in the double-blind phase.
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Sample Size Determination
A sample size of 75 seropositive participants per group are needed to provide at least 90% power to detect
standardized effect sizes of at least 0.57 at a two-sided significance level of 0.05, assuming a drop-out rate
of 20% at Week 24. A standardized effect size of 0.57 is based on estimates of between-group differences
(≥1.7) and standard deviations (approximately 3) from clinical trial simulations of the MG-ADL total score.
The sample size is based on a mixed effects model for repeated measures (MMRM) assuming 12 post-
baseline assessments over 24 weeks and a constant within-participant correlation of 0.5. At least 150
eligible seropositive participants will be enrolled. Seronegative participants will also be enrollede.
Primary Estimand (applicable to regions outside of the European Union [EU])
Population: Seropositive participants (anti-AChR positive, anti-MuSK positive, and/or anti-LRP4
positive) with gMG who are on a stable MG therapy (or who discontinued MG therapy due to
intolerance or lack of efficacy as defined in Inclusion Criterion #4).
Endpoint: Average change from baseline (screening and Day 1) in MG-ADL total score over Weeks
22, 23 and 24 of the double-blind placebo-controlled phase.
Intercurrent events and corresponding strategies:
Treatment discontinuation of study intervention only due to reasons other than initiation of rescue
medication (Hypothetical strategy: as if the intercurrent event had not occurred)
Treatment discontinuation of both background MG medication and study intervention due to
reasons other than initiation of rescue medication (Hypothetical strategy: see above)
Treatment discontinuation of study intervention due to initiation of rescue medication
(Hypothetical strategy: see above)
Treatment discontinuation of both background MG medication and study intervention due to
initiation of rescue medication (Hypothetical strategy: see above)
Change in background MG medication, (Hypothetical strategy: see above)
Summary measure: Difference between treatment means.
Treatment: 30 mg/kg loading dose followed by 15 mg/kg q2w of nipocalimab versus placebo.
Primary Estimand (applicable to the EU)
Population: Seropositive participants (anti-AChR positive, anti-MuSK positive, and/or anti-LRP4
positive) with gMG who are on a stable MG therapy (or who discontinued MG therapy due to
intolerance or lack of efficacy as defined in Inclusion Criterion #4).
Endpoint: Average change from baseline (screening and Day 1) in MG-ADL total score over Weeks
22, 23 and 24 of the double-blind placebo-controlled phase.
Intercurrent events and corresponding strategies:
Treatment discontinuation of study intervention only due to reasons other than initiation of rescue
medication (Treatment policy; irrespective of the occurrence of an intercurrent event)
Treatment discontinuation of both background MG medication and study intervention due to
reasons other than initiation of rescue medication (Treatment policy: see above)
e 
Seronegative participants are no longer being recruited; all participants must have a positive serologic test for a
gMG related pathogenic autoantibody (anti-AChR, anti-MuSK and/or anti-LRP4 autoantibodies), confirmed prior
to randomization.

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Treatment discontinuation of study intervention due to initiation of rescue medication
(Hypothetical strategy: as if the intercurrent event had not occurred)
Treatment discontinuation of both background MG medication and study intervention due to
initiation of rescue medication (Hypothetical strategy: see above)
Change in background MG medication, (Treatment policy: see above)
Summary measure: Difference between treatment means.
Treatment: 30 mg/kg loading dose followed by 15 mg/kg q2w of nipocalimab versus placebo.
Analysis Under the Primary Estimands
Regions outside of the EU
The primary efficacy endpoint, the average change from baseline in MG-ADL total score over Weeks 22,
23, and 24 of the double-blind placebo-controlled phase, will be analyzed using an MMRM with weekly
change from baseline as the dependent variable; factors for treatment, autoantibody status, region, week,
and treatment-by-week interaction; baseline MG-ADL total score as a covariate and participant as a random
effect. Baseline is defined as the arithmetic mean of the screening and Day 1 assessments. An unstructured
variance-covariance matrix will be used first. In case of convergence problems, alternative variance-
covariance structures will be tried in the following order, with the first structure that converges being used
in the analysis: heterogeneous Toeplitz, standard Toeplitz, and AR(1). The between-group difference of the
average change over Weeks 22, 23, and 24 of the double-blind placebo-controlled phase will be tested with
an F-test of the linear contrast that averages the change from baseline over those time points. The estimate
of this contrast and its 95% confidence interval will be provided. Observations after the occurrence of an
intercurrent event will not be included in the primary analysis, consistent with the hypothetical strategy for
handling intercurrent events. Missing data will be handled through the MMRM, assuming missing data are
Missing at Random (MAR).
Sensitivity analyses will include a tipping point analysis using multiple imputation with delta adjustment.
EU
The analysis will proceed in the same manner as described above for regions outside of the EU, except for
how observations collected after intercurrent events are handled. For intercurrent events addressed with the
treatment policy strategy, observations collected after the intercurrent event will be included in the analysis.
For intercurrent events addressed with the hypothetical strategy, observations collected after the intercurrent
event will not be included in the analysis. Missing data that may result after an intercurrent event will be
handled with a Copy Reference multiple imputation approach.
Sensitivity analyses will include a Jump to Reference multiple imputation approach.
Key Secondary Efficacy Endpoints
A fixed sequence approach will be applied to adjust for multiplicity and to control Type 1 error across the
primary and the 5 key secondary efficacy endpoints. The 5 key secondary endpoints will be analyzed
sequentially and will be considered statistically significant at the 2-sided 0.05 level only if the endpoint is
individually significant at the 2-sided 0.05 level and previous endpoints in the hierarchy were significant at
the 2-sided 0.05 level, including the primary endpoint. If the primary endpoint is statistically significant,
the selected secondary endpoints will be assessed in the following order:
1. 
The average change in the QMG score over Weeks 22 and 24. Analyzed using a similar method
(appropriate for the region) as for the primary efficacy endpoint, but since the QMG is not assessed at
Week 23, the contrast will average the change from baseline over Weeks 22 and 24 of the double-blind
placebo-controlled phase.

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2. 
Percentage of participants whose average MG-ADL total score over weeks 22, 23 and 24 of the
double-blind, placebo-controlled phase is at least a 2-point improvement compared to baseline. The
average score for a participant is the average of the non-missing values at Weeks 22, 23 and 24. A
participant must have a non-missing value at Week 24 and at least 1 non-missing value at Week 22 or
23 in order to have a non-missing average score. A participant with a missing average score will be
considered a nonresponder. Analyzed by Cochran-Mantel-Haenszel test controlling for the baseline
MG-ADL total score randomization strata (≤9, >9), autoantibody status, and region.
3. 
Loading dose response, defined for each participant as improvement in the MG-ADL total ≥2 points
at Week 1 and/or Week 2. A participant with a missing assessment at either time point will be
considered a nonresponder at that time point. Analyzed by Cochran-Mantel-Haenszel test controlling
for the baseline MG-ADL total score randomization strata (≤9, >9), autoantibody status, and region.
4. 
Sustainability of therapeutic response, defined as the percentage of participants with improvement in
MG-ADL total score of ≥ 2 points at Week 4 through Week 24, with no more than 2 non-consecutive
excursions allowed between Week 6 through Week 23 (excursions defined as loss of improvement in
MG-ADL score of ≥ 2 points from baseline). A participant with a missing assessment at a time point
will be considered a nonresponder at that time point. Analyzed by Cochran-Mantel-Haenszel test
controlling for the baseline MG-ADL total score randomization strata (≤9, >9), autoantibody status,
and region.
5. 
Percentage of participants whose average MG-ADL total score over weeks 22, 23 and 24 of the
double-blind, placebo-controlled phase is at least a 50% improvement compared to baseline. The
average score for a participant is the average of the non-missing values at Weeks 22, 23 and 24. A
participant must have a non-missing value at Week 24 and at least 1 non-missing value at Week 22 or
23 in order to have a non-missing average score. A participant with a missing average score will be
considered a nonresponder. Analyzed by Cochran-Mantel-Haenszel test controlling for the baseline
MG-ADL total score randomization strata (≤9, >9), autoantibody status, and region.
Other Efficacy Endpoints
Between-group differences and 95% confidence intervals of the change from baseline in MG-ADL score
at each timepoint will be estimated from the same MMRM described above (as appropriate for the region).
The percentage of MG-ADL responders, defined as improvement in the MG-ADL total score of ≥2 points,
will be summarized at each time point. Similar analyses will be performed for QMG, including
sustainability of response as defined for MG-ADL above, where QMG response is defined as improvement
of ≥3 points.
Time to first MG-ADL response in the double-blind placebo-controlled period will be summarized with
Kaplan-Meier estimates.
The percentage of participants with minimum symptom expression, defined as a MG-ADL total score of 0
or 1, will be summarized at each time point. The percent of participants with minimum symptom expression
at any time point, at 50% of all time points, and at 75% of all time points during the 24-week double-blind
placebo-controlled phase will also be summarized.
Change from baseline in the Neuro-QoL Fatigue total score, MG-QoL15r total score, and PGI-S will each
be analyzed using a similar MMRM described above for the primary efficacy endpoint. The frequency
distributions of PGI-S and PGI-C scores will also be summarized at each time point. Descriptive statistics
of the change from baseline in EQ-5D-5L visual analog scale and health status index will be summarized
at each time point. The distribution of the level of responses (level 1, 2, 3, 4, and 5) for each of the
EQ-5D-5L health dimensions of mobility, self-care, usual activity, pain and discomfort, and anxiety and
depression will be summarized at each time point.
Analyses of the MG-ADL described above, and for selected secondary efficacy endpoints, will be repeated
for the full analysis set (both seropositive and seronegative participants) and for the seronegative subgroup.

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Additional descriptive summaries of MG-ADL will be performed for each type of anti-autobody
(anti-AChR, anti-MuSK, anti-LRP4) as the sample size in each subgroup allows.
The raw data sampled by the actigraphy watch sensors will be transformed into derived digital health
endpoints, assessing the changes on physical activity, mobility and sleep parameters during the 24-week
double-blind placebo-controlled phase. Endpoints include, but are not limited to, step count, activity count,
sleep time, sleep efficiency, and percent mobile time.
Open-label Extension Phase
All efficacy data will be summarized using descriptive statistics.
Other Analyses
Serum nipocalimab concentrations will be summarized over time to assess the PK of nipocalimab.
The incidence and titers of antibodies to nipocalimab will be summarized by treatment group over time.
Selected circulating biomarkers will be assayed and their potential relationship to clinical status may be
explored.
A pharmacometrics model-based assessment will be conducted to describe the relationships of PK, PD (IgG
lowering), and efficacy (MG-ADL and QMG). Details will be provided in a model-based PK/IgG/efficacy
analysis plan, and results of the model-based PK/IgG/efficacy analysis will be presented in a separate
technical report.
Safety Analyses
Safety data will be analyzed for both study phases using the full analysis set.
The verbatim terms used in the electronic case report form (eCRF) by investigators to identify AEs will be
coded using the Medical Dictionary for Regulatory Activities (MedDRA). All reported AEs will be
included in the analysis. For each AE, the percentage of participants who experience at least 1 occurrence
of the given event will be summarized by treatment group. Separate summaries will be provided for each
phase of the study. Participants who die, who discontinue treatment due to an AE, or who experience an
SAE will be summarized separately. Listings of all participants with MACE (non-fatal myocardial
infarction, stroke, and cardiovascular death) will be provided.
The treatment-emergent AEs (TEAEs) of special interest (AESI) will be examined separately grouped in
the following categories: Severe or serious infections and hypoalbuminemia (<20 g/L). The AESIs will be
further listed in the SAP.
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly abnormal
results will be used in the summary of laboratory data. Descriptive statistics will be calculated for each
laboratory analyte at baseline and for observed values and changes from baseline at each scheduled time
point. Frequency tabulations of the abnormalities will be provided. A listing of participants with any
markedly abnormal laboratory results will also be provided.
The ECG data will be summarized by ECG parameter. Descriptive statistics will be calculated at baseline
and for observed values and changes from baseline at each scheduled time point. Frequency tabulations of
the abnormalities will be made. All clinically relevant abnormalities in ECG waveforms that are changes
from the baseline readings will be reported.
Descriptive statistics of temperature, pulse/heart rate, respiratory rate, body weight measurements, and
blood pressure (systolic and diastolic) values and changes from baseline will be summarized at each
scheduled time point. The percentage of participants with values beyond clinically important limits will be
summarized.

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The percentage of participants with suicidal ideation or suicidal behavior based on the C-SSRS will be
summarized.
1.2. 
Schema
Figure 1: 
Schematic Overview of the Study

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c
Phone visits are to be performed by telephone call only (notvideo call).
d
Must be signed before first study-related activity.
e
Minimum criteria for the availability of documentation supporting the eligibility criteria are described in Source Documentation in Appendix 4, Regulatory, Ethical,
and Study Oversight Considerations. Check clinical status again before first dose of study intervention.
f
These assessments should be performed for all participants. For participants who continue to the OLE phase, these assessments must be completed prior to the first
infusion of the OLE phase.
g
Participants who continue to OLE phase only.
h
The participant’s acetylcholinesterase inhibitor dose must be withheld for approximately 12 hours or longer prior to performing MG-ADL and QMG at
all visits, and attempts will be made to reschedule the visit within the per protocol visit window if the dose was taken <12 hours prior. Participants may take
their dose of acetylcholinesterase inhibitor once the MG-ADL and QMG are completed. All the efficacy assessments must be done starting at approximately the
same time of day (± 2 hours) as performed at screening, and prior to study intervention administration on infusion days. The following PROs must be completed
first: Neuro-QoL-Fatigue, PGI-S, PGI-C, MG-QoL15r, EQ-5D-5L followed by the MG-ADL and then the QMG (in that order). The C-SSRS should be performed
after completion of the efficacy assessments.
i
Complete physical examination, including assessments of the skin, head, eyes, ears, nose, throat, neck, thyroid, lungs, heart, abdomen, lymph nodes, extremities.
j
Focused physical examination for changes in neurologic function, upper respiratory tract (ears, nose, throat, and sinuses), eyes, and lungs, abdomen, or skin.
k
Vital signs (temperature, recumbent systolic blood pressure and diastolic blood pressure, respiratory rate, and pulse rate) will be measured prior to the start of each
infusion, 30 minutes post-infusion (all infusions), and 1-hour post-infusion (first 3 infusions).
l
Participants will be observed for safety 1-hour post-infusion after the first 3 infusions; if no clinically relevant AEs related to the infusion are observed in these first
3 infusions, participants will be observed for 30 minutes after subsequent infusions. Refer to Section 8.2.7 and Section 8.2.8 for details for infusion reaction
evaluation.
m
A full lipid panel will be collected at this visit. Lipid labs at Screening visit can be non-fasting, while all other lipid draws in the double-blind placebo-controlled
phase will be fasting. Fasting is recommended for at least 6 hours. Fasting lipid panel includes total cholesterol, HDL, LDL (calculated), and triglycerides. If
sites/participants cannot accommodate fasting for the duration of the double-blind placebo-controlled phase due to scheduling or medical issues, non-fasting may be
permitted following discussion with the sponsor’s medical monitor.
n
Women of childbearing potential only, including premenopausal or perimenopausal (ie, not postmenopausal where postmenopausal is defined as amenorrhea 12
months or greater), and also including those with a screening FSH ≤40 IU/L or 40 mIU/mL. Additional serum pregnancy testing may be performed at the discretion
of the investigator or if required by local regulations.
o
Test results must be read prior to dosing.
p
All blood samples for assessing predose serum nipocalimab concentration and antibodies to nipocalimab MUST be collected BEFORE the administration of the
study intervention. One blood sample (instead of 2) will be collected for PK/ADA and the obtained serum sample will be split for each assay. Postdose samples will
be collected 45 minutes (±15 minutes) after the end of infusion. The blood sample should be drawn from the opposite arm than the IV line.
q
In China, anti-LRP4 autoantibody collection will only be tested at Screening.
r
Exploratory biomarkers (including but not limited to IgG subtypes, IgM, IgA, and IgE) are not applicable for collection in China.
s
Medical resource utilization (MRU) data, associated with medical encounters, will be collected using the Healthcare Resource Use Questionnaire (HRUQ) and will
be reviewed at the scheduled visits and on an ongoing basis whenever an encounter occurs.

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t
Only applicable to participants randomized at select sites post-Amendment 1. The actigraphy watch will be provided to the participant at the screening visit and
worn continuously on the non-dominant wrist from the screening visit until Week 24/ET/EOP of the double-blind placebo-controlled phase. Participants who will
not prove eligible will return their actigraphy watch to the study site. Participants will bring the watch to each visit, during which the data from the watch may be
downloaded, as necessary. At the Week 24/ET/EOP visit, participants will return the actigraphy watch to the study site.
u
FSH at screening is required for female participants exhibiting amenorrhea for approximately 12 months (ie, perimenopausal). If the FSH is not elevated (i,. if FSH
is ≤40 IU/Lor 40 mIU/mL), they must follow contraception guidance for WOCBP. Women exhibiting amenorrhea for 12 months or greater are classified as post-
menopausal and do not need FSH testing.

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first: Neuro-QoL-Fatigue, PGI-S, PGI-C, MG-QoL15r, EQ-5D-5L followed by the MG-ADL and then the QMG (in that order). The C-SSRS should be performed
after completion of the efficacy assessments.
f
Full physical examinations to be performed at OLE enrollment and end of treatment/early termination, and a focused physical examination at all other site visits.
Focused physical examinations should determine if there has been any change in neurologic function, upper respiratory tract (ears, nose, throat, and sinuses), eyes
and lungs, abdomen, or skin.
g
Vital signs (temperature, recumbent systolic blood pressure and diastolic blood pressure, respiratory rate, and pulse rate) will be measured prior to the start of each
infusion, 30 minutes post-infusion (all infusions), and 1-hour post-infusion (first 3 infusions).
h
Participants will be observed for safety 1-hour post-infusion after the first 3 infusions; if no clinically relevant AEs related to the infusion are observed in these first
3 infusions, participants will be observed for 30 minutes after subsequent infusions. Refer to Section 8.2.7 and Section 8.2.8 for details for infusion reaction
evaluation.
i
Women of childbearing potential only, including premenopausal or perimenopausal (ie, not postmenopausal where postmenopausal is defined as amenorrhea
12 months or greater), and also including those with a screening FSH ≤40 IU/L or 40 mIU/mL. Additional serum pregnancy testing may be performed at the
discretion of the investigator or if required by local regulations.
j
Test results must be read prior to dosing.
k
Blood samples must be collected before the start of the nipocalimab infusion.
l
The serum from this blood sample will be split into aliquots and may be tested for nipocalimab concentrations, ADA, and NAb.
m
All blood samples for assessing predose serum nipocalimab concentration and antibodies to nipocalimab MUST be collected BEFORE the administration of the
study intervention. One blood sample (instead of 2) will be collected for PK/ADA and the obtained serum sample will be split for each assay.  The blood sample
should be drawn from the opposite arm than the IV line.
n
Exploratory biomarkers (including but not limited to IgG subtypes, IgM, IgA, and IgE) are not applicable for collection in China.
o
In China, anti-LRP4 will only be tested at screening.
p
Medical resource utilization (MRU) data, associated with medical encounters, will be collected using the Healthcare Resource Use Questionnaire (HRUQ) and will
be reviewed at the scheduled visits and on an ongoing basis whenever an encounter occurs.
q
FSH at screening is required for female participants exhibiting amenorrhea for approximately 12 months (ie, perimenopausal). If the FSH is not elevated (ie, if FSH
is ≤40 IU/L or 40 mIU/mL), they must follow contraception guidance for WOCBP. Women exhibiting amenorrhea for 12 months or greater are classified as post-
menopausal and do not need FSH testing.

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Footnotes:
a 
The participant’s acetylcholinesterase inhibitor dose must be withheld for approximately 12 hours or longer prior to performing MG-ADL and QMG at
all visits, and attempts will be made to reschedule the visit within the per protocol visit window if the dose was taken <12 hours prior. Participants may take
their dose of acetylcholinesterase inhibitor once the MG-ADL and QMG are completed. All the efficacy assessments must be done starting at approximately the
same time of day (± 2 hours) as performed at screening, and prior to study intervention administration on infusion days. The following PROs must be completed
first: Neuro-QoL-Fatigue, PGI-S, PGI-C, MG-QoL15r, EQ-5D-5L followed by the MG-ADL and then the QMG (in that order).  The C-SSRS should be performed
after completion of the efficacy assessments.
b 
Full physical examinations to be performed at study enrollment and end of treatment/early termination, and a focused physical examination at all other site visits.
Focused physical examinations should determine if there has been any change in neurologic function, upper respiratory tract (ears, nose, throat, and sinuses), eyes
and lungs, abdomen, or skin.
c 
Vital signs (temperature, recumbent systolic blood pressure and diastolic blood pressure, respiratory rate, and pulse rate) will be measured prior to the start of each
infusion and 30 minutes post-infusion.
d 
Participants will be observed for safety 1-hour post-infusion after the first 3 infusions; if no clinically relevant AEs related to the infusion are observed in these first
3 infusions, participants will be observed for 30 minutes after subsequent infusions. Refer to Section 8.2.7 and Section 8.2.8 for infusion reaction evaluation.
e 
Women of childbearing potential only. Additional serum pregnancy testing may be performed at the discretion of the investigator or if required by local regulations.
f 
Test results must be read prior to dosing.
g 
Blood samples must be collected before the start of the nipocalimab infusion.
h 
The serum from this blood sample will be split into aliquots and may be tested for ADA, nipocalimab concentrations, and NAb.
i 
All blood samples for assessing predose serum nipocalimab concentration and antibodies to nipocalimab MUST be collected BEFORE the administration of the
study intervention. One blood sample (instead of 2) will be collected for PK/ADA and the obtained serum sample will be split for each assay. The blood sample
should be drawn from the opposite arm than the IV line.
j 
Exploratory biomarkers (including but not limited to IgG subtypes, IgM, IgA, and IgE) are not applicable for collection in China
k 
In China, anti-LRP4 will only be tested at screening.

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Table 4: 
Safety Follow-up Phase
Phase
Safety Follow-up Visit
Study Week
Varies Per Participant
Visit
8 Weeks after the participants last infusion of study intervention
Visit Window, ±Days
±7
Study Procedure
Weight
X
Chemistry, hematology, non-fasting lipid panel, and urinalysis
X
Urine pregnancy testa
X
Physical examination
X
C-SSRS
X
Vital signs
X
12-lead ECG
X
Serum for, nipocalimab concentrations, ADA, and NAbb
X
Serum for Ig typesc
X
Adverse events
X
Concomitant medications
X
Participants who permanently discontinue or withdraw from any phase of the study will be requested to return to the study site 8 weeks from last infusion to complete
follow-up assessments
a 
Women of childbearing potential only.
b 
The serum from this blood sample will be split into aliquots and may be tested for ADA, nipocalimab concentrations, and NAb.
c 
Exploratory biomarkers (including but not limited to IgG subtypes, IgM, IgA, and IgE) are not applicable for collection in China.

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2. 
INTRODUCTION
With a prevalence of 15 to 25 cases per 100,000 individuals and an annual incidence of 0.8 to 1
case per 100,000 individuals (Carr 2010; Gilhus 2019), myasthenia gravis (MG) is a rare,
heterogeneous, neuromuscular disease characterized by fluctuating, fatigable muscle weakness.
Weakness most often affects ocular, bulbar, proximal extremity, neck, and respiratory muscles,
fluctuates during the day, and worsens with fatigue, repetitive activities, heat, infection, and stress
(Grob 2008). In most cases, initial symptoms are ocular and include ptosis and diplopia, but within
2 to 3 years of onset, the disease usually worsens and other muscles become affected; this is
referred to as generalized MG (gMG). Additional symptoms typically include difficulty chewing,
dysphagia, dysarthria, hypophonia, dyspnea, an inability to hold the mouth closed, a “snarling”
expression when attempting to smile, an appearance of sadness or sleepiness, difficulty holding
the head upright, and weakness in the hands and feet (Grob 2008; Scherer 2005). Disease
progression is associated with considerable morbidity due to aspiration, an increased incidence of
respiratory infections and of falls, and side effects of immunosuppressant therapies (Gilhus 2016a).
In addition, respiratory muscle weakness can lead to myasthenic crisis, which can be life
threatening and require hospitalization, mechanical ventilation, tube feeding, fast-acting
immunosuppressive agents, and intensive care (Gilhus 2016a; Sanders 2016).
Myasthenia gravis is caused by pathogenic autoantibodies that impair cholinergic transmission in
the postsynaptic membrane at the neuromuscular junction and impair or prevent muscle
contraction (Gilhus 2015; Gilhus 2016a; Gilhus 2016b). In approximately 85% of cases,
circulating antibodies target the acetylcholine receptor (AChR) itself. Up to half of the remaining
15% of patients have antibodies against muscle-specific tyrosine kinase (MuSK), an enzyme
critical for neuromuscular junction formation and agrin induced AChR clustering, while
approximately 7% to 8% of patients have neither anti-AChR nor anti-MuSK antibodies and have
historically been considered “seronegative” (Meriggioli 2012). In this latter group, approximately
10% have pathogenic autoantibodies against lipoprotein-related protein receptor 4, an end plate
protein that, along with MuSK, serves as an agrin receptor and is required for AChR clustering
and normal neuromuscular junction formation (Meriggioli, 2012; Zhang 2012).
There is no cure for MG and most patients require lifelong treatment (recently reviewed in
Barnett 2019; Dalakas 2019; Farmakidis 2018; Gilhus 2019; Mantegazza 2018; Morren 2020).
Preferred symptomatic treatment of gMG is with acetylcholinesterase inhibitors, such as
pyridostigmine (Sanders 2016). However, to meet the treatment goals of full or nearly full physical
function and a high quality of life, most patients with gMG also require thymectomy and/or
treatment with corticosteroids and/or immunosuppressive medications, such as azathioprine,
mycophenolate, mofetil/mycophenolic acid, cyclosporine, and tacrolimus (Barnett 2019). More
recently, targeted immunosuppressants have been used, such as rituximab, a B-cell depleting
monoclonal antibody and eculizumab, an inhibitor of C5 activation, which is a key step in
complement activation (Barnett 2019). Several new agents, including rozanolixizumab,
efgartigimod, and RVT-1401, are under investigation (Gable 2020). For acute severe episodes,
fast-acting therapeutic modalities aimed at removing autoantibodies, such as plasma exchange and
immunoadsorption, 
or producing 
immunomodulatory 
effects, 
such as 
intravenous

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immunoglobulin (IVIg), are often used. While many patients with gMG can be managed with
existing therapies, most of these treatments are associated with sometimes serious side effects,
pregnancy contraindication, accessibility issues, patient inconvenience, and overall time and cost
implications. Despite availability of treatment options, significant unmet need persists, as 10% to
20% of patients may not respond to treatment and are currently left with no viable therapeutic
options (Schneider-Gold 2019; Silvestri 2014); this significant unmet need was also reflected by
the 7% self-reported refractory cases in a recent survey of US MGFA registry participants
(Boscoe 2019). These patients either fail to respond adequately or cannot tolerate multiple
therapies for MG and continue to suffer profound muscle weakness and severe disease symptoms
that limit function and can be life threatening (Howard 2013; Mantegazza 2018; Sanders 2016;
Sathasivam 2014; Silvestri 2014). Thus, there is a clear unmet medical need for new safe and
effective treatments for gMG.
Nipocalimab (also referred to as JNJ-80202135 or 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 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 IgG, resulting in a decrease in circulating IgG antibody levels, including pathogenic
IgG autoantibodies and alloantibodies. FcRn has been shown also 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 immunoglobulin 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 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).

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For the most comprehensive nonclinical and clinical information regarding nipocalimab, refer to
the latest version of the Investigator's Brochure (IB).
The term “study intervention” throughout the protocol, refers to the biologic product as defined in
Section 6.1, Study Interventions Administered.
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
Results of clinical studies support nipocalimab’s safety and potential efficacy. As discussed in
Section 2.2, nipocalimab was well tolerated by healthy adults in 3 completed Phase 1 studies and
by adult patients with gMG in a completed Phase 2 study. In all studies, treatment with nipocalimab
produced marked and sustained reductions in IgG concentrations, confirming its intended
mechanism of action. In the Phase 2 gMG study, nipocalimab produced rapid, dose-dependent,
sustained IgG and anti-AchR autoantibody reduction. Correspondingly, clinically meaningful
improvement in disease manifestations as measured by the Myasthenia -Gravis-Activities of Daily
Living (MG-ADL) scale and other efficacy endpoints were observed. These data support continued
development of nipocalimab for gMG. The present study is a Phase 3 pivotal study to confirm
efficacy of nipocalimab in gMG.
2.2. 
Background
Nonclinical Studies
The nonclinical pharmacology, pharmacokinetics (PK), and toxicity of nipocalimab have been
adequately characterized in appropriately designed nonclinical studies that support the potential
efficacy, safety, and mechanism of action. Pharmacological 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.
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
receptor occupancy 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

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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 gMG.
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 of single ascending doses (SAD; n=34) up to 60 mg/kg
and multiple ascending doses (MAD; n=16) up to 30 mg/kg weekly for 4 weeks
(MOM-M281-001), a single-dose escalating infusion rate study (MOM-M281-007; n=40), and a
single escalating dose study conducted in Japanese adults (MOM-M281-010; n=24).
Pharmacokinetic parameters for IV nipocalimab showed dose dependency and likely
target-mediated disposition. Across the SAD dose groups (0.3 to 60 mg/kg), maximum serum
nipocalimab concentration (Cmax) increased in a dose-proportional manner, whereas area under the
concentration-time curve (AUC) increased in a greater than dose-proportional manner. Serum
clearance (CL) decreased nearly 50% from 10 to 60 mg/kg, while half-life (t1/2) increased with
increasing dose, from 7.36 hours at 3 mg/kg to 32.2 hours at 60 mg/kg. Pharmacokinetic
parameters of nipocalimab were not estimated for the MAD dose groups (15 or 30 mg/kg weekly
x 4) due to sparse PK sampling design on the MAD part of the study.
A close PK/PD relationship was observed, with the onset of PD effects (FcRn RO, 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
15 minutes to 2 hours.
In SAD and MAD in healthy participants, there was no clear relationship between nipocalimab
dose and the presence of neutralizing antibodies (NAbs), anti-drug antibodies (ADA), or ADA
titers.

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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; n=14], 30
mg/kg q4w [n=13], 60 mg/kg every 2 weeks [q2w; n=14], and 60 mg/kg single dose [n=13]) and
the IV placebo group (n=14). 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 Common
Terminology Criteria for Adverse Events ≥Grade 3, or adverse events of special interest (AESIs,
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
participant (30 mg/kg q4w) and 2 SAEs (ischaemic stroke, myasthenia gravis) were reported in
placebo-treated participants; none of the SAEs were considered by the investigator as related to
study intervention.
Preliminary safety data on a limited number of patients with gMG in the recently terminated long-
term extension study (MOM-M281-005) and in the wAIHA study have raised no safety concerns.
A Phase 2 study which is evaluating IV nipocalimab administered to pregnant women at high risk
for EOS-HDFN (MOM-M281-003) is ongoing. Refer to the IB for details.
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
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.
2.3. 
Benefit-Risk Assessment
The potential risks of exposure to nipocalimab based on its mechanism of action are summarized
in Table 5.
More detailed information about the known and expected benefits and risks of nipocalimab may
be found in the IB.

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2.3.1. 
Risks for Study Participation
Table 5: 
Potential Risks for Study Participation
Potential Risks of
Clinical Significance
Summary of Data/
Rationale for Risk  
Mitigation Strategy
Lack of improvement
or clinical worsening
of gMG
A Phase 2 study of nipocalimab in gMG has 
shown that the majority of, but not all, 
patients responded to nipocalimab. 
During the study, participants will be
permitted to continue treatment of
gMG with standard of care
medications (Section 6.8).
Participants may discontinue study
intervention if it is not in their best
interest or if they need to initiate
protocol-prohibited medications
including certain biologics
(Sections 6.8.1 and 7.1).
Participants will be allowed to use
rescue medications as needed
(Section 6.8.2).
Risks Due to Study Intervention(s)
Potential Increased
Risk for Infection
due to Decreased
Serum IgG
Concentrations
As predicted based on its mechanism of
action, nipocalimab was associated with
dose-dependent reductions in IgG of up to
80% to 85% of baseline in cynomolgus
monkey and human studies. However,
nipocalimab did not increase either the
incidence, severity, or duration of infection
in any of the nonclinical and clinical studies
conducted to date.
Patients with severe acute or chronic
infections requiring anti-infective
therapies are excluded from
participation in the study
(Section 5.2).
Temporary and permanent study
intervention stopping criteria for
infections are included in
Sections 7.1 and 7.2 respectively.
All infections will be monitored
closely. Treatment-emergent
infections meeting the AESI criteria
must be reported to the sponsor
within 24 hours (Section 8.3.6).
Participants who have had a live
vaccine within 4 weeks prior to
screening or have a known need to
receive a live vaccine during the
study, or within at least 8 weeks after
the last dose of study intervention in
this study are excluded from
participation in the study.
Reduced
Effectiveness of
Routine Vaccines due
to Decreased IgG
Due to the expected reduction in IgG as a 
result of the overall effect of nipocalimab on 
total IgG concentrations, a reduction in 
vaccine-specific IgG titers can be expected. 
While decreases in vaccine titers were
observed in the FIH study, there has been no
increase in the incidence, severity, or
duration of infection in any of the nonclinical
and clinical studies conducted to date.
It is recommended that participants
are up-to-date on all age-appropriate
vaccinations prior to screening as per
routine local medical guidelines.
Non-live vaccinations should be
administered as per the assessment
of the investigator.
Activation of Latent
Virus due to
Decreased IgG
Due to the expected reduction in IgG as a 
result of the overall effect of nipocalimab on 
IgG concentrations, activation of latent virus
Serology testing is done at screening
to exclude participants with HIV, or

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Table 5: 
Potential Risks for Study Participation
Potential Risks of 
Clinical Significance 
Summary of Data/
Rationale for Risk  
Mitigation Strategy
is a potential risk. To date, there has been no 
observed increase in the frequency of latent 
virus activation in clinical studies with 
nipocalimab. 
hepatitis B or C infection
(Section 5.2).
Temporary and permanent study
intervention stopping criteria for
infections are included in
Sections 7.1 and 7.2, respectively.
Infections will be monitored closely
and treatment-emergent infections
meeting the AESI criteria must be
reported to the sponsor within
24 hours (Section 8.3.6).
Clinical 
Manifestations of 
Hypoalbuminemia 
Nipocalimab selectively targets the IgG 
binding site on FcRn and does not block the 
albumin binding site. Reasons for observed 
albumin modulations are under investigation.
Nipocalimab was associated with modest,
self-limited, recoverable and asymptomatic
reductions in albumin, in both the nonclinical
and clinical studies conducted to date. 
Participants will be monitored for
albumin abnormalities by regular
safety laboratory assessments.
Hypoalbuminemia <20 g/L should
be reported as AESI within 24 hours
(Section 8.3.6).
Study intervention interruption rules
for 3+ pedal edema, ascites, or
pleural or pericardial effusions are
included in the protocol.
(Section 7.1.2)
Infusion Reaction  
Infusion reactions have been observed with 
the administration of biologics, and in 
particular with monoclonal antibodies.
For the most up to date information, refer to
the Infusion Reaction section of the
nipocalimab IB.
Participants will be monitored for
infusion reactions.
Drug-drug interaction  Nipocalimab is expected to reduce exposure 
of therapeutic agents that contain the Fc 
region of IgG (eg, IVIg, Fc-based biologics 
like eculizumab, rituximab, infliximab,
adalimumab, and Fc fusion proteins).
The DDI observed in study MOM-M281-008 
was consistent with the mechanism of action 
of nipocalimab and confirmed the hypothesis 
that nipocalimab could reduce the PK 
exposure of IgG-based mAbs via inhibition 
of FcRn mediated recycling. 
High doses of nipocalimab may reduce 
serum albumin up to 25%. The concomitant 
use of drugs with both high protein binding
rate (>95%) and narrow therapeutic index
may lead to higher free drug concentrations
which could increase the risk for potential
toxicities.
For the most up to date information, please
refer to Drug-drug Interactions section of the
nipocalimab IB.
Patients who are on IgG Fc-
containing protein therapeutics are
excluded from the study.
Patients treated with nipocalimab
and who are on concomitant
medications which have high protein
binding rate (>95%) and narrow
therapeutic index (such as but not
limited to warfarin, sulfasalazine,
mycophenolate mofetil, leflunomide)
should be monitored for potential
impacts of nipocalimab on efficacy
and safety of those medications.

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Table 5: 
Potential Risks for Study Participation
Potential Risks of 
Clinical Significance 
Summary of Data/
Rationale for Risk  
Mitigation Strategy
Increased lipids 
Elevations in total cholesterol and LDL were 
reported recently with another experimental 
drug in the same pharmacological class of 
FcRn antagonists. 
In the MOM-M281-001 and
MOM-M281-004 studies, asymptomatic,
dose dependent, reversible elevations in
non-fasting mean total cholesterol were
observed up to 25% of baseline. In both
studies, elevations in total cholesterol appear 
to mirror the kinetics of the decreases in 
albumin observed with nipocalimab. 
For the most up to date information, please 
refer to the Increased Lipids section of the 
nipocalimab IB. 
Participants with recent MI, stroke,
or unstable angina, within 12 weeks
of study entry will be excluded from
participation in the study.
Routine laboratory investigations for
lipid panel (Total cholesterol, LDL,
HDL, Triglycerides) will be
performed in the study.
Lipids are routinely monitored in
participants throughout the study.
In participants with elevated lipids at
any time during the study, it is
recommended that investigators
initiate or continue appropriate
therapy for dyslipidemia as per local
health guidelines. In participants
with persistently elevated lipids
(above LDL threshold of 190 mg/dL
or the triglyceride threshold of
1,000 mg/dL), it is strongly
recommended that investigators
initiate appropriate therapy or
modify current therapy for
dyslipidemia per local health
guidelines.
Placental infarction  
Abnormal placental infarctions have been 
observed in non-clinical and clinical studies 
of nipocalimab. Placental infarction could 
lead to reduced placental function, and, as a 
result, inadequate fetal growth and
development.
For the most up to date information, please
refer to the Placental Infarction section of the
nipocalimab IB.
Pregnant women are excluded from
this study and patients must agree to
use highly effective methods of
contraception.
Pregnancy tests are conducted
throughout. Participants who become
pregnant will be withdrawn and
followed up until delivery or
termination of pregnancy.
Low IgG in infants 
born to mothers with 
EOS-HDFN 
receiving 
nipocalimab during 
pregnancy  
Low IgG concentrations in infants born to 
mothers with EOS-HDFN receiving 
Nipocalimab during pregnancy (between 
Weeks 14 to 35) were observed. 
For the most up to date information, please
refer to the Low IgG in Infants Born to
Mothers With EOS-HDFN Having Received
Nipocalimab During Pregnancy section of
the nipocalimab IB.
Pregnant women are excluded from
this study and patients must agree to
use highly effective methods of
contraception.
Pregnancy tests are conducted
throughout. Participants who become
pregnant will be withdrawn and
followed up until delivery or
termination of pregnancy.
Abbreviations: AESI adverse event of special interest; DDI drug-drug interaction; EOS early onset severe;
Fc fragment crystallizable; FcRn neonatal Fc receptor; FIH first in human; gMG  generalized myasthenia
gravis; HDFN hemolytic disease of the fetus and newborn; HDL high density lipoprotein; virus; HIV human
immunodeficiency virus; IB investigator’s brochure; IgG immunoglobulin G; IVIg intravenous
immunoglobulin; LDL low density lipoprotein; mAb monoclonal antibody; MI myocardial infarction;
PK pharmacokinetic(s).

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2.3.2. 
Benefits for Study Participation
There is no established benefit to participants of receiving study intervention. There is evidence
that inflammation through autoantibodies and IgG-antigen immune complexes plays an important
role in the pathogenesis of gMG. Given the scientific rationale for FcRn blockade and that
nipocalimab shows early signs of efficacy in an autoantibody-driven disease like gMG,
nipocalimab may provide benefit in the treatment of gMG (Section 2.2). Participants in the study
will help in evaluating this study intervention in the treatment of gMG and increasing
understanding of gMG. Thus, the knowledge gained from this study has the potential to benefit
many more patients suffering from gMG and thus offers potential public health benefits.
Participants may also experience some benefit from the participation in a clinical study irrespective
of receiving study treatment, due to regular visits and assessments monitoring their overall health.
2.3.3. 
Benefit-Risk Assessment for Study Participation
The available results from nonclinical and clinical studies (Phase 1 and Phase 2 studies), the
scientific and clinical rationale for the anti-IgG mechanism of action in gMG, and the measures
taken to minimize the potential risks justify the potential benefits that may be provided to
participants with gMG in this study.
3. 
OBJECTIVES AND ENDPOINTS
The study objectives and related outcome measures are shown in the table below.
Objective 
Outcome Measures
Primary Objective
To evaluate the efficacy of nipocalimab 
compared to placebo based on the 
Myasthenia Gravis-Activities of Daily
Living (MG-ADL) scale, in
seropositive generalized myasthenia
gravis (gMG) participants when
treatment is taken as directed.
Average change from baseline in MG-ADL score over Weeks 22,
23, and 24 of the double-blind placebo-controlled phase.
Key Secondary Objectives
To evaluate the efficacy of nipocalimab 
compared to placebo based on the 
Quantitative Myasthenia Gravis
(QMG) scale, in seropositive gMG
participants when treatment is taken as
directed.
Average change in QMG score over Weeks 22 and 24 of the
double-blind placebo-controlled phase.
To evaluate the effect of nipocalimab 
compared to placebo in achieving the 
minimum clinically important 
difference (MCID) or better based on 
the MG-ADL scale, in seropositive
gMG participants when treatment is
taken as directed.
Percentage of participants whose average improvement in MG-
ADL total score over Weeks 22, 23, and 24 of the double-blind
placebo-controlled phase is at least a 2-point improvement
compared to baseline.
To evaluate the efficacy of nipocalimab 
loading dose compared to placebo 
based on the MG-ADL scale, in 
Percentage of participants with improvement in MG-ADL total
score ≥ 2 points at Week 1 and/or Week 2 of the double-blind
placebo-controlled phase.

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Objective 
Outcome Measures
seropositive gMG participants when
treatment is taken as directed.
To evaluate sustainability of
therapeutic response of nipocalimab
compared to placebo based on the MG-
ADL scale, in seropositive gMG
participants when treatment is taken as
directed.
Percentage of participants with improvement in MG-ADL total
score ≥ 2 points at Week 4 through Week 24 of the double-blind
placebo-controlled phase with no more than 2 non-consecutive
excursions allowed between Week 6 through Week 23 (excursion
defined as loss of improvement in MG-ADL score ≥2 points from
baseline).
To evaluate the effect of nipocalimab
compared to placebo on the percentage
of participants achieving ≥50%
symptom improvement based on the
MG-ADL scale, in seropositive gMG
participants when treatment is taken as
directed.
Percentage of participants whose average improvement in
MG-ADL total score over Weeks 22, 23, and 24 of the
double-blind, placebo-controlled phase is at least a 50%
improvement from baseline.
Other Secondary Objectives
To evaluate safety and tolerability of
treatment with nipocalimab.
Proportion of participants with adverse events (AEs), serious AEs
(SAEs), AEs of special interest (AESIs: severe or serious
infections and hypoalbuminemia < 20g/L).
Change in vital sign and clinical laboratory values.
Change in Columbia-Suicide Severity Rating Scale (C-SSRS)
score.
To evaluate sustainability of 
therapeutic response of nipocalimab 
compared to placebo based on the 
QMG scale, in seropositive gMG 
participants, when treatment is taken as 
directed.
Percentage of participants with improvement in QMG of ≥3 points
from baseline at Week 2 through Week 24 of the double-blind
placebo-controlled phase with no more than 2 non-consecutive
excursions allowed at Weeks 4 through 22 (excursions defined as
loss of improvement in QMG score of ≥3 points from baseline).
To evaluate the effect of nipocalimab 
compared to placebo on fatigue based 
on the Quality of Life in Neurological 
Disorders (Neuro-QoL) Fatigue scale,
in seropositive gMG participants when
treatment is taken as directed.
Average change from baseline in the Neuro-QoL Fatigue total
score over Weeks 22 and 24 of the double-blind placebo-
controlled phase.
To evaluate the effect of nipocalimab 
compared to placebo on health-related 
quality of life based on the15-item
Myasthenia Gravis –Quality of Life
(revised) instrument (MG-QoL15r) and
the EuroQol 5-Dimension 5-Level
(EQ-5D-5L) scale, in seropositive gMG
participants when treatment is taken as
directed.
Average change from baseline in the MG-QoL15r score over
Weeks 22 and 24 of the double-blind placebo-controlled phase.
Change from baseline in the visual analog scale and health status
index of the EQ-5D-5L over 24 weeks of the double-blind
placebo-controlled phase.
To evaluate the effect of nipocalimab 
compared to placebo on gMG 
minimum symptom expression based
on the MG-ADL scale, in seropositive
gMG participants when treatment is
taken as directed. 
Percentage of participants with MG-ADL score of 0 or 1 over time
in the double-blind, placebo-controlled phase.
Percentage of participants with MG-ADL score of 0 or 1 at any
time during the double-blind, placebo-controlled phase.
Percentage of participants with MG-ADL score of 0 or 1 at 50%
of timepoints during the double-blind, placebo-controlled phase.
Percentage of participants with MG-ADL score of 0 or 1 at 75% of
timepoints during the double-blind, placebo-controlled phase.

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Objective 
Outcome Measures
To evaluate pharmacokinetics (PK) and
immunogenicity of nipocalimab.
Serum nipocalimab concentrations over time
Incidence and titers of anti-drug antibodies (ADA) to nipocalimab
and presence of neutralizing antibodies (NAb) to nipocalimab
To evaluate pharmacodynamic (PD)
activity of nipocalimab.
PD outcome measure:
Effects on total serum immunoglobulin G (IgG) concentrations
To explore the effects of nipocalimab
treatment on biomarkers of MG disease
biology and response.
Effects on levels of autoantibodies associated with gMG.
Assessment of relationship between IgG lowering and MG-ADL
and QMG.
Evaluate the potential relationship between change in MG-ADL
and/or QMG score, and change in autoantibody levels in
seropositive participants (anti-AChR, anti-MuSK, anti-LRP4) f  
treated with nipocalimab.
Exploratory Objectives
To further evaluate clinically relevant
response to treatment with nipocalimab
compared to placebo in seropositive
gMG participants when treatment is
taken as directed.
Number of participants with a 2-, 3-, 4-, 5-, 6-, 7-, or ≥8 point
improvement in total MG-ADL score over time in the
double-blind placebo-controlled phase.
Number of participants with a 3-, 4-, 5-, 6-, 7-, 8-, or ≥9 point
improvement in total QMG score over time in the double-blind
placebo-controlled phase.
Time to first response (MG-ADL total score improvement of
≥2 points) in the double-blind placebo-controlled phase.
Time to treatment discontinuation during the double-blind
placebo-controlled phase for any reason.
Time to treatment discontinuation during the double-blind
placebo-controlled phase due to Clinical Deterioration requiring
hospitalization or rescue medication use.
Percentage of responders as measured by QMG (improvement on
QMG of ≥3 points) over time in the double-blind placebo-
controlled phase.
Number of participants with a total MG-ADL score of 0 or 1 over
time in the double-blind placebo-controlled phase.
Number of emergency room (ER) visits; number of
hospitalizations; average Length of Stay (LOS) from
hospitalization due to Clinical Deterioration over time in the
double-blind placebo-controlled phase.
To evaluate the efficacy of nipocalimab
compared to placebo in seronegative
gMG participants when treatment is
taken as directed.
Average change from baseline in MG-ADL score over Weeks 22,
23, and 24 of the double-blind placebo-controlled phase.
Average change from baseline in QMG score over Weeks 22 and
24 of the double-blind placebo-controlled phase.
Percentage of participants whose average MG-ADL total score
over weeks 22, 23 and 24 of the double-blind, placebo-controlled
phase is at least a 2-point improvement compared to baseline.
To explore the effects of nipocalimab
on biomarkers of MG disease biology
Evaluate exploratory biomarkersg (including but not limited to IgG
subtypes, IgM, IgA, IgE, MG-associated RNAs, complement
f
In China, anti-LRP4 autoantibody collection will only be tested at screening.
g
Exploratory biomarkers (including but not limited to IgG subtypes, IgM, IgA, IgE) are not applicable for collection
in China.

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Objective 
Outcome Measures
in gMG participants when treatment is
taken as directed.
proteins. Analyses could use proteomic, glycoprotein, and
metabolomic markers).
To explore the changes in physical
activity, mobility, and sleep, as
measured by accelerometry, in
nipocalimab compared to placebo in
seropositive gMG participants when
treatment is taken as directed (at
selected sites).
Change in Actigraphy watch-collected continuous data on
physical activity, mobility, and sleep (including but not limited to
step count, activity count, sleep time, sleep efficiency, and percent
mobile time) during the double-blind placebo-controlled phase (at
selected sites).
To explore the effects of nipocalimab
compared to placebo on fatigue based
on the meaningful change threshold
(MCT) of the Neuro-QoL Fatigue
scale, in seropositive gMG participants
when treatment is taken as directed.
Estimation of MCT threshold using anchor-based, and
distribution- based approaches.
Cumulative Distribution Function curves of change from baseline
in Neuro-QoL Fatigue over time.
Patient Global Impression of Change (PGI-C) and Patient Global
Impression of Severity (PGI-S) frequency distribution of
responses over time (anchoring for Neuro-QoL Fatigue) during the
double-blind placebo-controlled phase.
To explore the long-term efficacy of
nipocalimab 15 mg/kg q2w during the
open-label extension phase.
Change from baseline in the total MG-ADL score over time
during the open-label extension phase.
Number of participants with a 2-, 3-, 4-, 5-, 6-, 7-, or ≥8 point
improvement in total MG-ADL score over time during the open-
label extension phase.
Change from baseline in total QMG score over time during the
open-label extension phase.
Percentage of responders as measured by QMG (improvement on
QMG of ≥3 points) over time during the open-label extension
phase.
Change from baseline in Neuro-QoL Fatigue scores over time
during the open-label extension phase.
Number of participants with a total MG-ADL score of 0 or 1 over
time during the open-label extension phase.
Change from baseline in the MG-QoL15r score over time during
the open-label extension phase.
Change from baseline in the visual analog scale and health status
index of the EQ-5D-5L over time during the open-label extension
phase.
Number of participants having Clinical Deterioration requiring
hospitalization or rescue therapy during the open-label extension
phase.
PGI-C and PGI-S frequency distribution of responses over time
(anchoring for Neuro-QoL Fatigue) during the open-label
extension phase.
Changes in individualized concomitant medications for gMG over
time during the open-label extension phase.
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.

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HYPOTHESIS
The primary hypothesis of this study is that IV nipocalimab is superior to placebo as measured by
average change from baseline in the MG-ADL score over Weeks 22, 23 and 24 of the double-blind
placebo-controlled phase for seropositive participants (consisting of anti-AChR positive,
anti-MuSK positive, and/or anti-LRP4 positive).
4. 
STUDY DESIGN
4.1. 
Overall Design
This is a multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy
and safety of nipocalimab compared to placebo in participants with gMG who are inadequately
controlled with standard of care therapy. Participants who have completed the double-blind
placebo-controlled phase of the study have an option to receive open-label treatment of
nipocalimab to evaluate long-term safety and efficacy of nipocalimab.
Approximately 190 participants will be enrolled into the double-blind placebo-controlled phase of
this study with 95 in each treatment group. At least 150 eligible seropositive (anti-AChR positive,
anti-MuSK positive, and/or anti-LRP4 positive) participants will be enrolled. Seronegative
participants will also be enrolledh. Participants in each of the seropositive and seronegative groups
will be randomly assigned in a 1:1 ratio to receive either placebo or nipocalimab. The
randomization will be stratified by autoantibody status (anti-AChR and/or anti-MuSK positive,
anti-AChR negative and anti-MuSK negative), Day 1 MG-ADL score (≤9, >9) and region
(East Asia, United States [US], rest of world).
The study will consist of: a screening period of up to 4 weeks, a 24-week double-blind
placebo-controlled phase, and an open-label extension (OLE) phase that will be of variable
duration per participating country/territory depending on the timing of market authorization and
commercial availability of nipocalimab. For EU region  (EUR)-specific information, see
Section 10.10.1. Participants will continue to take their stable MG therapy(ies), if on any,
throughout the screening phase and the double-blind placebo-controlled phase. Tapering one of
the participant’s concomitant MG medications every 4 weeks is allowed in the OLE phase if the
disease has been stable in the past 4 weeks as reflected by MG-ADL scores and based on the
investigator’s discretion. Participants who discontinue or withdraw at any point during the study
will be requested to complete a follow-up assessment 8 weeks after their last infusion of study
intervention. Participants who discontinue study intervention for a reason other than Clinical
Deterioration requiring hospitalization or rescue therapy during the double-blind placebo-
controlled phase, will be encouraged to complete study procedures per the Schedule ofActivities
(Table 1) for the 24-week period. Rollover into the OLE of such participants will not be permitted
unless the 24 weeks of study procedures have been completed. Participants who permanently
discontinue or withdraw from the study either due to a clinical deterioration or for any other reason
h 
Seronegative participants are no longer being recruited; all participants must have a positive serologic test for a
gMG related pathogenic autoantibody (anti-AChR, anti-MuSK and/or anti-LRP4 autoantibodies), confirmed prior
to randomization.

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should complete the ET visit assessments. These participants should also return for a safety follow-
up visit 8 weeks after the last infusion.
Screening Phase
After providing written informed consent and within 28 days prior to the double-blind
placebo-controlled phase, participants will be screened to evaluate their eligibility for study
participation. Participants must have a diagnosis of MG with generalized muscle weakness
meeting the clinical criteria for gMG as defined by the Myasthenia Gravis Foundation of America
(MGFA) Clinical Classification Class II a/b, III a/b, or IV a/b that is not well controlled with stable
MG therapy (or, who discontinued MG therapy due to intolerance or lack of efficacy as specified
in Inclusion Criterion # 4), and MG-ADL score ≥6.
Safety evaluations (eg, physical examination, vital signs, electrocardiogram (ECG), and clinical
laboratory tests [including chemistry, hematology, lipid profiles, and urinalysis]) will be
performed. Adverse events will be collected from the time a signed and dated informed consent
form (ICF) is obtained until the completion of the last study procedure on the final follow-up visit.
Refer to Section 5.4, Screen Failures, for conditions under which the repeat of any screening
procedures are allowed.
Double-blind Placebo-controlled Phase
Participants who meet all inclusion criteria and none of the exclusion criteria will be randomly
assigned in a 1:1 ratio to receive either placebo or nipocalimab (30 mg/kg for first infusion,
15 mg/kg thereafter) once every 2 weeks (q2w). On the q2w schedule (starting from Day 1), the
participants will receive study intervention (placebo or nipocalimab) and undergo safety, efficacy,
PK, PD, and immunogenicity assessments. As outlined in the Schedule of Activities (Section 1.3,
Table 1), the participant will be contacted by phone for a remote assessment of MG-ADL, adverse
events (AEs), and concomitant medications for some assessment visits. Participants who
discontinue study intervention during the double-blind placebo-controlled phase for a reason other
than Clinical Deterioration requiring hospitalization or rescue therapy will be required to complete
study procedures per the Schedule of Activities (Table 1) for the 24-week phase. Rollover into
OLE of such participants will not be permitted unless the 24 weeks of study procedures have been
completed.
Participants will be observed for safety 1-hour post-infusion after the first 3 infusions; if no
clinically relevant AEs related to the infusion are observed in these first 3 infusions, participants
will be observed for 30 minutes after subsequent infusions.
Open-label Extension Phase
Participants who complete the double-blind placebo-controlled phase will continue in an OLE
phase where treatment with nipocalimab will continue until 2 years after marketing authorization
in a participant’s local country/territory or until nipocalimab becomes available commercially or
via other continued access program, whichever comes first. Details specific for sites in EU are
presented in Section 10.10.1. Assessments done at the Week 24 visit of the double-blind placebo-

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controlled phase will serve as baseline (first visit) of the OLE phase, and participants will receive
their first infusion of open-label nipocalimab during the same visit after completion of the Week 24
visit assessments. Please refer to Section 5.1.2 for information on participants eligible to enroll in
the OLE phase.
Due to the coronavirus disease 2019 (COVID-19) pandemic, the MOM-M281-005 study, an
open-label extension study to evaluate the safety, tolerability, and efficacy of nipocalimab
administered to participants with gMG, was placed on hold and subsequently terminated. As a
result, some participants from the MOM-281-004 study, a Phase 2, multicenter, randomized,
double-blind, placebo-controlled study to evaluate the safety, tolerability, efficacy,
pharmacokinetics and pharmacodynamics of M281 administered to adults with generalized
myasthenia gravis, were unable to enroll into the MOM-M281-005 study. Participants affected by
this study termination (either those who were ongoing in the MOM-M281-005 study at the time
of the hold or those who were unable to enroll from MOM-M281-004) will have the opportunity
to directly enter the OLE phase of the present study (bypassing the double-blind placebo-controlled
treatment phase of the present study). These participants will undergo a screening assessment to
confirm eligibility for entry into the OLE phase of the study. If eligible, the participant will start
the OLE phase at Extension Day 1 of the Schedule of Activities (ED1; Table 2).
All participants enrolling in the OLE phase will receive nipocalimab 15 mg/kg q2w by IV infusion
starting on OLE Day 1. Tapering one of the participant’s concomitant MG medications every 4
weeks is allowed in the OLE phase if the disease has been stable in the past 4 weeks as reflected
by MG-ADL scores and based on the investigator’s discretion. 
 No other nipocalimab dosing regimen should be used.
When considering tapering of concomitant MG medications, the investigator should adhere to
the following:
Taper 1 concomitant medication at a time, not 2 concomitant medications simultaneously;
When the decision has been made to taper a corticosteroid concomitant medication, the
following must be done:
For participants on a corticosteroid dose >30 mg per day, the dose should be decreased
by no more than 10 mg every 4 weeks, until a dose of ≤30 mg per day is reached. For
participants on a corticosteroid dose of ≤30 mg per day, the dose should be decreased by
no more than 5 mg every 4 weeks. Once the investigator considers the corticosteroid taper
completed, the participant should remain on the current dosing regimen for nipocalimab
and the concomitant MG medications for at least 4 weeks before considering tapering
another concomitant MG medication.
The tapering of mycophenolate mofetil, azathioprine, or methotrexate should be performed
no more frequently than every 6 months. The tapering of cyclosporine or tacrolimus should
be performed no more frequently than every 3 months.
CCI

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Recalculation of dose during the OLE phase for weight gained or lost will be based on the weight
measured for each participant every 4 weeks through Extension Week 24 and every 12 weeks
thereafter.
Participants will be observed for safety 1-hour post-infusion after the first 3 infusions; if no
clinically relevant AEs related to the infusion are observed in these first 3 infusions, participants
will be observed for 30 minutes after subsequent infusions.
Follow-Up/End of Study Visit
Participants who discontinue or withdraw at any point during the study will be requested to
complete a follow-up assessment 8 weeks after their last infusion of study intervention (Table 4).
An independent Data Monitoring Committee (DMC) and Major Adverse Cardiovascular Events
(MACE) Event Adjudication Committee (EAC) will be commissioned for this study. Refer to
Committees Structure in Appendix 4 (Section 10.4), Regulatory, Ethical, and Study Oversight
Considerations for details.
A diagram of the study design is provided in Section 1.2, Schema (Figure 1).
4.2. 
Scientific Rationale for Study Design
Participant Population
The study population will include adult participants (≥18 years of age) who meet MGFA Clinical
Classification Class II a/b, III a/b, or IV a/b for gMG that is not well controlled with stable MG
therapy (if on any). Published data show that approximately 85% patients with gMG are
anti-AChR positive (Meriggioli 2012). The sponsor proposes to enroll approximately 150 of the
total Phase 3 study population to be seropositive (anti-AChR positive, anti-MuSK positive, and/or
anti-LRP4 positive) and these participants will comprise the primary efficacy analysis set. To
further evaluate the efficacy and safety in seronegative patients, the sponsor proposes to enroll
approximately 40 participants who are seronegativei. Enrolling seronegative participants will help
address the unmet medical need of these patients who are often excluded from clinical trials.
Study Phase/Periods, Intervention Groups
This is a multi-phase study to address several questions. The first phase is a double-blind, placebo-
controlled phase to evaluate the efficacy and safety of nipocalimab compared to placebo in
participants with gMG. Participants will be randomized to nipocalimab (15 mg/kg q2w following
a loading dose of 30 mg/kg) or placebo for 24 weeks. Data collected in this phase address the
primary objective of efficacy of nipocalimab in comparison to placebo.
The second phase is an OLE phase to evaluate long-term safety and efficacy of nipocalimab in
participants with gMG. Participants who completed the double-blind placebo-controlled phase will
i 
Seronegative participants are no longer being recruited; all participants must have a positive serologic test for a
gMG related pathogenic autoantibody (anti-AChR, anti-MuSK and/or anti-LRP4 autoantibodies), confirmed prior
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have the option to receive open-label treatment with nipocalimab. Tapering one of the participant’s
concomitant MG medications every 4 weeks is allowed in the OLE phase if the disease has been
stable in the past 4 weeks as reflected by MG-ADL scores and based on the investigator’s
discretion.
A. 
Choice of Control Arm
The target population for the Phase 3 study is patients with moderate to severe gMG who are not
well controlled by their current standard of care MG therapy; thus, all eligible participants must
have MG-ADL scores ≥6 at screening and baseline and be on stable MG treatment (eg,
glucocorticoids, or immunosuppressants, or must have discontinued corticosteroids and/or
immunosuppressants ≥4 weeks prior to screening due to intolerance orlack of efficacy as specified
in Inclusion Criterion #4). A placebo comparator arm (placebo + standard of care) was chosen for
this study as it is an accepted approach for the conduct of pivotal trials in MG (Howard 2017),
allows for evaluation of a placebo response (Frisaldi 2019), and therefore, provides the most valid
comparison versus active treatment for the analyses of safety, tolerability, efficacy, PD, and
immunogenicity in the selected target population.
B. 
Double-blind Treatment Duration
The duration of the double-blind placebo-controlled phase (24 weeks) is anticipated to be sufficient
for assessment of efficacy and safety based on nipocalimab’s mechanism of action and results of
the Phase 2 study demonstrating efficacy on the MG-ADL as early as Week 2 and sustained up to
Day 57 (the primary assessment time point in Phase 2).
The maintenance of nipocalimab’s effect, as well as the long-term safety of nipocalimab will be
further evaluated in the OLE phase.
C. 
Choice of Primary and Key Secondary Endpoints
The primary endpoint is average change from baseline on the MG-ADL score over Weeks 22, 23
and 24 of the 24-week double-blind placebo-controlled phase. The MG-ADL is a widely used and
well validated patient-reported clinical outcome measure with a 1-week recall period. The
MG-ADL is an 8-item scale, including 2 items on daily life activities which are negatively affected
in most patients with gMG (ability to brush teeth or comb hair and limitations in the ability to rise
from a chair) and 6 items reflecting other MG manifestations (including diplopia, ptosis, chewing,
swallowing, voice/speech problems, and respiratory symptoms), and combines them into a single
scale. Each item is scored between 0 and 3, with total scores ranging from 0 to 24 and higher scores
indicating worse disease; a decrease of ≥2 points in total score for individual patients is considered
a clinically meaningful response (Muppidi 2011; Wolfe 1999). Analysis of the Phase 2 data has
shown that a maximum and stable decrease in MG-ADL is obtained at or before Week 8. Taking
the average score over Weeks 22, 23 and 24 is intended to reduce the variability and enable an
observation of stable response.
Key secondary efficacy endpoints (assessed in the 24-week double-blind placebo-controlled
phase) include the following:

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1. Average change from baseline in QMG score over weeks 22 and 24 of the double-blind,
placebo-controlled phase (scale is not assessed at Week 23).
2. MG-ADL response, defined as percentage of participants whose average MG-ADL total score
over weeks 22, 23 and 24 of the double-blind, placebo-controlled phase is at least a 2-point
improvement compared to baseline. The average score for a participant is the average of the
non-missing values at Weeks 22, 23 and 24. A participant must have a non-missing value at
Week 24 and at least one non-missing value at Week 22 or 23 in order to have a non-missing
average score. A participant with a missing average score will be considered a nonresponder.
3. Loading dose response, defined as percentage of participants with improvement in MG-ADL
total score of ≥2 points at Week 1 and/or Week 2. A participant with a missing assessment at
either time point will be considered a nonresponder at that time point.
4. Sustainability of therapeutic response, defined as the percentage of participants with
improvement in MG-ADL total score of ≥ 2 points at Week 4 through Week 24, with no more
than 2 non-consecutive excursions allowed between Week 6 through Week 23 (excursions
defined as loss of improvement in MG-ADL score of ≥ 2 points at baseline). A participant
with a missing assessment at a time point will be considered a nonresponder at that time point.
5. Percentage of participants whose average MG-ADL total score over weeks 22, 23 and 24 of
the double-blind, placebo-controlled phase is at least a 50% improvement compared to
baseline. The average score for a participant is the average of the non-missing values at Weeks
22, 23 and 24. A participant must have a non-missing value at Week 24 and at least 1 non-
missing value at Week 22 or 23 in order to have a non-missing average score. A participant
with a missing average score will be considered a nonresponder.
Analysis of the percentage of responders on the MG-ADL (ie, key secondary efficacy endpoint 2)
is considered a meaningful endpoint for physicians and patients alike. For measurement of MG-ADL
response (key secondary efficacy endpoint 4), allowing 2 non-consecutive excursions is intended to
account for variability of MG-ADL scores due to inherent disease fluctuation. Minimum symptom
expression, ie, an MG-ADL of 0 or 1 (secondary efficacy endpoint), is a desired treatment goal.
Since the final score achieved on the MG-ADL may vary depending on the baseline score, the study
will also evaluate the relative symptom improvement defined as ≥50% improvement on MG-ADL
score from the baseline score. This endpoint takes individual patient’s baseline score into
consideration and is a clinically meaningful endpoint for patients. A 50% improvement was chosen
also due to clinical considerations: per protocol inclusion criteria, participants are required to have
an MG-ADL score of ≥6 at screening/baseline, ie, moderate to severe disease; ≥50% improvement
will result in an MG-ADL score of 3 or better, corresponding to mild disease (Petersson 2021).
Conversely, the most severely affected participant with a maximal MG-ADL score of 24, would also
expect to experience substantial clinical benefit with a score of 12 or lower.
The QMG is a widely used and well validated clinician administered quantitative measure of MG
disease severity (Barnett 2018; Barohn 1998). It includes 13 items that measure endurance or
fatigability, taking into account the fluctuating nature of the disease. These items include ptosis,
diplopia, orbicularis oculi weakness, swallowing a cup of water, speech, percent predicted forced
vital capacity, grip strength (2 items), arm endurance (2 items), leg endurance (2 items), and neck
flexion endurance. All items are scored on a scale of 0 to 3, with total scores ranging from 0 to 39
and higher scores indicating greater disease severity. Demonstrating efficacy on QMG will provide

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additional evidence of efficacy through a clinician administered scale and support the primary
efficacy endpoint.
Biomarker Collection
Biomarker samples will be collected to help to explain interindividual variability in clinical
outcomes, to better understand the disease, or to help identify population subgroups that respond
differently to an intervention. The goal of the biomarker analyses is to evaluate the PD of
nipocalimab  to better understand the disease, and to aid in evaluating the intervention-clinical
response relationship.
Biomarker samples may be used to help address emerging issues and to enable the development
of safer, more effective, and ultimately individualized therapies.
Both serum total IgG and pathogenic AChR+, MuSK+, or LRP4+ autoantibody levels will be
measured throughout the study. The kinetic and maximal % reduction in IgG will be assessed as
PD readout. Biomarker data collected in the present study will further solidify the PK-PD-efficacy
model established from the Phase 2 study, to show drug response in MG processes or markers
previously shown to be responsive to other treatments, and to stratify and characterize the patient
population. Serum nipocalimab levels (PK), and incidences of ADA and NAb to nipocalimab will
be measured as secondary endpoints.
Additional exploratory biomarker samplesj will be collected to better understand the disease and
to aid in evaluating the intervention-clinical response relationship.
4.2.1. 
Study-Specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study, and, during
the study, participants will be given any new information that may affect their decision to continue
participation. They will be told that their consent to participate in the study is voluntary and may be
withdrawn at any time with no reason given and without penalty or loss of benefits to which they
would otherwise be entitled. Only participants who are fully able to understand the risks, benefits,
and potential AEs of the study, and provide their consent voluntarily will be enrolled.
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
US Department of Health and Human Services Office for Human Research Protections, and US
Food and Drug Administration (FDA) guidelines of 550 mL in any 8-week period,(US FDA
1998; US HHS 1998;) as well as the European Commission guidelines of 500 mL per donation and
3 L per consecutive 12 month period (EC 1998).
j 
Exploratory biomarkers (including but not limited to IgG subtypes, IgM, IgA, IgE) are not applicable for collection
in China.

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4.3. 
Justification for Dose
The proposed dose level and dosing regimen for the Phase 3 study in participants with gMG of
30 mg/kg IV loading dose on Day 1 followed by 15 mg/kg IV q2w maintenance doses from
Week 2 was based on observed data from the Phase 2 study and extensive modeling and simulation
of the dose response relationships for IgG and MG-ADL.
In the Phase 2 study, rapid, dose-dependent IgG lowering was observed one week after the initial
dose in all dose groups, with maximal IgG lowering achieved at Week 2 in the 60 mg/kg single
dose and 60 mg/kg q2w groups. Dose-dependent improvements in MG-ADL scores were also
observed, suggesting a correlation between IgG lowering and MG-ADL scores. Importantly,
nipocalimab was generally well tolerated across all dose groups.
Population PK/PD/efficacy modeling analyses were conducted using data obtained from
nipocalimab Phase 1 and 2 studies to evaluate the relationship between PK, IgG lowering, and
MG-ADL, in addition to other efficacy and safety endpoints (including serum albumin and total
cholesterol). The results indicated that the q2w dosing interval would provide more sustained IgG
lowering and MG-ADL reduction at all simulated dose levels when compared with the q4w dosing
interval. While modeling and simulation suggested numerical differences in IgG lowering and
MG-ADL reduction between the 15 and 30 mg/kg q2w dosing regimens (the model-predicted
mean IgG lowering is 73.8% versus 79.4%, respectively), the additional 5.6% IgG reduction with
30 mg/kg q2w is expected to have minimal additional MG-ADL improvement at steady-state
trough beyond the improvement expected with 15 mg/kg q2w (Figure 2). Therefore, the 15 mg/kg
q2w dose regimen is selected as the single maintenance dose regimen to be studied for this Phase
3 study in gMG since this is a rare disease with high unmet need. Lower doses would likely result
in suboptimal efficacy, while higher doses may not yield much difference in efficacy as predicted
for gMG.

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Figure 2: 
Model-Predicted IgG Reduction and MG-ADL Improvement with 15 mg/kg and 30 mg/kg
Q2W Maintenance Dosing
Abbreviations:  ADL  Activities of Daily Living; CFB  change from baseline; IgG  immunoglobulin G;
MG-ADL  Myasthenia Gravis-Activities of Daily Living; Q2W  every 2 weeks.
Colored lines and areas are the predicted mean and the associated 90% prediction interval.
To expedite the onset of an efficacy response, a loading dose of 30 mg/kg nipocalimab on Day 1
will be instituted prior to 15 mg/kg q2w maintenance dosing beginning at Week 2. It is anticipated
that the 30 mg/kg loading dose will generate a rapid and deep IgG lowering during the first 2 weeks
(model-predicted mean IgG lowering of 64% and 67%, respectively, at Weeks 1 and 2) with
potential early MG-ADL response, better than the expected response with a 15 mg/kg dose on
Day 1 (Figure 3).

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Figure 3: 
Model-Predicted IgG Reduction and MG-ADL Improvement with a 30 mg/kg Loading Dose
Abbreviations: ADL  Activities of Daily Living; CFB  change from baseline; IgG  immunoglobulin G;
MG-ADL  Myasthenia Gravis-Activities of Daily Living; Q2W  every 2 weeks.
The predicted exposure with a 30 mg/kg IV loading dose on Day 1 followed by 15 mg/kg IV q2w
maintenance doses is well below the observed PK exposure observed from 60 mg/kg q2w dosing
regimen in the Phase 2 gMG study (MOM-M281-004), which was generally well-tolerated based
on the currently available safety data. The dosing regimen planned for this study is expected to
have an average of <20% albumin lowering and <20% total cholesterol increase at steady state.
The magnitudes of albumin reduction and total cholesterol increase are not expected to be
clinically significant and are less than those observed in prior studies with 30 mg/kg IV weekly or
60 mg/kg IV q2w dose regimens. Therefore, the proposed dose regimen in this Phase 3 study is
expected to be safe and well-tolerated.
4.4. 
End of Study Definition
End of Study Definition
The end of study is considered as the last visit for the last participant in the study. The final data
from the study site will be sent to the sponsor (or designee) after completion of the final participant
assessment at that study site, within the timeframe specified in the Clinical Trial Agreement.
Study Completion Definition
A participant will be considered to have completed the study if the participant has completed
assessments at the last visit of the OLE phase.

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Participants entering the OLE phase will continue until 2 years after marketing authorization in
the participant’s local country/territory or until nipocalimab becomes available commercially or
via other continued access program, whichever comes first.
EUR-specific information is presented in Section 10.10.1.
5. 
STUDY POPULATION
Screening for eligible participants will be performed within 28 days before administration of the
study intervention. Refer to Section 5.4, Screen Failures for conditions under which the repeat of
any screening procedures are allowed.
The inclusion and exclusion criteria for enrolling participants in the double-blind
placebo-controlled phase 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.
Approximately 190 participants are planned to be randomized into the double-blind
placebo-controlled phase (95 in each treatment group of which approximately 75 per group will
be seropositive [anti-AChR positive, anti-MuSK positive, and/or anti-LRP4 positive]). To be
eligible, participants must have gMG that is not well controlled with stable MG therapy (or have
discontinued corticosteroids and/or immunosuppressants ≥4 weeks prior to screening due to
intolerance or lack of efficacy as specified in Inclusion Criterion #4) and must remain on their
stable MG therapy (if on any) throughout the study.
Approximately 150 participants will be seropositive and these participants will comprise the
primary efficacy analysis set. Approximately 40 participants will be seronegativek. Together with
the seropositive participants, these participants will comprise the full analysis set.
For a discussion of the statistical considerations of participant selection, refer to Section 9.2,
Sample Size Determination.
Enrollment of Participants from Phase 2
Due to the COVID 19 pandemic, the MOM-M281-005 OLE study an open-label extension study
to evaluate the safety, tolerability, and efficacy of nipocalimab administered to participants with
gMG, was placed on hold and subsequently terminated. As a result, some participants from the
MOM-M281-004 study, a Phase 2, multicenter, randomized, double-blind, placebo-controlled
study to evaluate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of
nipocalimab administered to adults with generalized myasthenia gravis, were unable to enroll into
the MOM-M281-005 study. Participants affected by this study termination (either those who were
ongoing in the MOM-M281-005 study at the time of the hold or those who were unable to enroll
from MOM-M281-004) will have the opportunity to directly enter the OLE phase of the present
k 
Seronegative participants are no longer being recruited; all participants must have a positive serologic test for a
gMG related pathogenic autoantibody (anti-AChR, anti-MuSK and/or anti-LRP4 autoantibodies), confirmed prior
to randomization.

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study (bypassing the double-blind placebo-controlled phase). These participants will undergo a
screening assessment to confirm eligibility for entry into the OLE phase of the study.
5.1. 
Inclusion Criteria
5.1.1. 
Inclusion Criteria for Double-blind Placebo-Controlled Phase Entry
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
Age
1. 
Criterion modified per Amendment 1.
1.1 ≥18 years of age at the time of consent, and as applicable, must also meet the legal
age of consent in the jurisdiction in which the study is taking place.
Type of Participant and Disease Characteristic
2. 
Criterion modified per Amendment 2
2.1 Diagnosis of MG with generalized muscle weakness meeting the clinical criteria for
gMG as defined by the MGFA Clinical Classification Class II a/b, III a/b, or IVa/b at
screening.l
3. 
MG-ADL score of ≥6 at screening and baseline.
4. 
Criterion modified per Amendment 1.
4.1 Has suboptimal response to current stable therapy for gMG according to the
investigator. Stable therapy is defined as the following, as applicable to their specific
therapy(ies):
a. 
If taking an acetylcholinesterase inhibitor, the participant must have been on a stable
dose and regimen for at least 2 weeks prior to screening. Changes to the dose of
acetylcholinesterase inhibitors may be permitted if medically necessary during any
phase of the trial.
b. 
If taking a glucocorticosteroid, the participant must have been on a stable dose and
regimen for at least 4 weeks prior to baseline.
c. 
If currently receiving immunosuppressants, the participant must have been on the
given immunosuppressant for ≥6 months and on a stable dose for ≥3 months prior
to baseline. Allowed concomitant immunosuppressants are azathioprine,
l 
Seronegative participants are no longer being recruited; all participants must have a positive serologic test for a
gMG-related pathogenic autoantibody (anti-AChR, anti-MuSK and/or anti-LRP4 autoantibodies), confirmed prior
to randomization.

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mycophenolate mofetil/mycophenolic acid, methotrexate, cyclosporine, tacrolimus,
or cyclophosphamide.
OR
Has discontinued corticosteroids and/or immunosuppressants/immunomodulators
including eculizumab or other novel approved immune agents at least 4 weeks prior to
screening due to intolerance or lack of efficacy.
Note: All above background medications must be optimized and unchanged for the
duration specified in Criteria #4 prior to screening and/or baseline visits. Investigators are
encouraged to consider all treatment escalation options, including thymectomy, prior to
enrolling. Participants started on new treatments must meet the above stable dose duration
rules, and cannot meet exclusion criterion #6 as defined in Section 5.2.
5. 
A participant using herbal, naturopathic, traditional Chinese remedies, ayurvedic or
nutritional supplements, or medical marijuana (with a doctor’s prescription) is eligible if
the use of these medications is acceptable to the investigator. These remedies must remain
at a stable dose and regimen from baseline through the double-blind placebo-controlled
phase of the study.
6. 
Criterion modified per Amendment 1.
6.1 Participants who have undergone splenectomy (if local regulatory  authority has not
requested exclusion of participants with splenectomy) must be at least 3 months post resection
prior to screening and must be vaccinated as per the United States Center for Disease Control
and Prevention annual Recommended Immunization Schedule for Adults Aged 19 Years or
Older, United States. (https://www.cdc.gov) OR must be vaccinated as per country- or
territory-specific guidelines or local regulations.
Note: This criterion is not applicable if splenectomy is excluded by the local authority.
7. 
Has sufficient venous access to allow drug administration by infusion and blood sampling
as per the protocol.
8. 
Criterion modified per Amendment 1.
8.1 Is recommended to be up to date on all age-appropriate vaccinations prior to screening
as 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.

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Sex and Contraceptive/Barrier Requirements
9. 
Criterion removed per Amendment 1.
10. 
A woman of childbearing potential must have a negative highly sensitive serum ( -human
chorionic gonadotropin [ -hCG]) at Screening and a negative urine pregnancy test at
Day 1 prior to administration of study intervention.
11. 
Criterion modified per Amendment 1.
11.1 A woman must be (as defined in Section 10.6, Appendix 6, Contraceptive and Barrier
Guidance)
a. Not of childbearing potential
b. Of childbearing potential and
o Practicing a highly effective, preferably user-independent method of
contraception (failure rate of <1% per year when used consistently and
correctly) and agrees to remain on a highly effective method while receiving
study intervention and until 30 days after last dose - the end of relevant
systemic exposure. The investigator should evaluate the potential for
contraceptive method failure (eg, noncompliance, recently initiated) in
relationship to the first dose of study intervention. Examples of highly
effective methods of contraception are located in Section 10.6, Appendix 6
Contraceptive and Barrier Guidance.
Note: Labeling requirements of concomitant treatment a participant is currently
receiving will supersede if more stringent.
12. 
A woman must agree not to donate eggs (ova, oocytes), or freeze for future use for the
purposes of assisted reproduction, during the study and for a period of 30 days after the
administration of study intervention.
13. 
Criterion modified per Amendment 1
13.1 A male participant must wear a condom when engaging in any activity that allows
for passage of ejaculate to another person during the study and for at least 90 days after
receiving the last administration of study intervention. In addition, male participants with
partners who are a woman of childbearing potential are highly encouraged to inform their
partner to use highly effective contraception methods that result in a low failure rate (less
than 1% per year). See Section 10.6, Appendix 6, Contraceptive and Barrier Guidance.
14. 
A male participant must agree not to donate sperm for the purpose of reproduction during
the study and for a minimum 90 days after receiving the last administration of study
intervention.

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Informed Consent
15. 
Criterion modified per Amendment 1.
15.1 Must sign an ICF indicating that the participant understands the purpose of, and
procedures required for, the study and is willing to voluntarily participate in the study and
comply with all study procedures. Participants who initially provide consent and
subsequently withdraw it prior to randomization, will be deemed as having failed this
inclusion criterion. Must be legal age of consent in the jurisdiction in which the study is
taking place, at the time of consent.
16. 
Must be able to read and write.
5.1.2. 
Inclusion Criteria for Open-label Extension Phase Entry
The OLE phase is open to 2 groups of participants: participants who have completed the 24-week
double-blind placebo-controlled phase and former participants in the nipocalimab MOM-M281-004
study or MOM-M281-005 study.
Participants who have completed the 24-week double-blind placebo-controlled phase will continue
to the OLE phase. Participants who had study intervention discontinued for a reason other than a
Clinical Deterioration requiring hospitalization or rescue therapy (IVIg, plasmapheresis), and who
completed the scheduled of assessments for the full 24-week double-blind placebo-controlled
phase, may enter the OLE based on the investigator’s discretion. Participants who had study
intervention discontinued because of rescue therapy during the double-blind phase are eligible to
enter the OLE phase based on investigator’s discretion after completion of an End of Phase (EOP)
Visit. In these instances, the EOP visit assessments must not be combined with those of the OLE
Day 1 assessments. Additionally, while there is no fixed duration limit between EOP and OLE
Day 1, in instances where the interval is greater than 4 weeks, the investigator should assess if it
is appropriate to continue treatment in the OLE phase in consultation with the sponsor’s medical
monitor. Participants who received IVIg as rescue treatment during the double-blind
placebo-controlled phase would need to wait at least 4 weeks before receiving nipocalimab in the
OLE.
Participants affected by interruption of the MOM-M281-005 study due to the COVID 19 pandemic
must meet the following Inclusion Criteria:
1. 
The investigator has confirmed that the participant is not receiving, or has not received
since the interruption of the Phase 2 study, any medication that might put the participant
at risk when receiving nipocalimab or might interfere with the assessment of the safety of
nipocalimab.
2. 
Criterion modified per Amendment 1

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2.1 Participants who have undergone splenectomy (if local regulatory authority has not
requested exclusion of participants with splenectomy) must be at least 3 months post resection
prior to screening and must be vaccinated as per the United States Center for Disease Control
and Prevention annual Recommended Immunization Schedule for Adults Aged 19 Years or
Older, United States. (https://www.cdc.gov) OR must be vaccinated as per country- or
territory-specific guidelines or local regulations.
Note: This criterion is not applicable if splenectomy is excluded by the local authority.
3. 
Has sufficient venous access to allow drug administration by infusion and blood sampling
as per the protocol.
4. 
Criterion modified per Amendment 1.
4.1 Is recommended to be up to date on all age-appropriate vaccinations prior to screening
as 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.
5. 
Sex and Contraceptive/Barrier 
Requirements 
as outlined 
in Double-blind
Placebo-Controlled Phase inclusion criteria # 9, #10, #11, #12, #13, and #14 above.
6. 
Criterion modified per Amendment 1.
6.1 Must sign an ICF indicating that the participant understands the purpose of, and
procedures required for, the study and is willing to voluntarily participate in the study and
comply with all study procedures. Participants who initially provide consent and
subsequently withdraw it prior to randomization, will be deemed as having failed this
inclusion criterion. Must be legal age of consent in the jurisdiction in which the study is
taking place, at the time of consent.
5.2. 
Exclusion Criteria for Double-blind Placebo-Controlled Phase Entry and
Open-label Extension Phase Entry of Returning Phase 2 Participants
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. 
Criterion modified per Amendment 1.
1.1 
Has 
a 
history 
of 
severe 
and/or 
uncontrolled 
hepatic 
(eg,
viral/alcoholic/autoimmune hepatitis/cirrhosis and/or metabolic liver disease),

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gastrointestinal, renal, pulmonary, cardiovascular, psychiatric, neurological
musculoskeletal disorder, hypertension, any other medical disorder(s) (eg, diabetes
mellitus), or clinically significant abnormalities in screening laboratory, that might
interfere with the patient’s full participation in the study, and/or might jeopardize the
safety of the participant or the validity of the study results.
Note: Any condition for which, in the opinion of the investigator, participation would
not be in the best interest of the participants (eg, compromise well-being) or that could
prevent, limit, or confound the protocol-specified assessments.
2. 
Has any confirmed or suspected clinical immunodeficiency syndrome not related to
treatment of his/her gMG, or has a family history of congenital or hereditary
immunodeficiency unless confirmed absent in the participant.
3. 
Criterion modified per Amendment 1.
3.1 Has MGFA Class I disease or presence of MG crisis (MGFA Class V) at screening,
history of MG crisis within 1 month of screening, or fixed weakness (and/or ‘burnt
out’ MG). (Note: Participants should not be actively deteriorating at the screening or
baseline visit such that they meet the criteria for Clinical Deterioration as defined in
Section 6.8.2).
4. 
Is dependent on gastric tube for nutritional needs or is ventilator-dependent.
5. 
Is 
actively 
undergoing 
radiation 
or chemotherapy 
for 
an 
unresected
thymoma/malignant thymoma. Participants with stable, benign thymoma (stage I or
IIa, for example) for which no treatment has been undertaken in the past 3 years may
be allowed following discussion with the sponsor’s medical monitor.
6. 
Has had a thymectomy within 12 months prior to screening, or thymectomy is planned
during the study.
7. 
Has current or a history of any neurologic disorder other than MG that might interfere
with the accuracy of study assessments, including but not limited to any chronic
neurodegenerative disease, altered level of consciousness, dementia, abnormal mental
status, major congenital neurologic defect, Lambert-Eaton myasthenic syndrome, drug
induced MG, or hereditary forms of myasthenic syndrome.
8. 
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 3 months [defined as a minimum of 12 weeks] before the first study
intervention administration or cervical carcinoma in situ that has been treated with no
evidence of recurrence for at least 3 months before the first study intervention
administration).

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9. 
Has known allergies, hypersensitivity, or intolerance to nipocalimab or its excipients
(refer to the IB).
10. 
Has shown a previous severe immediate hypersensitivity reaction, such as anaphylaxis
to therapeutic proteins (eg, monoclonal antibodies).
11. 
Has experienced myocardial infarction, unstable ischemic heart disease, or stroke
within 12 weeks of screening.
12. 
Is planning to father a child while enrolled in this study or donate sperm within 90 days
after the last administration of study intervention.
13. 
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 dose of study
intervention.
14. 
History of moderate or severe substance or alcohol use disorder according to
Diagnostic and Statistical Manual of Mental Disorders (5th edition) (DSM-5) criteria,
except nicotine or caffeine, within 1 year before screening.
Concomitant or Previous Medical Therapies Received
15. 
Criterion modified per Amendment 1.
15.1 Is currently taking eculizumab or other novel immune agents, IgG Fc-related
protein therapeutics, or Fc-conjugated therapeutic agents, including factor or enzyme
replacement.
16. 
Has received, rituximab within 6 months prior to first administration of study
intervention. This criterion does not apply to returning Phase 2 participants.
17. 
Criterion modified per Amendment 1.
17.1 Has received, or is expected to receive, a live vaccine within 4 weeks prior to
screening or has a known need to receive a live vaccine during the study, or within 8
weeks after the last administration of study intervention. For the Bacille Calmette-
Guerin (BCG) vaccine, see exclusion criterion 33. Participants are allowed to
receive a vaccine conditionally approved by their regional health advisory for
emergency use for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),
unless it is a live vaccine. Concomitant enrollment in an investigational trial for any
SARS-CoV-2 (COVID-19) vaccine while participating in this study is not permitted.
18. 
Has received plasmapheresis, immunoadsorption therapy, or IVIg within 6 weeks prior
to baseline.

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19. 
Has another medical condition that requires oral or parenteral corticosteroids unless
the dose has been stable for at least 4 weeks prior to baseline and is expected to remain
stable during the study. Inhaled, intra-articular, topical or ocular corticosteroids are not
exclusionary. This criterion does not apply to returning Phase 2 participants.
20. 
Has another medical condition that requires an immunosuppressive agent unless the
medication has been used for at least 6 months, the dose has been stable for at least
3 months prior to baseline and the medication and the dose are expected to remain
stable during the study. This criterion does not apply to returning Phase 2
participants.
21. 
Has previously received nipocalimab. This criterion does not apply to returning
Phase 2 participants.
Prior/Concurrent Clinical Study Experience
22. 
Has received an investigational intervention (including investigational vaccines)
within 3 months or 5 half-lives (whichever is longer) or used an invasive
investigational medical device within 3 months before the planned first dose
administration of study intervention [or is currently enrolled in an investigational
study]. Participants are allowed to receive a vaccine conditionally approved by their
regional health advisory for emergency use for SARS-CoV-2.
Infections or Predisposition to Infections
23. 
Has a severe infection including opportunistic infections (eg, pneumonia, biliary tract
infection, 
diverticulitis, 
Clostridium 
difficile 
infection, 
cytomegalovirus,
pneumocystosis, aspergillosis, etc.) 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 participant may be rescreened after the 8-week
exclusionary period has passed.
24. 
Has a chronic infection (eg, bronchiectasis, chronic osteomyelitis, chronic
pyelonephritis) or requires chronic treatment with anti-infectives (eg, antibiotics,
antivirals).
25. 
Tests positive for hepatitis B virus (HBV) infection (see Appendix 3, [Section 10.3]).
26. 
Is seropositive for antibodies to hepatitis C virus (HCV), unless they satisfy 1 of the
following conditions:
Has a history of successful treatment, defined as being negative for HCV RNA
at least 24 weeks after completing antiviral treatment, and has a negative HCV
RNA test result at screening,

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OR
While seropositive, has a negative HCV RNA test result at least 24 weeks prior
to screening and a negative HCV RNA test at screening.
27. 
History of being human immunodeficiency virus (HIV)1 or HIV2 antibody-positive,
or tests positive for HIV at screening.
28. 
COVID-19 infection:
During the 6 weeks prior to screening, have had ANY of
(a) confirmed SARS-CoV-2 (COVID-19) infection (test positive), OR
(b) suspected SARS-CoV-2 infection (clinical features without documented test
results), OR
(c) close contact with a person with known or suspected SARS-CoV-2 infection:
Exception: may be included with a documented negative result for a validated
SARS-CoV-2 test
obtained at least 2 weeks after conditions (a), (b), (c) above (timed from
resolution of key clinical features if present, e.g. fever, cough, dyspnea)
AND
with absence of ALL conditions (a), (b), (c) above during the period between
the negative test result and the baseline study visit
NOTES on COVID-related exclusion:
The field of COVID-related testing (for presence of, and immunity to, the
SARS-CoV-2 virus) is rapidly evolving. Additional testing may be performed as
part of screening and/or during the study if deemed necessary by the investigator
and in accordance with current regulations/guidance from authorities/standards of
care.
Precaution: for those who may carry a higher risk for severe COVID-19 illness,
follow guidance from local health authorities when weighing the potential benefits
and risks of enrolling in the study, and during participation in the study.
Other Exclusions
29. 
Criterion modified per Amendment 1.

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29.1 Has current suicidal ideation evidenced by a “yes” response to Questions 4 or 5
in the Suicidal Ideation section of the C-SSRS at screening or baseline, or a history of
active suicidal ideation or suicidal behavior in the past year prior to screening.
NOTE: If a participant meets protocol exclusion criterion 29, then the results should
be discussed with the sponsor’s medical monitor, unless urgency of the participant’s
medical situation prevents this, and along with screen-failing the participant,
appropriate medical interventions and measures should be undertaken by the
investigator. Clinically significant findings based on C-SSRS should be reported as
AEs/SAEs as applicable.
30. 
Had major surgery (eg, requiring general anesthesia) 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.
31. 
Criterion removed per Amendment 1.
32. 
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.
Prior/Concurrent Clinical Study Experience
33. 
Has had a BCG vaccination within 1 year of first administration of study intervention.
Infections or Predisposition to Infections
34. 
Has a history of active granulomatous infection, including histoplasmosis or
coccidioidomycosis, before screening.
NOTE: Investigators must ensure that all study enrollment criteria have been met at screening
and baseline where applicable. If a participant's clinical status changes (including any available
laboratory results or receipt of additional medical records) after screening but before the first
dose of study intervention is given such that the participant no longer meets all eligibility criteria,
then the participant must be excluded from participation in the study. Section 5.4, Screen
Failures, describes options for retesting. The required source documentation to support meeting
the enrollment criteria are noted in Appendix 4, Regulatory, Ethical, and Study Oversight
Considerations.
5.3. 
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions
during the course of the study to be eligible for participation:

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1. 
Refer to Section 6.8, Concomitant Therapy for details regarding prohibited and
restricted therapy during the study.
2. 
Agree to follow all requirements that must be met during the study as noted in the
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
3. 
Agree not to receive a live vaccine (including BCG) during the study and for 8 weeks
after receiving the last dose of study intervention.
5.3.1. 
Meals and Dietary Restrictions
In the double-blind placebo-controlled phase, participants are required to fast for at least 6 hours
prior to collection of blood for clinical laboratory assessments at baseline, Weeks 4, 8, 12, and 24.
If sites/participants cannot accommodate fasting due to scheduling or medical issues for the
duration of the double-blind placebo-controlled phase, non-fasting may be permitted following
discussion with the sponsor's medical monitor. In both the double-blind placebo-controlled phase
and the OLE phase, when not fasting, participants may only have room-temperature food/fluids
during the 1 hour preceding the collection of efficacy assessments and until efficacy assessments
are completed.
5.3.2. 
Activity
Participants may continue their usual activities, including exercise, during the study, but are
recommended to not have excessive exertion on the day of or day before an infusion/assessment
visit.
5.4. 
Screen Failures
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy
identification of each participant during and after the study. This document will be reviewed by
the sponsor study site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed
by the investigator in the study file. To ensure participant confidentiality, no copy will be made.
All reports and communications relating to the study will identify participants by participant
identification and age at initial informed consent. In cases where the participant is not randomized
into the study, the date seen and age at initial informed consent will be used.
Individuals who do not meet the criteria for participation in this study (screen failure) may be
rescreened once with approval of the sponsor’s medical monitor. Rescreened participants must be
assigned new participant numbers.
In some cases, participants who fail screening for reasons that are subsequently addressed may be
considered for rescreening. Reasons to consider rescreening include any transient condition that
resulted in screen failure and has since resolved.

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Participants being rescreened must sign a new ICF and undergo appropriate screening evaluation
according to the Schedule of Activities (Section 1.3). This will include interim medical history,
safety assessments, clinical laboratory assessments, and ECG, as discussed with the sponsor's
medical monitor. Follicle-stimulating hormone (FSH) tests do not need to be repeated if the results
at screening indicated menopause status. If rescreening takes place less than 3 months after
screening, the HIV and hepatitis B and C tests do not need to be repeated if theirresults at screening
did not meet exclusion criterion #25, exclusion criterion #26, and exclusion criterion #27.
5.5. 
Criteria for Temporarily Delaying Administration of Study Intervention
Guidelines for study intervention administration affected by the COVID-19 pandemic are found
in Appendix 8 (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 Intervention(s) Administered
The designation of Auxiliary Medicinal Product(s) (AxMP) is provided in compliance with the
EU CTR in the table below and is applicable to countries within the EU/EEA.
Designation 
Product
Investigational Medicinal Product(s) 
Authorization status in the EU:
Saline (placebo) is being used in accordance with the terms
of its marketing authorization.
Authorized 
Placebo (saline)
Unauthorized 
Nipocalimab
Auxiliary Medicinal Product(s)
(AxMP)
Authorization status in the EU:
IVIg and standard of care medications will be used in
accordance with the terms of their marketing authorization.
Authorized 
IVIg, Standard of care
background treatment (as
defined in Inclusion
Criterion #4)
Unauthorized 
N/A
Study intervention administration must be captured in the source documents and the case report
form (CRF).
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.

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For details on rescue medications, refer to Section 6.8.2, Rescue Medication. For a definition of
study intervention overdose, refer to Section 6.7, Treatment of Overdose.
Guidelines for study intervention administration affected by the COVID-19 pandemic are found
in Section 10.8.
Description of Interventions
Double-blind Placebo-controlled Phase
Participants in the study will maintain their standard of care treatment (if any, see also Section
5.1.1, Inclusion Criterion #4) and will be randomized to 1 of 2 treatment groups described below:
Nipocalimab: Participants will receive nipocalimab 30 mg/kg loading dose, followed by
nipocalimab 15 mg/kg IV q2w.
Placebo: Participants will receive placebo IV q2w.
Participants will remain on their assigned treatment through Week 24. All participants will receive
a planned total of 12 IV infusions over a 24-week period.
Recalculation of dose during the double-blind placebo-controlled phase for weight gained or lost
will based on the weight measured for each participant every 4 weeks.
Participants should continue their stable standard of care therapy for gMG (if on any, see also
Section 5.1.1, Inclusion Criterion #4) and should maintain the same dose and regimen throughout
the double-blind placebo-controlled phase. Tapering of prior MG medications may be performed
during the OLE phase (see next section). An increase in dose of the stable standard of care therapy
is not permitted at any point in the study, nor is the addition of new immunomodulatory therapies.
Open-label Extension Phase
All participants enrolling in the OLE phase will receive nipocalimab 15 mg/kg q2w by IV infusion
starting on OLE Day 1. No other nipocalimab dosing regimen should be used. Recalculation of
dose during the OLE phase for weight gained or lost will based on the weight measured for each
participant every 4 weeks through Extension Week 24 and every 12 weeks thereafter.
Tapering one of the participant’s concomitant MG medications every 4 weeks is allowed in the
OLE phase if the disease has been stable in the past 4 weeks as reflected by MG-ADL scores and
based on the investigator’s discretion. When considering tapering of concomitant MG medications,
the investigator should adhere to the following:
Taper 1 concomitant medication at a time, not 2 or more concomitant medications
simultaneously
When the decision has been made to taper a corticosteroid concomitant medication, the
following must be done:
For participants on a corticosteroid dose >30 mg per day, the dose should be decreased
by no more than 10 mg every 4 weeks, until a dose of ≤30 mg per day is reached. For

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participants on a corticosteroid dose of ≤30 mg per day, the dose should be decreased by
no more than 5 mg every 4 weeks. Once the investigator considers the corticosteroid taper
completed, the participant should remain on the current dosing regimen for nipocalimab
and the concomitant MG medications for at least 4 weeks before considering tapering
another concomitant MG medication.
The tapering of mycophenolate mofetil, azathioprine, or methotrexate should be performed
no more frequently than every 6 months. The tapering of cyclosporine or tacrolimus should
be performed no more frequently than every 3 months.
Note:
6.2. 
Preparation/Handling/Storage/Accountability
For nipocalimab IV administrations, the study intervention will be supplied as a sterile solution in
a single-use glass vial. Saline will be used as placebo. Study intervention will be prepared for IV
administration based on the instructions provided to clinical sites in the investigational product
and procedures instructions (IPPI) by an unblinded pharmacist.
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 avoid direct exposure to sunlight. Aseptic
techniques must be used during the preparation and administration of the study intervention
material for IV administration.
Placebo will be a commercially available saline infusion bag or bottle. Refer to the IPPI and study
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 maintained by the
unblinded pharmacist. All study intervention will be stored and disposed of according to the
sponsor's instructions. Study site personnel must not combine contents of the study intervention
containers.
Study intervention must be handled in strict accordance with the protocol and the container label
and must be stored at the study site in a limited-access area or in a locked cabinet under appropriate
environmental conditions. Unused study intervention  must be available for verification by the
sponsor's study site monitor during on-site monitoring visits. The return to the sponsor of unused
study intervention, or used returned study intervention for destruction, will be documented on the
intervention return form. When the study site is an authorized destruction unit and study
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intervention supplies are destroyed on-site, this must also be documented on the intervention return
form.
Potentially hazardous materials, such as used needles and syringes, should 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 only
be used for individuals participating in the study. Study intervention may not be relabeled or
reassigned for use by other participants. The investigator agrees neither to dispense the study
intervention from, nor store it at, any site other than the study sites agreed upon with the sponsor.
Further guidance and information for the final disposition of unused study interventions are
provided in the SIPPM.
6.3. 
Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Procedures for Randomization and Stratification
Eligible participants will be randomized on Day 1 to a treatment assignment according to a
randomization schedule generated by the sponsor or designee. The study personnel will use an
interactive web response system (IWRS) to obtain the randomization number for each eligible
participant.
Central randomization will be implemented in this study. Participants will be randomly assigned
to 1 of 2 intervention groups (nipocalimab or placebo) based on a computer-generated
randomization schedule prepared before the study by or under the supervision of the sponsor. The
randomization will be balanced by using randomly permuted blocks and will be stratified by
autoantibody status (anti-AChR positive and/or anti-MuSK positive, anti-AChR negative and anti-
MuSK negative), Day 1 MG-ADL total score (≤9 >9), and region (East Asia, US, rest of world).
The IWRS will assign a unique intervention code, which will dictate the intervention. The
requestor must use his or her own user identification and personal identification number when
contacting the IWRS which will then give the relevant participant details to uniquely identify the
participant.

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Blinding
The participant, investigator, and sponsor will be blinded to study treatment for the duration of the
blinded period. An unblinded site pharmacist will be responsible for storage, preparing, and
documentation of the study intervention for infusion while all other site personnel will remain
blinded. Selected data will be handled with special care to minimize any potential impact on
blinding/bias. This can include masking/segregating the data in question from view by the
investigators, clinical team, or others as appropriate until the primary analysis CSR is complete.
The following measurements obtained after screening (during the double-blind period) will
be masked to the investigator, study team members and participants during study conduct:
nipocalimab concentrations, total serum IgG and IgG subtypes (IgG1, IgG2, IgG3, and IgG4),
IgA, IgM, IgE, anti-AChR/anti-MuSK/anti-LRP4 autoantibodies, anti-nipocalimab
antibodies, total serum protein, and serum albumin.
The following measurements will remain masked to the investigator, study team members,
and participants during the double-blind placebo-controlled phase: serum lipid profiles, c-
reactive protein, complement proteins (C3, C4, CH50, C5a), circulating immune complexes
(CIC), and striational antibodies.
Given that albumin laboratory results are masked, the investigator and sponsor will be notified if
their patient meets the laboratory criteria for hypoalbuminemia <20 g/L (<2.0 g/dL). These
hypoalbuminemia AESI cases will be handled similarly to an SAE for reporting purposes and
reviewed by the DMC as they occur. Similarly, the investigator and sponsor will be alerted if LDL
and/or triglycerides are significantly elevated; the criteria for these alerts are defined within the
Laboratory Manual. If there is sufficient safety concern such that the investigator draws local
laboratory samples 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.
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.
Under normal circumstances, the blind must not be broken until the primary analysis CSR is
complete. 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 by the IWRS 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.

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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).
If a participant is unblinded by the site, the information must be entered in the appropriate section
of the eCRF and in the participant's source documents.
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.
The blind will be maintained until the last participant completes the double-blind
placebo-controlled phase Week 24 evaluations (or the last participant completes their last visit in
double-blind placebo-controlled phase) and the data are locked. Investigative sites and participants
will remain blinded to initial intervention assignment until after the primary analysis CSR is
completed.
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 will be conducted according to the IPPI.
Additional details may be provided in the site sIPPM that is provided separately. Compliance with
the treatment schedule is required.
6.5. 
Dose Modification
No dose modification is permitted during the double-blind placebo-controlled phase of the study.
All participants in the OLE phase of the study will receive nipocalimab infusion q2w (15 mg/kg).
No other dosing regimen should be used. Tapering one of the participant’s concomitant MG
medications every 4 weeks is allowed in the OLE phase if the disease has been stable in the past 4
weeks as reflected by MG-ADL scores and based on the investigator’s discretion.
Note:
6.6. 
Continued Access to Study Intervention After the End of the Study
Local regulations on continued access will always take precedence. Plans for continued access
stated in this protocol may change if new information on the benefit-risk profile of nipocalimab
becomes available during the study or program.
Participants who complete the double-blind placebo-controlled phase will continue to the OLE
phase. The duration of each participant’s participation in the OLE phase will continue until 2 years
CCI

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after marketing authorization in the participant’s local country/territory or until nipocalimab
becomes available commercially or via other continued access program, whichever comes first.
Details specific for sites in EUR are presented in Section 10.10.1.
6.7. 
Treatment of Overdose
For this study, any dose of study intervention greater than 10% of the intended 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 sponsor’s medical monitor immediately.
Closely monitor the participant for AE/SAE and laboratory abnormalities.
Discuss with the sponsor’s medical monitor if 1 or more additional serum samples for PK
analysis will be required and at what time points.
6.8. 
Concomitant Therapy
Concomitant therapies must be recorded throughout the study beginning from the time the
participant signs the ICF to 8 weeks after the last dose of study intervention.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special
diets, exercise regimens, or other specific categories of interest) different from the study
intervention must be recorded in the CRF. Recorded information will include a description of the
type of therapy, duration of use, dosing regimen, route of administration, and indication.
Modification of an effective pre-existing 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
investigators initiate or continue appropriate therapy for dyslipidemia as per local health
guidelines.
6.8.1. 
Prohibited Therapies
Use of additional immunosuppressants or immunomodulators (including mAbs) for MG or other
background medical conditions, other than those explicitly allowed in the inclusion/exclusion
criteria (Sections 5.1 and 5.2), are prohibited. Use of a mAb specifically approved for treatment of
COVID-19 infections, including emergency use-authorized mAbs for COVID-19 per local
regulations, may be permitted for participants who medically require it. Because concomitant
exposure to nipocalimab may reduce the efficacy of anti-COVID-19 mAbs, study intervention
must be withheld upon administration of anti-COVID-19 mAbs. It is unknown how long
nipocalimab has to be stopped to minimize its effect on the efficacy of anti-COVID-19 mAbs. The
resumption of the study intervention may be considered for participants who have recovered from

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COVID-19 and must be discussed with the sponsor’s medical monitor. Prohibited therapies
include, but are not limited to, the following:
IgG-Fc-related protein therapeutics (for example, mAbs, among others)
rituximab
eculizumab
botulinum toxin
As these lists cannot be exhaustive, please consult the medical monitor and/or study sponsor to
discuss prior to starting or continuing any biologic or other advanced therapies. In addition, other
medications per label may interfere with the function of the neuromuscular junction and worsen
the clinical symptoms of MG. Local health guidance, clinical judgement, and the risk-to-benefit
ratio of the medication should be taken into consideration before prescribing or continuing such
medications in this study.
For France-specific requirements see Section 10.10.2.
6.8.2. 
Rescue Medication/Therapy/Clinical Deterioration
Clinical Deterioration is defined as any of the following:
An MG crisis, defined as MG-related weakness sufficiently severe to necessitate intubation,
or requires noninvasive ventilation to avoid intubation, or would be severe enough to delay
extubation following surgery (Sanders 2016), with the respiratory failure being due to
weakness of respiratory muscles. Severe bulbar (oropharyngeal) muscle weakness may
accompany respiratory muscle weakness, or may be the predominant feature in some patients.
An MG flare, exacerbation or deterioration reflected by worsening in MG strength or clinical
assessment scores, warranting hospitalization or MG rescue therapy. Of note, an MG
worsening in strength or clinical assessment scores that does not warrant hospitalization or
rescue therapy would not be considered Clinical Deterioration.
Any participant whom the investigator believes will jeopardize his/her health if MG rescue
therapy is not given (eg, emergent situations).
In participants experiencing a Clinical Deterioration, the use of rescue therapy (IVIg,
plasmapheresis) will be permitted, as per the clinical judgment of the investigator. The use of other
medications as rescue therapy, such as increasing doses of background standard of care
medications, or prescribing oral or IV corticosteroids, is not permitted.
If rescue therapy is needed during the double-blind placebo-controlled phase, the participant will
be discontinued from the phase. Participants receiving IVIg or plasmapheresis rescue therapy
should not receive study intervention (nipocalimab or placebo) concomitantly due to the potential
for nipocalimab to reduce the efficacy of IVIg as rescue therapy and additional IgG reduction post
plasmapheresis. (Section 1.3).
Participants who require rescue treatment during the double-blind phase must complete an EOP
visit and are eligible to enter the OLE phase based on investigator’s discretion. In these instances,

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the EOP visit assessments must not be combined with those of the OLE Day 1 assessments.
Additionally, while there is no fixed duration limit between EOP and OLE Day 1, in instances
where the interval is greater than 4 weeks, the investigator should assess if it is appropriate to
continue treatment in the OLE phase in consultation with the sponsor’s medical monitor.
Participants who received IVIg as rescue treatment during the double-blind placebo-controlled
phase must wait at least 4 weeks before receiving a subsequent dose of nipocalimab in the OLE.
For participants who require rescue treatment during the OLE phase, their continued participation
in the study must be discussed with the sponsor’s medical monitor. Participants who are confirmed
that they can continue may complete an Unscheduled visit prior to continuing in the OLE phase.
Participants who received IVIg as rescue treatment during the OLE phase must wait at least 4
weeks before receiving a subsequent dose of nipocalimab in the OLE. Participants who discontinue
from the OLE phase must complete an ET visit. Every effort should be made to notify the sponsor
within 24 hours should a participant require a rescue therapy. Routine use of Plasma Exchange or
IVIg as maintenance therapy to control MG symptoms outside of rescue is not permitted.
The study site will supply rescue medication that will be obtained locally.
The date and time of rescue medication administration as well as the name and dosage regimen of
the rescue medication must be recorded.
6.8.3. 
Vaccinations (Including COVID-19)
When considering use of locally approved non-live vaccines (including emergency-use-authorized
COVID-19 vaccines) in study participants, follow the 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 the COVID-19 vaccine, it is recommended
that, where possible, vaccine and study intervention be administered on different days, separated
by as large an interval as is practical within the protocol.
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.
A participant develops an infection with life-threatening consequences and requiring urgent
interventions.
A participant develops an infection that is unresponsive or worsening while on anti-infective
therapy.
A participant develops a Clinical Deterioration requiring hospitalization or rescue therapy.
Please see Section 6.8.2 for next steps after discontinuation.

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The investigator believes that for safety reasons or tolerability reasons (eg, AE) it is in the
best interest of the participant to discontinue study intervention.
The participant develops a severe allergic reaction and/or severe infusion reaction related to
the study intervention (eg, anaphylaxis as per Sampson's (2006) criteria [Appendix 9,
Section 10.9]).
The sponsor’s medical monitor should be notified of discontinuation of study intervention for any
of these reasons.
If a participant discontinues study intervention before the end of the double-blind placebo-
controlled phase for a reason other than Clinical Deterioration requiring hospitalization or rescue
therapy, the participant will continue all other assessments per the Schedule of Activities
(Section 1.3; Table 1) until completion of the phase. Rollover into OLE of such participants will
not be permitted unless the 24 weeks of study procedures have been completed. Participants who
permanently discontinue or withdraw during the double-blind placebo-controlled phase should
complete the ET visit assessments. These participants should also return for a safety follow-up
visit 8 weeks after the last infusion (Table 4). Study intervention assigned to the participant who
discontinued study intervention may not be assigned to another participant. Participants who
discontinue will not be replaced.
7.1.1. 
Liver Chemistry Stopping Criteria
Study intervention will be discontinued for a participant if liver chemistry stopping criteria are met
as outlined in Appendix 7 (Section 10.7) Liver Safety: Suggested Actions and Follow-Up
Assessments or in the presence of abnormal liver chemistries not meeting protocol-specified
stopping rules if the investigator believes that it is in best interest of the participant
7.1.2. 
Temporary Discontinuation
Study intervention administration may be interrupted, and the sponsor’s medical monitor notified,
for the following events:
If a participant develops a severe or medically significant but not immediately life-threatening
infection requiring IV anti-infective or operative/invasive intervention and requiring
hospitalization or prolongation of existing hospitalization, the investigator should consider
withholding study intervention until the clinical scenario clarifies whether the infection is
improving or getting worse.
If a participant develops 3+ pedal edema, ascites, or pleural or pericardial effusions.
7.2. 
Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons:
Lost to follow-up
Withdrawal of consent
Death

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When a participant withdraws before study completion, the reason for withdrawal is to be
documented in the eCRF and in the source document.
Withdrawal of Consent
A participant may withdraw consent to further study treatment while maintaining consent for
further assessments in the double-blind placebo-controlled phase, Safety Follow-up Phase, and/or
subsequent contact with site personnel to provide information about their health status. A
Withdrawal of Consent Form may be used to confirm which study activities the participant is
withdrawing consent. If the participant withdraws consent during the double-blind
placebo-controlled phase and declines participation in the Safety Follow-up Phase, or enters the
Safety Follow-up Phase and subsequently withdraws consent prior to completion of the Safety
Follow-up Visit, the participant should be encouraged to consent to subsequent contact by site
personnel 8 weeks from last infusion of study intervention. This could include telephone contact
with the participant, caregiver, or treating physician to inquire about the participant’s health status.
During this contact, site personnel will collect information about concomitant medications, AEs,
and SAEs that may have occurred within the 8 weeks since last infusion of study intervention. If
the participant withdraws all consent, including withdrawal of consent from future contact by site
personnel, no additional assessments or data collection will occur.
7.2.1. 
Withdrawal From the Use of Research Samples
Withdrawal From the Use of Samples in Future Research
The participant may withdraw consent for use of samples for research (refer to Long-Term
Retention of Samples for Additional Future Research in Appendix 4, Regulatory, Ethical, and
Study Oversight Considerations; Section 10.4.5). 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.
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, and to ascertain whether the participant wishes to or should continue in the
study.

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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.
8. 
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedule of Activities (Table 1, Table 2, Table 3, and Table 4) summarizes the frequency and
timing of efficacy, immunogenicity, PK, PD, and safety measurements applicable to this study.
All patient-reported outcome (PRO) assessments should be conducted/completed before any tests,
procedures, or other consultations to prevent influencing participant responses. Training will be
provided for administration of PROs.
Blood Sample Collection
The total blood volume to be collected will be approximately 1,100 to 1,200 mL for participants
in China and approximately 1,600 to 1,700 mL for all other participants. The total blood volume
is inclusive of the full duration of the double-blind placebo-controlled phase and up to Week 240
of the OLE.
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 Schedule of Activities (Section 1.3; Table 1, Table 2, Table 3, and Table 4) 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:

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Investigator Site File (includes protocol and nipocalimab IB)
Study site investigational product and procedures manual, laboratory manual(s), and
laboratory supplies. Certain Clinical Outcome Assessments (COAs; includes both PROs and
rater administered assessments) will be collected using an electronic device while others will
be collected on paper worksheets. Therefore, the following materials will be provided:
IWRS user guide and worksheets
eCRF completion instructions
Sample ICFs
Any other manual or guideline that is deemed necessary for good execution of the study,
including MACE Adjudication, if applicable
8.1. 
Efficacy Assessments
Investigator assessments and PROs of efficacy are included in this section.
For PRO measures:
The PRO instrument will be provided in the local language in accordance with local
guidelines.
The PRO instrument must be available for regulators and for IRB/ERC submissions, therefore
the PRO instrument or screen shots need to be attached to the protocol or provided in a
companion manual with the instruments that will be submitted with the protocol.
The PRO and AE data will not be reconciled with one another.
8.1.1. 
Myasthenia Gravis –Activities of Daily Living
The MG-ADL is administered by a trained qualified healthcare professional (eg, physician,
physician assistant, nurse practitioner, nurse) and provides a rapid assessment of the patient’s MG
symptom severity. The MG-ADL should be administered by the same healthcare professional for
a given participant throughout the study. In certain  circumstances a change in rater may be
permitted when it is unavoidable (eg, rater left the institution, rater unavailable for several weeks,
etc). It is recommended that the reasons for an upcoming rater change be discussed in advance
with the sponsor, if possible. The assessment should be performed at approximately the same time
of day from Screening Visit, throughout the study. The participant’s acetylcholinesterase inhibitor
dose must be withheld for approximately 12 hours or longer prior to performing MG-ADL at all
visits, and attempts made to reschedule the visit within the per protocol visit window if the dose
was taken <12 hours prior. Eight functions (talking, chewing, swallowing, breathing, impairment
of ability to brush teeth or comb hair, impairment of ability to arise from a chair, double vision,
eyelid droop) are rated on a 4-point scale.  The total score can range from 0 to 24.  A higher score
indicates greater symptom severity.
8.1.2. 
Quantitative Myasthenia Gravis
The QMG test is a standardized quantitative strength assessment comprising 13 components (and
is administered by a trained qualified healthcare professional eg, physician, physician assistant,

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nurse practitioner, nurse). The QMG should be administered by the same healthcare professional
for a given participant throughout the study. In certain circumstances a change in rater may be
permitted when it is unavoidable (eg, rater left the institution, rater unavailable for several weeks,
etc). It is recommended that the reasons for an upcoming rater change be discussed in advance
with the sponsor, if possible. The assessment should be performed at approximately the same time
of day from Screening Visit throughout the study. The participant’s acetylcholinesterase inhibitor
dose must be withheld for approximately 12 hours or longer prior to performing QMG at all visits,
and attempts made to reschedule the visit within the per protocol visit window if the dose was
taken <12 hours prior. The quantitative results of each strength component are mapped to the
following 4-point scale:
0 = None
1 = Mild
2 = Moderate
3 = Severe
The total score can range from 0 to 39.  A higher score indicates greater weakness.
8.1.3. 
Revised Myasthenia Gravis Quality of Life –15
The MG-QoL15r is a patient-reported outcome instrument that measures MG-specific health-
related quality of life (Burns 2016). The MG-QoL15r contains 15 items that evaluate patients’
experience related to Myasthenia Gravis over the “past few weeks” on a 3-point Likert-type scale
(0=Not at all; 1=Somewhat; 2=Very much). The total score can range from 0 to 30. A higher score
indicates more limitation.
8.1.4. 
Neuro-QoL-Fatigue
The Neuro-QoL Fatigue version 1.0 is a 19-item questionnaire developed and validated for use in
common neurological conditions which assesses patient-reported fatigue and associated impact on
physical, mental, and social activities during the past 7 days (Health Measures n.d.). Each item
included in the Neuro-QoL Fatigue questionnaire is graded on a 5-point Likert-type scale
(1=Never; 2=Rarely; 3=Sometimes; 4=Often; 5=Always) with higher scores reflecting more
fatigue. The total raw scores are calculated by summing 19 items and raw score is converted to a
T-score.
8.1.5. 
Patient Global Impression of Severity
The PGI-S will be used to assess the severity of fatigue due to gMG. The PGI-S will be
administered at the same timepoints as the Neuro-QoL Fatigue. The participant will answer the
following question:

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Please choose the response below that best describes the overall severity of your fatigue over the
past 7 days.
1 = None
2 = Mild
3 = Moderate
4 = Severe
5 = Very Severe
8.1.6. 
Patient Global Impression of Change
The PGI-C, derived from the scale published by the National Institute of Mental Health, assesses
if there has been an improvement or decline in patient-reported status since the beginning of the
treatment. The participant will answer the following question:
Please choose the response below that best describes the overall change in your fatigue compared
to your first study visit:
1 = Much better
2 = Moderately better
3 = A little better
4 = No change
5= A little worse
6 = Moderately worse
7 = Much worse
8.1.7. 
EuroQol 5-Dimension 5-Level
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome, primarily
designed for self-completion by respondents. It consists of the EQ-5D-5L descriptive system and
the EQ visual analogue scale (EQ-VAS). The EQ-5D-5L descriptive system comprises the
following 5 dimensions: Mobility, self-care, usual activities, pain/discomfort and
anxiety/depression. Each of the 5 dimensions is divided into 5 levels of perceived problems
(Level 1 indicating no problem, Level 2 indicating slight problems, Level 3 indicating moderate
problems, Level 4 indicating severe problems, and Level 5 indicating extreme problems).
(EuroQol 2021; EuroQol 2019)
The participant selects an answer for each of the 5 dimensions considering the response that best
matches his or her health “today.” The descriptive system can be represented as a health state. The

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EQ-VAS self-rating records the respondent’s own assessment of his or her overall health status at
the time of completion, on a scale of 0 to 100.
The time taken to complete the questionnaire varies with age, health status, and setting but is likely
to be approximately 1 minute.
8.1.8. 
Treatment Satisfaction Questionnaire for Medication
The Treatment Satisfaction Questionnaire for Medication (TSQM-9) (Atkinson 2004) is a 9-item
generic patient reported outcome instrument to assess patients’ satisfaction with medication. It is
derived from the longer TSQM Version 1.4 (Bharmal 2009) and covers domains of effectiveness,
convenience, and global satisfaction. The instrument is scored by domain with scores ranging from
0-100 where a lower score indicates lower satisfaction. The recall period is “the last 2-3 weeks”.
It takes approximately 5 minutes to complete.
8.1.9. 
Digital Health –Actigraphy Measurements (at Selected Sites)
Actigraphy, a non-invasive method of monitoring human rest/activity patterns, will be performed
using a wrist-worn actigraphy watch in newly screened participants post-Amendment 1 at select
sites globally. Participants who will not prove eligible will return their actigraphy watch to the
study site. Only accelerometry measurements will be collected from actigraphy watches, with the
data utilized to assess physical activity, mobility, and sleep parameters. Participants will be asked
to continuously wear the watch on the non-dominant wrist from Screening Visit until Week
24/ET/EOP of the double-blind placebo-controlled phase, and will download data from the watch
prior to the site visit. Sites and participants will not have access to data generated from the use of
the watch. All actigraphy watches will be collected from participants at their respective Week
24/ET/EOP visit.
8.2. 
Safety Assessments
Details regarding the independent Data Monitoring Committee are provided in Committees
Structure in Appendix 4, Regulatory, Ethical, and Study Oversight Considerations.
Adverse events will be reported and followed by the investigator as specified in Section 8.3,
Adverse Events, Serious Adverse Events, and Other Safety Reporting, and Appendix 5
(Section 10.5), Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-Up, and
Reporting.
Any clinically relevant changes occurring during the study must be recorded on the Adverse Event
section of the eCRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will be
followed by the investigator until resolution or until a clinically stable condition is reached.
The study will include the following evaluations of safety and tolerability according to the time
points provided in the Schedule of Activities (Table 1, Table 2, Table 3, and Table 4).

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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; Table 1, Table 2, Table 3,
and Table 4). 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.
Height will be measured at screening only. Weight will be measured at screening, at Day 1,
Week 4, and then every 4 weeks through the first 24 weeks of the OLE. Thereafter, weight will be
measured every 12 weeks. A full physical examination will be performed visits specified in the
Schedule of Activities (Section 1.3). At all other visits, a focused physical examination will be
performed to determine if there has been any change in neurologic function, upper respiratory tract
(ears, nose, throat, and sinuses), eyes and lungs, abdomen, or skin.
8.2.2. 
Vital Signs
Temperature, pulse/heart rate, respiratory rate, and blood pressure will be assessed.
Blood pressure and pulse/heart rate measurements will be assessed with a completely automated
device after the participant has been resting in the recumbent position for 3 to 5 minutes. Manual
techniques will be used only if an automated device is not available.
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. Vital signs should
also be obtained 1 hour after completion of the IV infusions for the first 3 visits in the double-blind
placebo-controlled phase and the OLE phase as outlined in the Schedule of Activities (Section 1.3;
Table 1, Table 2, and Table 3).
The investigator will determine if any of the vital sign measurements are clinically significant (CS)
or not clinically significant (NCS). Clinical significance is defined as any variation in assessment
results that have medical relevance and may result in an alteration in medical care (eg, active
observation, diagnostic measures, or therapeutic measures). If a CS change from a screening value
is noted, the CS value and reason for clinical significance will be documented on the AE page of
the patient’s eCRF.
8.2.3. 
Electrocardiograms
A 12-lead electrocardiogram will be as specified in the Schedule of Activities (Section 1.3; Table 1,
Table 2, Table 3, and Table 4). The investigator will determine if the ECG is CS or NCS.
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.

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8.2.4. 
Clinical Safety Laboratory Assessments
Blood samples for safety laboratory assessments, such as serum chemistry, hematology, and lipid
profiles and a random urine sample for urinalysis, will be collected as noted in Appendix 2
(Section 10.2), Clinical Laboratory Tests. The investigator must review the laboratory results,
determine if abnormal clinical laboratory results are CS or NCS, 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. As described in Section 6.3, data that
may potentially unblind study intervention assignment will be handled with special care to ensure
that the integrity of the blind is maintained and the potential for bias is minimized.
8.2.5. 
Pregnancy
Urine pregnancy testing will be done for women of childbearing potential only (performed
locally), see definition in Section 10.6. Additional serum or urine pregnancy  tests may be
performed, as determined necessary by the investigator or required by local regulation, to establish
the absence of pregnancy at any time during the participation in the study.
8.2.6. 
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 1-hour post-infusion after the first 3 infusions in the double-blind placebo-controlled phase;
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 for the duration of the
phase.  During the OLE phase, participants will be observed for safety 1-hour post-infusion after
the first 3 infusions; if no clinically relevant AEs related to the infusion are observed with these
3 infusions, participants will be observed for 30 minutes after subsequent infusions.
8.2.7. 
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 a SAE, the infusion may be restarted with caution.
8.2.8. 
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).

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In the case of a severe allergic reaction (eg, anaphylaxis [Sampson 2006]), 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 serious adverse reactions related to an injection or infusion should be discontinued
from further study intervention administrations.
8.2.9. 
Suicidal Ideation and Behavior Risk Monitoring
Although preclinical and clinical studies with nipocalimab did not indicate any central nervous
system effects, the C‑SSRS will be used in this study as an additional safety assessment based on
the recommendation by the United States Food and Drug Administration (US FDA) for all clinical
studies involving the development of drugs or biologics for neurologic indications to assess suicide
risk. The US FDA has provided guidance to prospectively assess suicidal ideation and behavior in
clinical studies to ensure that participants in clinical studies who are experiencing suicidal ideation
and behavior are properly recognized and adequately treated and to ensure the collection of more
timely and more complete data on suicidal ideation and behavior than have been collected in the
past (US FDA 2012)
Baseline assessment of suicidal ideation and behavior and intervention-emergent suicidal ideation
and behavior will be assessed during the study using the C-SSRS. If a participant’s C-SSRS results
indicate active suicidal ideation and/or a plan/intent, the results should be discussed with the
sponsor’s medical monitor as soon as reasonably possible, unless urgency of the participant’s
medical situation prevents this, and the participant may be discontinued from the study at the
discretion of the investigator. Appropriate medical interventions and measures should be
undertaken in such cases by the investigator. Clinical findings based on C-SSRS should be reported
as AEs/SAEs as applicable.
8.2.10. 
Benefit-Risk Balance
Benefit-risk balance of nipocalimab for adults with gMG will be explored. Refer to Section 9.4.6,
Benefit-Risk Analysis for details.
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 (PQC), from clinical studies are crucial for the protection of
participants, investigators, and the sponsor, and are mandated by regulatory agencies worldwide.
The sponsor has established Standard Operating Procedures in conformity with regulatory
requirements worldwide to ensure appropriate reporting of safety information; all clinical studies
conducted by the sponsor or its affiliates will be conducted in accordance with those procedures.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate,
or the participant's legally acceptable representative) for the duration of the study.
Further details on AEs, SAEs, and PQC can be found in Appendix 5, Adverse Events, Serious
Adverse Events, Product Quality Complaints, and Other Safety Reporting: Definitions and
Procedures for Recording, Evaluating, Follow-Up, and Reporting.

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8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information
All Adverse Events
All AEs and special reporting situations, whether serious or non-serious, will be reported from the
time a signed and dated ICF is obtained until completion of the participant's last study-related
procedure, which may include contact for follow-up of safety.
Serious Adverse Events
All SAEs and AESIs, as well as PQC, occurring during the study must be reported to the
appropriate sponsor contact person by study site personnel within 24 hours of their knowledge of
the event.
Serious adverse events, including those spontaneously reported to the investigator within 8 weeks
after the last dose of study intervention, must be reported. The sponsor will evaluate any safety
information that is spontaneously reported by an investigator beyond the time frame specified in
the protocol.
A possible Hy’s law Case is defined by the occurrence of ALT/AST ≥3 x ULN, alkaline
phosphatase <2 x ULN together with total bilirubin (Tbili) ≥2 x 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 CRF, which must be completed and reviewed by a physician
from the study site, and transmitted to the sponsor within 24 hours. The initial and follow-up
reports of 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 a specific package of
information for evaluation. Further details will be provided in a procedural manual. The EAC will
assess such events according to the committee’s charter and will independently classify the events
while blinded to treatment assignment.
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting 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

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PQC as fully as possible. This may include additional laboratory tests or investigations,
histopathological examinations, or consultation with other health care professionals.
Adverse events, including pregnancy, will be followed by the investigator as specified in
Appendix 5, Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and
Reporting.
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events and
Anticipated Events
The sponsor assumes responsibility for appropriate reporting ofAEs to the regulatory authorities.
The sponsor will also report to the investigator (and the head of the investigational institute where
required) all suspected unexpected serious adverse reactions (SUSARs). The investigator (or
sponsor where required) must report SUSARs to the appropriate Independent Ethics
Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless otherwise
required and documented by the IEC/IRB. A SUSAR will be reported to regulatory authorities
unblinded. Participating investigators and IEC/IRB will receive a blinded SUSAR summary,
unless otherwise specified.
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 SAEs will
be considered anticipated events: myasthenia gravis crisis and myasthenia gravis.
These anticipated events will be periodically analyzed in aggregate by the sponsor during study
conduct. The sponsor will prepare a safety report in narrative format if the aggregate analysis
indicates that the anticipated event occurs more frequently in the 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 events is specified in a separate Anticipated
Events Safety Monitoring Plan. The assessment of causality will be made by the sponsor’s
unblinded safety assessment committee.
The sponsor assumes responsibility for appropriate reporting of the listed anticipated events
according to the requirements of the countries/territories in which the studies are conducted.
8.3.5. 
Pregnancy
All initial reports of pregnancy in female participants or partners of male participants must be
reported to the sponsor by the study site personnel within 24 hours of their knowledge of the event
using the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg,
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are
considered SAEs and must be reported using an SAE reporting form. Any participant who becomes
pregnant during the study must be promptly withdrawn from the study and discontinue further
study intervention.

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Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the
infant will be required. (see Appendix 6 [Section 10.6] Contraceptive and Barrier Guidance and
Collection of Pregnancy Information and Appendix 5 [Section 10.5], Adverse Events, Serious
Adverse Events, Product Quality Complaints, and Other Safety Reporting: Definitions and
Procedures for Recording, Evaluating, Follow-Up, and Reporting).
8.3.6. 
Adverse Events of Special Interest
Treatment-emergent AEs associated with the following situations are considered an AESI:
1. 
Infections that are severe (as defined in Section 10.5.3) or require IV anti-infective or
operative/invasive intervention.
2. 
Hypoalbuminemia with albumin <20 g/L (<2.0 g/dL); applicable to participants who have
albumin >20 g/L at previous assessments. Those who enter with <20 g/L and stay below this
level should not be reported as an AESI. Those who enter with an albumin > 20g /L or those
who enter with albumin <20g/L and then  have an increase in albumin >20 g/L which
subsequently decreases to <20 g/L should be reported as an AESI.
These AEs occurring after the first study intervention administration(s) in participants participating
in this clinical study must be reported by the investigator to the sponsor or designee within 24 hours
after being made aware of the event, according to the procedures in Appendix 5 (Section 10.5),
Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-Up, and
Reporting, for SAEs. These events are to be considered serious only if they meet the definition of
an SAE.
8.4. 
Pharmacokinetics
Blood samples will be taken as described in the Schedule of Activities (Section 1.3; Table 1,
Table 2, and Table 3) for measurement of serum nipocalimab concentrations to assess the PK of
nipocalimab. Additionally, serum samples should also be collected at the end of treatment visit
from participants who discontinued study intervention or were withdrawn from the study. At
each sampling timepoint, aliquots of serum samples will be taken for PK, immunogenicity, and
back-up, respectively.
8.4.1. 
Evaluations
Blood samples will be collected for measurement of serum concentrations of nipocalimab  and
should be drawn from a different arm than that of the IV infusion line if study agent is administered
at that visit.
Blood samples will be collected and each serum sample will be divided into aliquots (for PK,
anti-nipocalimab antibodies, and back-up). All pre-dose samples must be collected before study
intervention administration at visits when a study intervention administration is scheduled. At
study visits where postdose samples are collected, a blood sample will be collected 45 minutes
(± 15 minutes) after the end of infusion. Samples collected for analyses of nipocalimab  serum
concentration 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

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samples. Participant confidentiality will be maintained. Additional information about the
collection, handling, and shipment of biological samples can be found in the laboratory manual.
8.4.2. 
Analytical Procedures
Serum samples will be analyzed to determine concentrations of nipocalimab using a validated,
specific, and sensitive immunoassay method by the sponsor’s bioanalytical facility or under the
supervision of the sponsor. The sponsor, or it’s designee, under conditions in which participants’
identity remains blinded, will assay these samples.
8.5. 
Genetics and Pharmacogenomics
Pharmacogenomics and genetics are not evaluated in this study.
8.6. 
Biomarkers
Biomarker assessments will be performed to examine the biologic response to treatment and to
identify biomarkers that are relevant to nipocalimab treatment and/or MG, where local regulations
permit. Blood samples for biomarker research will be collected from participants who agree during
the consenting process as specified in the SoA (Section 1.3; Table 1, Table 2, and Table 3). The
samples will be used to address scientific questions related to circulating biomarkers thought to
play a role in any effect of nipocalimab and/or MG, including research to help develop ways to
detect, monitor or treat the disease. The analyses could use proteomics, RNA expression and/or
metabolomics to understand disease characteristics and response to nipocalimab. No genetic
analysis will be performed.
Sample collection and testing will comply with local regulations.
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
Blood samples will be collected for measurement of concentrations of total serum IgG, IgG
subtypes (IgG1, IgG2, IgG3, and IgG4), IgA, IgM, IgE, and levels of anti-AChR, anti-MuSK, and
anti-LRP4 autoantibodies. In participants seronegative for anti-AChR and anti-MuSK
autoantibodies, other autoantibodies that have been implicated in gMG may be assessedm. For
stratification purposes, the levels of anti-AChR and anti-MuSK will be tested on all samples
m Exploratory biomarkers (including but not limited to IgG subtypes, IgM, IgA, and IgE) are not applicable for
collection in China.
1

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collected at Screening; anti-LRP4 will also be collected to assess seropositivity.n Blood samples
will be collected at the time points specified in the Schedule of Activities (Section 1.3; Table 1,
Table 2, and Table 3).
8.7. 
Immunogenicity Assessments
Antibodies to nipocalimab  will be evaluated in serum samples collected from all participants
according to the Schedule of Activities (Section 1.3; Table 1, Table 2, and Table 3). Additionally,
serum samples should also be collected at the end of treatment visit from participants who
discontinued study intervention or were withdrawn from the study. At each sampling timepoint,
aliquots of serum samples will be taken for PK, immunogenicity, and back-up, respectively.
Serum samples will be screened for antibodies binding to nipocalimab and the titer of confirmed
positive samples will be reported. Other analyses may also be performed to verify the stability of
antibodies to nipocalimab and/or further characterize the immunogenicity of nipocalimab (such as
for the incidence of NAb to nipocalimab).
Samples collected for immunogenicity analyses may additionally be used to evaluate safety or
efficacy aspects that address concerns arising during or after the study period. Genetic analyses
will not be performed on these serum samples. Participant confidentiality will be maintained.
Analytical Procedures
The detection and characterization of antibodies to nipocalimab  will be performed using a
validated method by the sponsor’s bioanalytical facility or under the supervision of the sponsor.
All samples collected for detection of antibodies to nipocalimab  will also be evaluated for
nipocalimab serum concentration to enable interpretation of the antibody data. Antibodies may be
further characterized and/or evaluated for their ability to neutralize the activity of the study
intervention(s).
8.8 Medical Resource Utilization and Health Economics
Medical resource utilization data, associated with medical encounters, will be collected using the
Healthcare Resource Use Questionnaire (HRUQ) on an ongoing basis whenever an encounter
occurs and will be reviewed as indicated in the Time and Events Schedule. The HRUQ includes
information regarding utilization of healthcare services (including the timing and type of services),
enabling changes in level and quantity of services to be considered as a variable in economic
models.
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).
n 
In China, anti-LRP4 autoantibody collection will only be tested at Screening.

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9.1. 
Statistical Hypotheses
The primary hypothesis of this study is that IV nipocalimab is superior to placebo as measured by
average change from baseline in the MG-ADL score over Weeks 22, 23, and 24 for participants
who are seropositive (anti-AChR positive, anti-MuSK positive, and/or anti-LRP4 positive).
9.2. 
Sample Size Determination
Double-blind Placebo-controlled Phase
A sample size of 75 seropositive participants per group are needed to provide at least 90% power
to detect standardized effect sizes of at least 0.57 at a two-sided significance level of 0.05,
assuming a drop-out rate of 20% at Week 24. A standardized effect size of 0.57 is based on
estimates of between-group differences (≥1.7) and standard deviations (approximately 3) from
clinical trial simulations of the MG-ADL total score. The sample size is based on a mixed effects
model for repeated measures (MMRM) assuming 12 post-baseline assessments over 24 weeks and
a constant within-participant correlation of 0.5 (Donohue 2020; Lu 2008). At least 150 eligible
seropositive participants will be enrolled. Seronegative participants will also be enrolledo.
The sample size of 75 participants per group also provides at least 90% power to detect a
standardized effect size of at least 0.57 for the QMG key secondary endpoint. Based on estimates
of the standard deviation of changes from baseline in this endpoint in published gMG studies
(approximately 5 [Howard 2017, 2019, 2020]), a standardized effect size of 0.57 translates to a
between-group difference of approximately 2.9.
Table 6 below summarizes the between-group differences in proportions that can be detected with
at least 90% (80%) power for the key secondary endpoint of response, assuming 75 participants
per group, two-sided significance level of 0.05, and a Pearson chi-square test. The assumed percent
responders in the placebo group were derived from clinical trial simulations.
Table 6: 
Between-group Differences in Proportions That can be Detected With at Least 90% (80%)
Power for the Key Secondary Endpoints
Key secondary endpoint 
Percent in placebo 
arm  
Smallest difference in proportions (percent in nipocalimab
arm) that can be detected with the given power
(N/group  75; two-sided α  0.05)
Power  90%  
Power  80%
Response 
45% 
0.26 (71%) 
0.23 (68%)
Type I error is controlled over the primary and key secondary objectives at two-sided 0.05 by
employing a fixed sequence testing approach described below (refer to Section 9.4.2.2).
o 
Seronegative participants are no longer being recruited; all participants must have a positive serologic test for a
gMG related pathogenic autoantibody (anti-AChR, anti-MuSK and/or anti-LRP4 autoantibodies), confirmed prior
to randomization.

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9.3. 
Populations for Analysis Sets
For purposes of analysis, the following populations are defined:
Analysis Sets 
Description
Enrolled 
All participants who sign the ICF.
Randomized 
The randomized analysis set includes all participants
who were randomized in the study.
Full Analysis Set 
The full analysis set includes all randomized participants
who received at least 1 dose (partial or complete) of any
study intervention in the double-blind phase
Full Analysis Set (OL) 
The full analysis set (OL) includes all participants who
received at least 1 dose (partial or complete) of
nipocalimab in the OLE phase
Primary Efficacy Analysis Set 
The primary efficacy analysis set includes all
randomized seropositive participants who received at
least 1 dose (partial or complete) of any study
intervention in the double-blind phase
Anti-AChR Positive Efficacy Analysis Set 
The anti-AChR positive efficacy analysis set includes all
randomized anti-AChR positive participants who
received at least 1 dose (partial or complete) of any
study intervention in the double-blind phase
Seropositive Efficacy Analysis Set (OL) 
The seropositive efficacy analysis set (OL) includes all
seropositive participants who received at least 1 dose
(partial or complete) of nipocalimab in the OLE phase
Safety (DB) 
The safety analysis set includes all randomized
participants who received at least 1 dose (partial or
complete) of any study intervention in the double-blind
phase
Safety (OL) 
The safety analysis set (OL) includes all participants
who received at least 1 dose (partial or complete) of
nipocalimab in the OLE phase
Safety  
The safety analysis set includes all participants who
received at least 1 dose (partial or complete) of any
study intervention in either the double-blind or OLE
phase
All Nipocalimab  
The all nipocalimab analysis set includes all participants
who received at least 1 dose (partial or complete) of
nipocalimab in either the double-blind or OLE phase
Pharmacokinetics (PK) Analysis Set 
The PK analysis set is defined as all participants who
received at least 1 complete dose of nipocalimab in
either the double-blind or OLE phase and have at least 1
valid post-dose blood sample drawn for PK analysis
Immunogenicity Analysis Set 
The immunogenicity analysis set is defined as all
participants who received at least 1 dose (partial or
complete) of nipocalimab in either the double-blind or
OLE phase and have at least 1 post-dose serum sample
evaluable for antibodies to nipocalimab
Pharmacodynamic (PD) Analysis Set 
The PD analysis set is defined as all participants who
received at least 1 dose (partial or complete) of
nipocalimab in either the double-blind or OLE phase
and have at least 1 valid post-dose blood sample drawn
for PD analysis

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9.4. 
Statistical Analyses
The SAP will be finalized prior to unblinding and it will include a more technical and detailed
description of the statistical analyses described in this section. This section is a summary of the
planned statistical analyses of the most important endpoints including primary and key secondary
endpoints.
9.4.1. 
General Considerations
The primary and key secondary efficacy analyses will be tested at a two-sided significance level
of 0.05 and point estimates and 95% confidence intervals will be presented. The testing strategy
to control Type I error over the primary and key secondary endpoints is described in
Section 9.4.2.2, below. A different testing strategy will be employed for submission to Japan and
is described in Section 9.4.3.
Other secondary and exploratory endpoints will be summarized with estimates and 95%
confidence intervals and/or descriptive statistics.
The analysis ofthe 24-week double-blind placebo-controlled phase will be performed after the last
participant completes the Week 24 visit.
A final analysis, including the OLE phase, will be performed after the last participant, last visit in
the OLE phase.
9.4.2. 
Double-blind Placebo-controlled Phase
9.4.2.1. 
Primary Endpoint
Primary Estimand (applicable to regions outside of the European Union [EU])
Population: Seropositive participants with gMG who are on a stable MG therapy (or who
discontinued MG therapy due to intolerance or lack of efficacy as defined in Inclusion
Criterion #4).
Endpoint: Average change from baseline (screening and Day 1) in MG-ADL total score over
Weeks 22, 23 and 24.
Intercurrent events and corresponding strategies:
Treatment discontinuation of study intervention only due to reasons other than initiation
of rescue medication use (Hypothetical strategy: as if the intercurrent event had not
occurred) (ICH Guidance E9 [R1] 2019)
Treatment discontinuation of both background MG medication and study intervention
due to reasons other than initiation of rescue medication use (Hypothetical strategy: see
above)
Treatment discontinuation of study intervention only due to initiation of rescue
medication use (Hypothetical strategy: see above)
Treatment discontinuation of both background MG medication and study intervention
due to initiation of rescue medication use (Hypothetical strategy: see above)

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Change in background MG medication (Hypothetical strategy: see above)
Summary measure: Difference between treatment means.
Treatment: 30 mg/kg loading dose followed by 15 mg/kg q2w of nipocalimab versus placebo.
Primary Estimand (applicable to the EU)
Population: Seropositive participants with gMG who are on a stable MG therapy (or who
discontinued MG therapy due to intolerance or lack of efficacy as defined in Inclusion
Criterion #4).
Endpoint: Average change from baseline (screening and Day 1) in MG-ADL total score over
Weeks 22, 23 and 24.
Intercurrent events and corresponding strategies:
Treatment discontinuation of study intervention only due to reasons other than initiation
of rescue medication use (Treatment policy: irrespective of the occurrence of an
intercurrent event) (ICH Guidance E9 [R1] 2019)
Treatment discontinuation of both background MG medication and study intervention
due to reasons other than initiation of rescue medication use (Treatment policy: see
above)
Treatment discontinuation of study intervention only due to initiation of rescue
medication use (Hypothetical strategy: as if the intercurrent event had not occurred)
Treatment discontinuation of both background MG medication and study intervention
due to initiation of rescue medication use (Hypothetical strategy: see above)
Change in background MG medication (Treatment policy: see above)
Summary measure: Difference between treatment means.
Treatment: 30 mg/kg loading dose followed by 15 mg/kg q2w of nipocalimab versus placebo.
Analysis Under the Primary Estimands
Regions outside of the EU
The primary efficacy endpoint, the average change from baseline in MG-ADL total score over
Weeks 22, 23 and 24 of the double-blind placebo-controlled phase, will be analyzed using an
MMRM with weekly change from baseline as the dependent variable; factors for treatment,
autoantibody status, region, week, and treatment-by-week interaction; baseline MGADL total
score as a covariate and participant as a random effect. Baseline is defined as the arithmetic mean
of the screening and Day 1 assessments. An unstructured variance-covariance matrix will be used
first. In case of convergence problems, alternative variance-covariance structures will be tried in
the following order, with the first structure that converges being used in the analysis:
heterogeneous Toeplitz, standard Toeplitz, and AR(1). The between-group difference of the
average change over Weeks 22, 23, and 24 will be tested with an F-test of the linear contrast that
averages the change from baseline over those time points. The estimate of this contrast and its 95%
confidence interval will be provided. Observations after the occurrence of an intercurrent event
will not be included in the primary analysis, consistent with the hypothetical strategy for handling

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intercurrent events. Missing data will be handled through the MMRM, assuming missing data are
Missing at Random.
Sensitivity analyses will include a tipping point analysis using multiple imputation with delta
adjustment. The frequency of the intercurrent events of treatment discontinuation and rescue
medication use will be summarized.
EU
The analysis will proceed in the same manner as described above for regions outside of the EU,
except for how observations collected after intercurrent events are handled. For intercurrent events
addressed with the treatment policy strategy, observations collected after the intercurrent event
will be included in the analysis. For intercurrent events addressed with the hypothetical strategy,
observations collected after the intercurrent event will not be included in the analysis. Missing data
that may result after an intercurrent event will be handled with a Copy Reference multiple
imputation approach.
Sensitivity analyses will include a Jump to Reference multiple imputation approach.
The Statistical Analysis Plan may specify supplementary estimands in addition to the primary
estimands specified above.
9.4.2.2. 
Secondary Endpoint(s)
Key Secondary Efficacy Endpoints
A fixed sequence approach will be applied to adjust for multiplicity and to control Type 1 error
across the primary and the 5 key secondary efficacy endpoints. The 5 key secondary endpoints
will be analyzed sequentially and will be considered statistically significant at the 2-sided 0.05
level only if the endpoint is individually significant at the 2-sided 0.05 level and previous endpoints
in the hierarchy were significant at the 2-sided 0.05 level, including the primary endpoint. If the
primary endpoint is statistically significant, the selected secondary endpoints will be assessed in
the following order:
1. Average change from baseline in QMG score over weeks 22 and 24. Analyzed using a similar
method (appropriate for the region) as for the primary efficacy endpoint, but since the QMG
is not assessed at Week 23, the contrast will average the change from baseline over Weeks 22
and 24 of the double-blind placebo-controlled phase.
2. Percentage of participants whose average MG-ADL total score over weeks 22, 23 and 24 of
the double-blind placebo-controlled phase is at least a 2-point improvement compared to
baseline. The average score for a participant is the average of the non-missing values at Weeks
22, 23 and 24. A participant must have a non-missing value at Week 24 and at least 1
non-missing value at Week 22 or 23 in order to have a non-missing average score. A
participant with a missing average score will be considered a nonresponder. Analyzed by
Cochran-Mantel-Haenszel test controlling for the baseline MG-ADL total score
randomization strata (≤9, >9), autoantibody status, and region.

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3. Loading dose response, defined as percentage of participants with improvement in MG-ADL
total score of ≥2 points at Week 1 and/or Week 2. A participant with a missing assessment at
either time point will be considered a nonresponder at that time point. Analyzed by Cochran-
Mantel-Haenszel test controlling for the baseline MG-ADL total score randomization strata
(≤9, >9), autoantibody status, and region.
4. Sustainability of therapeutic response, defined as the percentage of participants with
improvement in MG-ADL total score of ≥ 2 points at Week 4 through Week 24, with no more
than 2 non-consecutive excursions allowed between Week 6 through Week 23 (excursions
defined as loss of improvement in MG-ADL score of ≥2 points from baseline). A participant
with a missing assessment at a time point will be considered a nonresponder at that time point.
Analyzed by Cochran-Mantel-Haenszel test controlling for the baseline MG-ADL total score
randomization strata (≤9, >9), autoantibody status, and region.
5. Percentage of participants whose average MG-ADL total score over weeks 22, 23 and 24 of
the double-blind, placebo-controlled phase is at least a 50% improvement compared to
baseline. The average score for a participant is the average of the non-missing values at Weeks
22, 23 and 24. A participant must have a non-missing value at Week 24 and at least 1 non-
missing value at Week 22 or 23 in order to have a non-missing average score. A participant
with a missing average score will be considered a nonresponder. Analyzed by Cochran-
Mantel-Haenszel test controlling for the baseline MG-ADL total score randomization strata
(≤9, >9), autoantibody status, and region.
Estimands for Responder-type Key Secondary Endpoints (applicable to all regions)
Population: seropositive participants with gMG who are on a stable MG therapy (or who
discontinued MG therapy due to intolerance or lack of efficacy as defined in Inclusion
Criterion #4).
Endpoint: As defined above for “response”, “loading dose response”, “minimum symptom
expression”, and sustainability of therapeutic response.
Intercurrent events and corresponding strategies:
Treatment discontinuation of study intervention only due to reasons other than initiation
of rescue medication (Composite strategy: endpoint is defined as “non-response” at time
points after the intercurrent event) (ICH Guidance E9 [R1] 2019)
Treatment discontinuation of both background MG medication and study intervention
due to reasons other than initiation of rescue medication (Composite strategy: see above)
Change in background MG medication (Composite strategy: see above)
Treatment discontinuation of study due to initiation of rescue medication (Composite
strategy; see above)
Treatment discontinuation of both background MG medication and study intervention
due to initiation of rescue medication (Composite strategy; see above)
Summary measure: Difference between proportion of responder in each treatment group.
Treatment: 30 mg/kg loading dose followed by 15 mg/kg q2w of nipocalimab versus placebo.
The estimands for the QMG endpoint are similar to the primary estimand with the same
intercurrent events and intercurrent events strategies.

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Sensitivity analyses to evaluate missing data assumptions in the estimators of the key secondary
endpoints will be described in the SAP.
Other Efficacy Endpoints
Between-group differences and 95% confidence intervals of the change from baseline in MG-ADL
score at each time point will be estimated from the same MMRM described above (as appropriate
for the region). Similar analyses will be conducted for QMG.
The percentage of MG-ADL responders, defined as improvement in the MG-ADL total score of
≥2 points, will be summarized at each time point. Participants with a missing value at a time point
will be considered a non-responder at that time point. A similar analysis will be conducted for
QMG, including sustainability of response as defined for MG-ADL above, where QMG response
is defined as improvement of ≥3 points.
Time to first MG-ADL response in the double-blind, placebo-controlled period will be
summarized with Kaplan-Meier estimates.
The percentage of participants with minimum symptom expression, defined as a MG-ADL total
score of 0 or 1, will be summarized at each time point. The percent of participants with minimum
symptom expression at any time point, at 50% of all time points, and at 75% of all time points
during the 24-week double-blind placebo-controlled phase will also be summarized.
Change from baseline in the Neuro-QoL Fatigue total score, MG-QoL15r total score, and PGI-S
will each be analyzed using a similar MMRM described above for the primary efficacy endpoint.
The frequency distributions of PGI-S and PGI-C scores will also be summarized at each time point.
Descriptive statistics of the change from baseline in EQ-5D-5L visual analog scale and health
status index will be summarized at each time point. The distribution of the level of responses (level
1, 2, 3, 4, and 5) for each of the EQ-5D-5L health dimensions of mobility, self-care, usual activity,
pain and discomfort, and anxiety and depression will be summarized at each time point.
Analyses of the MG-ADL described above, and for selected secondary efficacy endpoints, will be
repeated for the full analysis set (both seropositive and seronegative participants) and for the
seronegative subgroup. Additional descriptive summaries of MG-ADL will be performed for each
type of anti-autobody (anti-AChR, anti-MuSK, anti-LRP4) as the sample size in each subgroup
allows.
Actigraphy will be performed at selected sites globally. The raw data sampled by the actigraphy
watch sensors will be transformed into derived digital health endpoints, assessing the changes on
physical activity, mobility, and sleep parameters during the 24-week double-blind placebo-
controlled phase. Endpoints include, but are not limited to, step count, activity count, sleep time,
sleep efficiency and percent mobile time.
Additional actigraphy endpoints may be derived using emerging algorithms. Associations between
actigraphy endpoints and other endpoints may be explored. All actigraphy-related analyses are
considered exploratory and will be summarized in a separate report.

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9.4.3. 
Testing Strategy for Japan
For submission in Japan 2 primary endpoint families of 3 statistical hypotheses will be tested:
Primary Endpoint Family 1
Efficacy of 24 weeks of nipocalimab treatment compared to placebo for generalized
myasthenia gravis (gMG), based on the MG-ADL scale, in seropositive participants when
treatment is taken as directed.
Efficacy of 24 weeks of nipocalimab treatment compared to placebo for generalized
myasthenia gravis (gMG), based on the MG-ADL scale, in anti-AChR positive participants
when treatment is taken as directed.
Primary Endpoint Family 2
Efficacy of 24 weeks of nipocalimab treatment compared to placebo for generalized
myasthenia gravis (gMG), based on the MG-ADL scale, in seropositive and seronegative
participants when treatment is taken as directed.
The estimands for each hypothesis are the same as the primary estimand described above for
regions outside of the EU with only the population changing depending on the hypothesis. The
analysis under each estimand will be the same as the analysis under the primary estimand,
employing the appropriate analysis set for the given estimand.
The primary analyses for Japan will be conducted at the 2-sided 0.05 level for both the seropositive
and anti-AChR positive analysis sets. If both are statistically significant, the null hypotheses for
primary endpoint family 1 will be rejected and the analysis for the full analysis set (including both
seropositive and seronegative participants) will be conducted at the 2-sided 0.05 level. If the
analysis for either the seropositive analysis or the anti-AChR positive analysis is not statistically
significant (at 2-sided 0.05), then the analysis for the full analysis set will not be conducted.
This serial gatekeeping strategy maintains Type I error control over the two families of 3
hypotheses at the 2-sided 0.05 level.
Further details about analyses specific for the Japan submission will be described in the Statistical
Analysis Plan.
9.4.4. 
Open-label Extension Phase
All efficacy data will be summarized using descriptive statistics. Two treatment groups are defined
for this phase based on the sequence of assigned treatments in the double-blind placebo-controlled
phase: 1) nipocalimab 15 mg/kg q2w - nipocalimab 15 mg/kg q2w; 2) placebo - nipocalimab
15 mg/kg q2w.
Change from the double-blind placebo-controlled baseline over time will be summarized for
MG-ADL, QMG, Neuro-QoL Fatigue total score, MG-QoL15r total score, and PGI-S.

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The percentage of MG-ADL responders and QMG responders over time will be summarized. The
percentage of participants with minimal symptom expression (MSE) will be summarized at each
time point.
The frequency distributions of PGI-S and PGI-C scores will also be summarized at each time point.
Descriptive statistics of the change from baseline in EQ-5D-5L visual analog scale and health
status index will be summarized at each time point. The frequency distribution of level of responses
(level 1, 2, 3, 4, and 5) for each of the EQ-5D-5L health dimensions of mobility; self-care; usual
activity; pain and discomfort; and anxiety and depression will also be summarized at each time
point.
The treatment groups may also be combined for summaries of OLE phase timepoints since all
participants will be assigned the same nipocalimab dose for the first 6 months of the phase.
9.4.5. 
Safety Analyses
All safety analyses will be made on the full analysis set.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the
Medical Dictionary for Regulatory Activities (MedDRA). All reported AEs with onset during a
phase will be included in the analysis. For each AE, the percentage of participants who experience
at least 1 occurrence of the given event will be summarized by treatment group. Separate
summaries will be provided for each phase of the study. Participants who die, who discontinue
treatment due to an AE, or who experience an SAE will be summarized separately. Listings of all
participants with MACE (non-fatal myocardial infarction, stroke, and cardiovascular death) will
be provided.
The TEAEs of special interest will be examined separately grouped in the following categories:
Severe or serious infections, hypoalbuminemia <20 g/L. The AESIs will be further listed in the
SAP.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly
abnormal results will be used in the summary of laboratory data. Descriptive statistics will be
calculated for each laboratory analyte at baseline and for observed values and changes from
baseline at each scheduled time point. Frequency tabulations of the abnormalities will be provided.
A listing of participants with any markedly abnormal laboratory results will also be provided.
Electrocardiogram
The ECG data will be summarized by ECG parameter. Descriptive statistics will be calculated at
baseline and for observed values and changes from baseline at each scheduled time point.
Frequency tabulations of the abnormalities will be made. All clinically relevant abnormalities in
ECG waveforms that are changes from the baseline readings will be reported.

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Vital Signs
Descriptive statistics of temperature, pulse/heart rate, respiratory rate, body weight measurements,
and blood pressure (systolic and diastolic) values and changes from baseline will be summarized
at each scheduled time point. The percentage of participants with values beyond clinically
important limits will be summarized.
Physical Examinations
Physical examination findings will be summarized at each scheduled time point. Descriptive
statistics will be calculated at baseline and for observed values and changes from baseline at each
scheduled time point. Frequency tabulations of the abnormalities will be made.
C-SSRS
The percentage of participants with suicidal ideation or suicidal behavior based on the C-SSRS
will be summarized.
9.4.6. 
Other Analyses
Pharmacokinetic Analyses
For each intervention group, serum nipocalimab concentrations will be summarized over time to
assess the PK of nipocalimab. Descriptive statistics, including arithmetic mean, SD, coefficient of
variation, median, minimum, and maximum will be calculated for serum nipocalimab
concentrations. All concentrations below the lowest quantifiable concentration or missing data will
be labeled as such in the concentration database. All participants and samples excluded from the
analysis will be clearly documented in the study report.
Biomarkers Analyses
Changes in serum IgG, or other biomarkers over time will be summarized by intervention group.
Planned biomarker analyses may be deferred if emerging study data show no likelihood of
providing useful scientific information. Results of biomarker analysis will be presented in a
separate report.
Immunogenicity Analyses
The incidence and titers of anti-nipocalimab antibodies will be summarized by treatment group for
all participants who receive at least 1 dose of nipocalimab  and have appropriate samples for
detection of antibodies to nipocalimab.
A listing of participants who are positive for anti-drug antibodies to nipocalimab will be provided.
The maximum titers of anti-drug antibodies to nipocalimab will be summarized for participants
who are positive for anti-drug antibodies to nipocalimab.
The incidence of NAbs to nipocalimab will be summarized for participants who are positive for
anti-drug antibodies to nipocalimab and have samples evaluable for NAbs to nipocalimab.

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Pharmacokinetic/Pharmacodynamic Analyses
A pharmacometrics model-based analyses will be conducted to describe the relationships of PK,
PD (IgG lowering), and efficacy (MG-ADL and/or QMG). Details will be given in a model-based
PK/IgG/efficacy analysis plan, and results of the model-based PK/IgG/efficacy analysis will be
presented in a separate technical report.
Benefit-Risk Analysis
Benefit-risk assessment of nipocalimab vs placebo for participants with gMG will be assessed
using a structured framework approach. Benefits in the assessment may include the primary
efficacy endpoint and improvement from baseline in measures of disease activity and functions,
such as MG-ADL and QMG. Risks in the assessment may include clinically meaningful,
treatment-emergent AEs or adverse drug reactions.
The benefit-risk assessment will be evaluated over the double-blind placebo-controlled period
based on the between treatment differences (eg, risk difference or excess number of events) for
efficacy and safety endpoints at Week 24. Kaplan-Meier Product-Limit estimates may also be used
to display and evaluate benefits and risks over time. To compare efficacy and safety endpoints in
similar units (proportions to proportions, or rates to rates), MG-ADL and QMG will be assessed
as the proportions of participants which show a clinically meaningful change or response, and the
risks will be shown as proportions or rates. Benefit-risk results will be depicted with effect tables
and with other visual representations (eg, forest plots).
9.5. 
Interim Analysis
Analyses of the OLE data may be performed periodically to assess safety and/or efficacy.

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Abbreviations
AChR  
acetylcholine receptor
ADA  
anti-drug antibody
AE 
adverse event
AESI 
adverse event of special interest
ALT  
alanine aminotransferase
AST  
aspartate aminotransferase
BCG  
Bacille Calmette-Guerin
CIC  
circulating immune complex
CK  
creatine kinase
COVID-19 
coronavirus disease 2019
CRF  
case report form
CS  
clinically significant
C-SSRS  
Columbia-Suicide Severity Rating Scale
CV  
coefficient of variation
DMC  
Data Monitoring Committee
EAC  
Event Adjudication Committee
ECG  
Electrocardiogram
eCRF  
electronic case report form
EMA  
European Medicines Agency
EOS-HDFN  
early onset severe hemolytic disease of the fetus and newborn
EU CTR  
European Union Clinical Trial Regulation
EQ-VAS  
EQ visual analogue scale
FcRn  
neonatal Fc receptor
FIH  
first-in-human
FSH  
follicle-stimulating hormone
GCP  
Good Clinical Practice
gMG  
generalized myasthenia gravis
HBV  
hepatitis B virus
HCV  
hepatitis C virus
HIV  
human immunodeficiency virus
IB  
investigator’s brochure
ICF  
informed consent form
ICH  
International Council for Harmonisation
IEC  
Independent Ethics Committee
Ig 
Immunoglobulin
IRB  
Institutional Review Board
IV  
Intravenous
IVIg 
intravenous immunoglobulin
IWRS  
interactive web response system
LRP4 
lipoprotein-related protein receptor 4
MACE 
Major Adverse Cardiovascular Events

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MAD  
multiple ascending dose
MCID  
minimum clinically important difference
MedDRA  
Medical Dictionary for Regulatory Activities
MG  
myasthenia gravis
MG-ADL 
Myasthenia Gravis –Activities of Daily Living
MGFA  
Myasthenia Gravis Foundation of America
MG-QoL15r 
Revised Myasthenia Gravis Quality of Life –15 Scale
MMRM  
mixed effects model repeated measures
MSE 
minimum symptom expression
MuSK  
muscle-specific kinase
Nab  
neutralizing antibody
NCS  
not clinically significant
Neuro-QoL 
Fatigue
fatigue items of the quality of life in neurological disorders scale
OLE 
open-label extension
PD 
Pharmacodynamic(s)
PGI-C  
Patient Global Impression of Change
PG-S  
Patient Global Impression of Severity
PK 
Pharmacokinetic(s)
PMDA  
Pharmaceuticals and Medical Devices Agency
PQC  
Product Quality Complaint
PRO  
patient-reported outcome(s) (paper or electronic as appropriate for this study)
q2w  
every 2 weeks
q4w  
every 4 weeks
QMG  
Quantitative Myasthenia Gravis
QTc 
QT interval corrected for heart rate
SAE 
serious adverse event
SAP  
statistical analysis plan
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2
SIPPM  
site investigational product procedures manual
SUSAR  
suspected unexpected serious adverse reaction
TEAE 
treatment-emergent adverse event
TSQM-9 
Treatment Satisfaction Questionnaire for Medication;
ULN  
upper limit of normal
US  
United States
US FDA  
United States Food and Drug Administration
wAIHA  
warm autoimmune hemolytic anemia
WOCBP  
woman of child bearing potential

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Serum follicle-stimulating hormone (for female participants exhibiting amenorrhea
for approximately 12 months (ie, perimenopausal) at screening only).
Serology (HIV antibody, hepatitis B surface antigen [HBsAg], anti-HBc antibody,
anti-HBs antibody, and hepatitis C virus test [including HCV ribonucleic acid test
if necessary) at screening only.

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10.4. Appendix 4: Regulatory, Ethical, and Study Oversight Considerations
10.4.1. 
Regulatory and Ethical Considerations
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and
country- or territory-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing,
conducting, recording, and reporting studies that involve the participation of human participants.
Compliance with this standard provides public assurance that the rights, safety, and well-being of
study participants are protected, consistent with the principles that originated in the Declaration of
Helsinki, and that the study data are credible.
Protocol Clarification Communications
If text within a final approved protocol requires clarification (eg, current wording is unclear or
ambiguous) that does not change any aspect of the current study conduct, a protocol clarification
communication (PCC) may be prepared. The PCC Document will be communicated to the
Investigational Site, Site Monitors, 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 non-acceptance, except when
necessary to eliminate immediate hazards to the participants, in which case the amendment must
be promptly submitted to the IEC/IRB and relevant competent authority. Documentation of
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the
change(s) involve only logistic or administrative aspects of the study, the IEC/IRB (where
required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable,
the investigator or other physician in attendance will contact the appropriate sponsor representative
listed in the 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

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situation and agree on an appropriate course of action. The data recorded in the CRF and source
documents will reflect any departure from the protocol, and the source documents will describe
this departure and the circumstances requiring it.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities
in each respective country/territory, if applicable. A study may not be initiated until all local
regulatory requirements are met.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study intervention
to the study site:
Protocol and amendment(s), if any, signed and dated by the principal investigator.
A copy of the dated and signed (or sealed, where appropriate per local regulations), written
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if
applicable, participant compensation programs. This approval must clearly identify the
specific protocol by title and number and must be signed (or sealed, where appropriate per
local regulations) by the chairman or authorized designee.
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their
function, with a statement that it is organized and operates according to GCP and the
applicable laws and regulations. Ifaccompanied 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.
Country/Territory Selection
This study will only be conducted in those countries/territories where the intent is to launch or
otherwise help ensure access to the developed product if the need for the product persists, unless
explicitly addressed as a specific ethical consideration in Section 4.2.1, Study-Specific Ethical
Design Considerations.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
10.4.2. 
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial
information in accordance with local regulations to allow the sponsor to submit complete and
accurate financial certification or disclosure statements to the appropriate regulatory authorities.
Investigators are responsible for providing information on financial interests during the course of
the study and for 1 year after completion of the study.

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Refer to Required Prestudy Documentation (above) for details on financial disclosure.
10.4.3. 
Informed Consent Process
Each participant must give written consent according to local requirements after the nature of the
study has been fully explained. Each participant must be legal age of consent in the jurisdiction in
which the study is taking place, at the time of consent. 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 the aims, methods, reasonably anticipated benefits, and
potential hazards of the study, and any discomfort participation in the study may entail. Participants
will be informed that their participation is voluntary and that they may withdraw consent to
participate at any time. They will be informed that choosing not to participate will not affect the
care the participant will receive. Finally, they will be told that the investigator will maintain a
participant identification register for the purposes of long-term follow-up if needed and that their
records may be accessed by health authorities and authorized sponsor personnel without violating
the confidentiality of the participant, to the extent permitted by the applicable law(s) or regulations.
By signing the ICF the participant is authorizing such access, 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 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 the participant's personally dated signature. After having obtained the consent, a copy of
the ICF must be given to the participant.
Participants who are rescreened are required to sign a new ICF.
10.4.4. 
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.

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The informed consent obtained from the participant includes information about, and where
required per applicable regulations, explicit consent for the processing of personal data and for the
investigator/institution to allow direct access to his or her original medical records (source
data/documents) for study-related monitoring, audit, IEC/IRB review, and regulatory inspection.
The informed consent also provides information to address the lawful transfer of the data to other
entities and to other countries/territories.
The participant has the right to request through the investigator access to his or her personal data
and the right to request rectification of any data that are not correct or complete, or make requests
concerning his or her personal data in accordance with applicable data protection law. Reasonable
steps will be taken to respond to such a request, taking into consideration the nature of the request,
the conditions of the study, and the applicable laws and regulations.
In the event of a data security breach, the sponsor will apply measures to adequately manage and
mitigate possible adverse effects taking into consideration the nature of the data security breach as
necessary to address other obligations such as notifying appropriate authorities in accordance with
applicable data protection law.
Exploratory 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.
10.4.5. 
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. Remaining study samples may be used to help develop ways to better
understand the effect of nipocalimab and/or ways to detect, monitor or treat the disease. The
research may begin at any time during the study or the post-study storage period.
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).
10.4.6. 
Committees Structure
Data Monitoring Committee
An independent Data Monitoring Committee (DMC) and Major Adverse Cardiovascular Events
(MACE) Event Adjudication Committee (EAC) will be established to monitor data on an ongoing
basis and to ensure the continuing safety of the participants enrolled in this study. The DMC will
consist of at least one medical expert in the relevant therapeutic area and at least one statistician.
Committee membership responsibilities, authorities, and procedures of each committee will be
documented in separate DMC and EAC charters.

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10.4.7. 
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 of nipocalimab, and thus may be disclosed
as required to other clinical investigators or regulatory agencies. To permit the information derived
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all
data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and
will contain data from all study sites that participated in the study as per protocol. Recruitment
performance or specific expertise related to the nature and the key assessment parameters of the
study will be used to determine a coordinating investigator for the study. Results of exploratory
biomarker analyses performed after the Clinical Study Report has been issued will be reported in
a separate report and will not require a revision of the Clinical Study Report.
Study participant identifiers will not be used in publication of results. Any work created in
connection with performance of the study and contained in the data that can benefit from copyright
protection (except any publication by the investigator as provided for below) shall be the property
of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary (multicenter)
data and information without approval from the investigator. The investigator has the right to
publish study site-specific data after the primary data are published. If an investigator wishes to
publish information from the study, a copy of the manuscript must be provided to the sponsor for
review at least 60 days before submission for publication or presentation. Expedited reviews will
be arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in
writing, the investigator will withhold such publication for up to an additional 60 days to allow for
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

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will be no multicenter study publication. Authorship of publications resulting from this study will
be based on the guidelines on authorship, such as those described in the ICMJE Recommendations
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which
state that the named authors must have made a significant contribution to the conception or design
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the
work or revised it critically for important intellectual content; and given final approval of the
version to be published; and agreed to be accountable for all aspects of the work in ensuring that
questions related to the accuracy or integrity of any part of the work are appropriately investigated
and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required
by law. The disclosure of the final study results will be performed after the end of study in order
to ensure the statistical analyses are relevant.
10.4.8. 
Data Quality Assurance
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified
investigators and appropriate study sites, review of protocol procedures with the investigator and
study site personnel before the study, periodic monitoring visits by the sponsor, direct transmission
of clinical laboratory data from a central laboratory, and direct transmission of efficacy data from
an eCOA/ePRO vendor into the sponsor's database. Written instructions will be provided for
collection, handling, storage, and shipment of samples.
Guidelines for CRF completion will be provided and reviewed with study site personnel before
the start of the study. The sponsor will review CRF for accuracy and completeness during on-site
monitoring visits and after transmission to the sponsor; any discrepancies will be resolved with the
investigator or designee, as appropriate. After upload of the data into the study database they will
be verified for accuracy and consistency with the data sources.
10.4.9. 
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 CRF. All CRF entries, corrections, and
alterations must be made by the investigator or authorized study site personnel. The investigator
must verify that all data entries in the CRF are accurate and correct.
The study data will be transcribed by study site personnel from the source documents onto an
electronic CRF, if applicable. Study-specific data will be transmitted in a secure manner to the
sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any
such worksheets will become part of the participant's source documents. Data must be entered into

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CRF in English. The CRF must be completed as soon as possible after a participant visit and the
forms should be available for review at the next scheduled monitoring visit.
All participative measurements (eg, pain scale information or other questionnaires) will be
completed by the same individual who made the initial baseline determinations whenever possible.
If necessary, queries will be generated in the eDC tool. If corrections to a CRF are needed after
the initial entry into the CRF, this can be done in either of the following ways:
Investigator and study site personnel can make corrections in the eDC tool at their own
initiative or as a response to an auto query (generated by the eDC tool).
Sponsor or sponsor delegate can generate a query for resolution by the investigator and study
site personnel.
10.4.10. 
Source Documents
At a minimum, source documents consistent in the type and level of detail with that commonly
recorded at the study site as a basis for standard medical care must be available for the following:
participant identification, eligibility, and study identification; study discussion and date of signed
informed consent; dates of visits; results of safety and efficacy parameters as required by the
protocol; record of all AEs and follow-up of AEs; concomitant medication; intervention
receipt/dispensing/return records; study intervention administration information; and date of study
completion and reason for early discontinuation of study intervention or withdrawal from the
study, if applicable.
The author of an entry in the source documents should be identifiable. Given that PROs are reports
of a patient's health condition that come directly from the patient, without interpretation by a
clinician or anyone else, the responses to PRO measures entered by study participants into source
records cannot be overridden by site staff or investigators.
Specific details required as source data for the study and source data collection methods will be
reviewed with the investigator before the study and will be described in the monitoring guidelines
(or other equivalent document).
The following data will be recorded directly into the CRF and will be considered source data:
Race
Blood pressure and pulse/heart rate
Height and weight
Details of physical examination
The minimum source documentation requirements for Section 5.1, Inclusion Criteria and
Section 5.2, Exclusion Criteria that specify a need for documented medical history are as follows:
Referral letter from treating physician or

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Complete history of medical notes at the site
Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a
minimum by participant interview or other protocol-required assessment (eg, physical
examination, laboratory assessment) and documented in the source documents.
An eSource system may be utilized, which contains data traditionally maintained in a hospital or
clinic record to document medical care (eg, electronic source documents) as well as the clinical
study-specific data fields as determined by the protocol. This data is electronically extracted for
use by the sponsor. If eSource is utilized, references made to the CRF in the protocol include the
eSource system but information collected through eSource may not be limited to that found in the
CRF.
10.4.11. 
Monitoring
The sponsor will use a combination of monitoring techniques: central, remote, or on-site
monitoring to monitor this study.
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will
record dates of the visits in a study site visit log that will be kept at the study site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the
monitor will compare the data entered into the CRF with the source documents
(eg, hospital/clinic/physician’s office medical records). The nature and location of all source
documents will be identified to ensure that all sources of original data required to complete the
CRF are known to the sponsor and study site personnel and are accessible for verification by the
sponsor study site contact. If electronic records are maintained at the study site, the method of
verification must be discussed with the study site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of verifying
that the recorded data are consistent with the original source data. Findings from this review will
be discussed with the study site personnel. The sponsor expects that, during monitoring visits, the
relevant study site personnel will be available, the source documents will be accessible, and a
suitable environment will be provided for review of study-related documents. The monitor will
meet with the investigator on a regular basis during the study to provide feedback on the study
conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these
remote contacts, study site personnel will be available to provide an update on the progress of the
study at the site.
Central monitoring will take place for data identified by the sponsor as requiring central review.

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10.4.12. 
On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at
any time during or after completion of the study to conduct an audit of the study in compliance
with regulatory guidelines and company policy. These audits will require access to all study
records, including source documents, for inspection. Participant privacy must, however, be
respected. The investigator and study site personnel are responsible for being present and available
for consultation during routinely scheduled study site audit visits conducted by the sponsor or its
designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part
of a national GCP compliance program or to review the results of this study in support of a
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
10.4.13. 
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRF and
all source documents that support the data collected from each participant, as well as all study
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical
Trial, and all study documents as specified by the applicable regulatory requirement(s). The
investigator/institution will take measures to prevent accidental or premature destruction of these
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing
application in an ICH region and until there are no pending or contemplated marketing applications
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical
development of the investigational product. These documents will be retained for a longer period
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the
responsibility of the sponsor to inform the investigator/institution as to when these documents no
longer need to be retained. For trials performed under Regulation [EU] No. 536/2014, the sponsor
and the investigator shall archive the content of the clinical trial master file for at least 25 years
after the end of the clinical trial.
If the responsible investigator retires, relocates, or for other reasons withdraws from the
responsibility of keeping the study records, custody must be transferred to a person who will accept
the responsibility. The sponsor must be notified in writing of the name and address of the new
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any
documentation relating to this study, the investigator/institution must permit access to such reports.

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10.4.14. 
Study and Site Start and Closure
First Act of Recruitment
The first site open is considered the first act of recruitment and it becomes the study start date.
Study/Site Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been collected
and a study site closure visit has been performed.
The investigator may initiate study site closure at any time, provided there is reasonable cause and
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not
limited to:
Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or
local health authorities, the sponsor's procedures, or GCP guidelines
Inadequate recruitment of participants by the investigator
Discontinuation of further study intervention development

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10.5. Appendix 5: Adverse Events, Serious Adverse Events, Product Quality
Complaints, and Other Safety Reporting: Definitions and Procedures for
Recording, Evaluating, Follow-up, and Reporting
10.5.1. 
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a
pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have
a causal relationship with the intervention. An AE can therefore be any unfavorable and unintended
sign (including an abnormal finding), symptom, or disease temporally associated with the use of a
medicinal (investigational or non-investigational) product, whether or not related to that medicinal
(investigational or non-investigational) product. (Definition per International Conference on
Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the
baseline condition, or abnormal results of diagnostic procedures, including laboratory test
abnormalities.
Note: The sponsor collects AEs starting with the signing of the ICF (refer to All Adverse Events
under Section 8.3.1, Time Period and Frequency for Collecting Adverse Events and Serious
Adverse Events Information, for time of last AE recording).
Serious Adverse Event
A SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for Human
Use is any untoward medical occurrence that at any dose:
Results in death.
Is life-threatening
(The participant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe).
Requires inpatient hospitalization or prolongation of existing hospitalization.
Results in persistent or significant disability/incapacity.
Is a congenital anomaly/birth defect.
Is a suspected transmission of any infectious agent via a medicinal product.
Is Medically Important.*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is
also appropriate in other situations, such as important medical events that may not be immediately
life threatening or result in death or hospitalization but may jeopardize the participant or may
require intervention to prevent one of the other outcomes listed in the definition above. These
should usually be considered serious.

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If a serious and unexpected AE occurs for which there is evidence suggesting a causal relationship
between the study intervention and the event (eg, death from anaphylaxis), the event must be
reported as a serious and unexpected suspected adverse reaction even if it is a component of the
study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable product
reference safety information. For nipocalimab, the expectedness of an AE will be determined by
whether or not it is listed in the IB. For standard of care medication (that is required to be continued
along with the study intervention) 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.
10.5.2. 
Attribution Definitions
Assessment of Causality
The causal relationship to study intervention is determined by the investigator.
The assessment of causality must consider the following factors:
Temporal relationship
Clinical characteristics of event
Pharmacological plausibility
Confounding risk factors:
Concomitant medication
Underlying/concurrent disease
Family/social history
Challenge:
De-challenge: Did the reaction improve when the investigational product was withdrawn,
in the absence of any other treatment?
Re-challenge: What happens if participant is re-challenged with investigational product?
Other considerations: Participant characteristics and past medical history, and quality of
information
The following selection must be used to assess all AEs.
Related
There is a reasonable causal relationship between study intervention administration and the AE.

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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.
10.5.3. 
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).
10.5.4. 
Special Reporting Situations
Safety events of interest on a sponsor study intervention in an interventional study that may require
expedited reporting or safety evaluation include, but are not limited to:
Overdose of a sponsor study intervention
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
Special reporting situations must be recorded in the CRF. Any special reporting situation that
meets the criteria of an SAE should be recorded on the SAE page of the CRF.
10.5.5. 
Procedures
All Adverse Events
All AEs, regardless of seriousness, severity, or presumed relationship to study intervention, must
be recorded using medical terminology in the source document and the CRF. Whenever possible,
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough,
runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory
infection"). Investigators must record in the CRF their opinion concerning the relationship of the

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AE to study therapy. All measures required for AE management must be recorded in the source
document and reported according to sponsor instructions.
For all studies with an outpatient phase, including open-label studies, the participant must be
provided with a "wallet (study) card" and instructed to carry this card with them for the duration
of the study indicating the following:
Study number
Statement, in the local language(s), that the participant is participating in a clinical study
Investigator's name and 24-hour contact telephone number
Local sponsor's name and 24-hour contact telephone number (for medical personnel only)
Site number
Participant number
Any other information that is required to do an emergency breaking of the blind
Serious Adverse Events
All SAEs that have not resolved by the end of the study, or that have not resolved upon the
participant's discontinuation from the study, must be followed until any of the following occurs:
The event resolves
The event stabilizes
The event returns to baseline, if a baseline value/status is available
The event can be attributed to agents other than the study intervention or to factors unrelated
to study conduct
It becomes unlikely that any additional information can be obtained (participant or health care
practitioner refusal to provide additional information, lost to follow-up after demonstration of
due diligence with follow-up efforts)
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during
participation in the study must be reported as an SAE, except hospitalizations for the following:
Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as pending
placement in long-term care facility).
Surgery or procedure planned before entry into the study (must be documented in the CRF).
Note: Hospitalizations that were planned before the signing of the ICF, and where the
underlying condition for which the hospitalization was planned has not worsened, will not be
considered SAEs. Any AE that results in a prolongation of the originally planned
hospitalization is to be reported as a new SAE.
For convenience the investigator may choose to hospitalize the participant for the duration of
the intervention period.

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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.
10.5.6. 
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.
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.
10.5.7. 
Contacting Sponsor Regarding Safety, Including Product Quality
The names (and corresponding telephone numbers) of the individuals who must be contacted
regarding safety issues, PQC, 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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10.6. Appendix 6: Contraceptive and Barrier Guidance
Participants must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria.
Pregnancy information will be collected and reported as noted in Section 8.3.5, Pregnancy and
Appendix 5 Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and
Reporting.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless
permanently sterile (see below).
Woman Not of Childbearing Potential
premenarchal
A premenarchal state is one in which menarche has not yet occurred.
postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical
cause. A high follicle-stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the
postmenopausal range may be used to confirm a postmenopausal state in women not using
hormonal contraception or hormonal replacement therapy (HRT), however in the absence of
12 months 
of 
amenorrhea, 
a 
single 
FSH 
measurement 
is 
insufficient.
If there is a question about menopausal status in women on HRT, the woman will be required
to use one of the non-estrogen-containing hormonal highly effective contraceptive methods if
she wishes to continue HRT during the study.
permanently sterile (for the purpose of this study)
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral
oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually
active becomes active), a woman must begin a highly effective method of contraception, as
described throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
Contraceptive (birth control) use by men or women should be consistent with local regulations
regarding the acceptable methods of contraception for those participating in clinical studies.
Typical use failure rates may differ from those when used consistently and correctly. Use should
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 DURING THE STUDY INCLUDE:
USER INDEPENDENT
Highly Effective Methods That Are User Independent Failure rate of <1% per year when used
consistently and correctly.
Implantable progestogen-only hormone contraception associated with inhibition of ovulationb
Intrauterine device (IUD)
Intrauterine hormone-releasing system (IUS)
Bilateral tubal occlusion
Azoospermic partner (vasectomized or due to medical cause)
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the
sole sexual partner of the woman of childbearing potential and the absence of sperm has been
confirmed. If not, additional highly effective method of contraception should be used.
Spermatogenesis cycle is approximately 74 days.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used
consistently and correctly.
Combined (estrogen- and progestogen-containing) hormonal contraception associated with
inhibition of ovulationb
oral
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.
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 (LAM)

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a) Typical use failure rates may differ from those when used consistently and correctly. Use should be
consistent with local regulations regarding the use of contraceptive methods for 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 should not be used together (due to risk of failure with friction).

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10.7. Appendix 7: Liver Safety: Suggested Actions and Follow-up Assessments
10.7.1. 
STOPPING ALGORITHM
Study intervention will be discontinued for a participant if liver chemistry stopping criteria are
met.
Liver Chemistry Stopping Criteria and Increased Monitoring Algorithm (no preexisting
liver disease)
10.7.2. 
Follow-Up Assessments
B. 
FOLLOW-UP ASSESSMENTS
Liver chemistry stopping criteria are designed to assure participant safety and to evaluate liver
event etiology.
Liver Chemistry Stopping Criteria and Follow-Up Assessments
Liver Chemistry Stopping Criteria
ALT/AST- 
absolute
ALT or AST 5×ULN
ALT/AST 
Increase 
If not able to monitor:
ALT or AST 3×ULN and cannot be monitored weekly for 4 weeks
Or if able to monitor:
ALT or AST 3×ULN persists for 4 weeks
Total bilirubin1, 2 
ALT or AST 3×ULN and total bilirubin 2×ULN (or at least a
doubling of direct bilirubin in known Gilbert’s syndrome)

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INR2 
ALT or AST 3×ULN and international normalized ratio (INR) >1.5, if
INR measured
Symptomatic3 
ALT or AST 3×ULN associated with symptoms (new or worsening)
believed to be related to liver injury or hypersensitivity
Suggested Actions, Monitoring and Follow-up Assessments
Actions 
Follow-Up Assessments
Immediately stop study intervention 
Report the event to the sponsor within 
24 hours 
Complete the eCRF according to eCRF 
completion guidelines, and complete an SAE 
data collection tool if the event also met the 
criteria for an SAE2 
Perform follow-up assessments as described in 
the Follow-Up Assessment column  
Monitor the participant until liver chemistry 
test abnormalities resolve, stabilize, or return 
to baseline (see MONITORING) 
MONITORING:
If ALP<2×ULN, ALT or AST 3×ULN AND 
total bilirubin 2×ULN (or at least a doubling of 
direct bilirubin in known Gilbert’s syndrome) or 
INR >1.5 (if measured): 
Repeat liver chemistry tests (include ALT, 
aspartate transaminase [AST], alkaline 
phosphatase, total and direct bilirubin and 
INR) and perform liver event follow-up 
assessments within 24 hours 
Monitor participant twice weekly until liver 
chemistry test abnormalities resolve, stabilize, 
or return to baseline 
A specialist or hepatology consultation is 
recommended 
If ALT or AST 3×ULN AND total bilirubin 
<2×ULN and INR 1.5 (if measured): 
Repeat liver chemistry tests (include ALT, 
AST, alkaline phosphatase, total and direct 
bilirubin and INR) and perform liver chemistry 
follow-up assessments within 24 to 72 hours 
Monitor participants weekly until liver 
chemistry abnormalities resolve, stabilize, or 
return to baseline 
Viral hepatitis serology4
Obtain INR and recheck with each
liver chemistry assessment until the
transaminases values show downward
trend
Obtain blood sample for
pharmacokinetic (PK) analysis 45
minutes after the most recent dose5
Obtain serum creatine phosphokinase
(CPK), lactate dehydrogenase (LDH),
gamma-glutamyltransferase [GGT],
glutamate dehydrogenase [GLDH],
and serum albumin
Fractionate bilirubin
Obtain complete blood count with
differential to assess eosinophilia
Record the appearance or worsening of
clinical symptoms of liver injury, or
hypersensitivity, on the eCRF as per
eCRF completion guidelines
Record use of concomitant
medications (including
acetaminophen, herbal remedies,
recreational drugs and other over-the-
counter medications)
Record alcohol use on the eCRF as per
eCRF completion guidelines
If ALT or AST 3×ULN AND total
bilirubin 2×ULN or INR >1.5 (if
measured) obtain the following in
addition to the assessments listed above:
Anti-nuclear antibody, anti-smooth
muscle antibody, Type 1 anti-liver
kidney microsomal antibodies, and
quantitative total immunoglobulin G
(IgG) or gamma globulins
Serum acetaminophen adduct assay,
when available, to assess potential

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RESTART/RECHALLENGE  
If liver event causality is determined to be 
“not related”, restart may be permitted 
upon written approval of the sponsor. See 
restart guidelines 
acetaminophen contribution to liver
injury in participants with definite or
likely acetaminophen use in the
preceding week
Liver imaging (ultrasound, magnetic
resonance, or computerized
tomography) and/or liver biopsy to
evaluate liver disease; complete eCRF
per eCRF completion guidelines
Liver biopsy may be considered and
discussed with local specialist if
available:
In participants when serology
raises the possibility of
autoimmune hepatitis (AIH)
In participants when suspected
DILI progresses or fails to resolve
on withdrawal of study
intervention
In participants with acute or
chronic atypical presentation
If liver biopsy conducted complete
eCRF as per eCRF completion guidelines
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not
immediately available, discontinue study intervention if ALT 3×ULN and total bilirubin 2×ULN.
Additionally, if serum bilirubin fractionation testing is unavailable, record the absence/presence of
detectable urinary bilirubin on dipstick which is indicative of direct bilirubin elevations suggesting liver
injury.
2. All events of ALP <2×ULN, ALT or AST ≥3xULN and total bilirubin ≥2 x ULN (or at least a doubling of
direct bilirubin in known Gilbert’s syndrome) or ALP <2×ULN, ALT or AST 3 ×ULN and INR >1.5 (if
measured) may indicate severe liver injury (possible ‘Hy’s law’) and must be reported to sponsor in an
expedited manner and as an SAE if SAE criteria met (excluding studies of hepatic impairment or
cirrhosis). The INR stated threshold value will not apply to participants receiving anticoagulants.
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right
upper quadrant pain or tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia).
4.
Includes: hepatitis A immunoglobulin M (IgM) antibody; HBsAgG and HBcAB; hepatitis C RNA;
cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile
antibody or monospot testing); and hepatitis E IgM antibody.
5. Record the date/time of the PK blood sample draw and the date/time of the last dose of study intervention prior
to the blood sample draw on the eCRF. If the date or time of the last dose is unclear, provide the participant’s
best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be
collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and
shipping are in the Study Reference Manual.

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Liver Chemistry Increased Monitoring Criteria with Continued Study Intervention
Liver Chemistry Increased Monitoring Criterion and Actions with Continued Study
Intervention
Criterion  
Actions
ALT or AST 3×ULN and <5×ULN 
and total bilirubin <2×ULN or 
INR<1.5 (if measured), without 
symptoms believed to be related to 
liver injury or hypersensitivity, and  
who can be monitored weekly for 4 
weeks
Notify the sponsor within 24 hours of learning of
the abnormality to discuss participant safety
Participant must return weekly for repeat liver
chemistry tests (ALT, AST, alkaline phosphatase,
total bilirubin) until the abnormalities resolve,
stabilize or return to baseline
If at any time, the participant meets liver chemistry
stopping criteria, proceed as described in
Section 7.1.1
If, after 4 weeks of monitoring, ALT or
AST<3×ULN and total bilirubin <2×ULN,
monitor participants twice monthly until liver
chemistry tests resolve, stabilize, or return to
baseline
References
James LP, Letzig L, Simpson PM, et al, Pharmacokinetics of Acetaminophen-Adduct in Adults
with Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.

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10.8. Appendix 8: Study Conduct During a Natural Disaster
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 (CORONAVIRUS)
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.
Temporary measures may be implemented for study-related participant management in the event
of disruption to the conduct of the study as determined appropriate by the investigator to maintain
continuity of patient care and study integrity. 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 may 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.
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 monitor 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
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

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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: Criteria for Assessing Potential Cases of Anaphylaxis
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled (Sampson 2006):
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal
tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING:
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced 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
Key: BP=blood pressure; PEF=Peak expiratory flow.
*Low systolic blood pressure 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: Country/Territory-specific Requirements
10.10.1. 
Requirements for EU Region (EUR)
Requirements for EUR
Section 
Requirement 
Amendment Number
1.1 Synopsis, Open-label Extension 
Phase; 
4.1 Overall Design; 
4.4 End of Study Definition; 
6.6 Continued Access to Study 
Intervention After the End of the 
Study
Study Completion Definition 
A participant will be considered to
have completed the study if the
participant has completed
assessments at the last visit of the
OLE phase.
Participants entering the OLE phase
will continue until 240 Weeks after
the double-blind phase of the study
has been completed
2
10.10.2. 
Requirements for FRANCE (FRA)
Requirements for FRA
Section 
Requirement 
Amendment Number
6.8.1 Prohibited Therapies 
Therapies to be Administered with 
Caution:
The following medications may
interfere with the function of the
neuromuscular junction and worsen
the clinical symptoms of MG per
the National Protocol of Diagnosis
and Care (PNDS) Autoimmune
Myasthenia gravis (PNDS 2015).
Clinical judgement and the risk-to-
benefit ratio of the drug should be
taken into consideration before
prescribing the following:
Aminoglycosides, colimycin,
polymyxin, telithromycin,
injectable cyclins, macrolides,
fluoroquinolones
Quinines, quinidine,
hydroxychloroquine,
procainamide
Beta-blockers (even eye drops)
Diphenyl-hydantoin,
trimethadione
Dantrolene
D-penicillamine
Magnesium
Curarisants: the use of non-
depolarizing molecules of rapid
degradation, such as
2

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atracurium, is allowed, but
precise monitoring is needed
Benzodiazepines
Neuroleptics (phenothiazine)
Carbamazepine
Lithium
Allopurinol
Injection of iodine for
radiological contrast
examination
Interferon alpha and beta
Nicotine patches
Statins

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10.11. Appendix 11: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly after the Table of Contents.
Amendment 2 (11 January 2023)
Overall Rationale for the Amendment:To revise the key secondary endpoints, to
 and to update the protocol based on EU Clinical Trial Regulation (EU CTR).
Section Number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
Added a summary ofthe benefit-risk
assessment.
To align with the EU CTR
requirements.
1.1 Synopsis, Objectives and 
Endpoints; 
1.1 Synopsis Statistical 
Methods; 
3 Objectives and Endpoints; 
4.2 Scientific Rationale for 
Study Design; 
9.4.2.2 Secondary 
Endpoint(s) 
Revised key secondary endpoint for sustained
response and moved from #5 to #4.
Added a new key secondary endpoint (#5) to
evaluate the effect of nipocalimab compared
to placebo on symptom improvement based
on the MG-ADL scale, in seropositive gMG
participants when treatment is taken as
directed.
Moved MSE to other secondary endpoints.
Minimal symptom expression, as
defined by the MG-ADL, is a
desired treatment goal and
retained as a secondary endpoint.
Since the final score achieved on
MG-ADL may vary depending
on the baseline score, relative
symptom improvement defined
as ≥50% improvement on MG-
ADL score from the baseline
score will be evaluated as a key
secondary.
1.1 Synopsis, Objectives and
Endpoints;
3 Objectives and Endpoints
Clarified description for key secondary
objective #2 from clinically important
individual response to the minimum clinically
important difference (MCID) or better.
The MCID is the accurate term
for the smallest clinically
important individual response;
this is formally stated now.
1.1 Synopsis, Overall
Design;
1.1 Synopsis, Number of
Participants;
4.1 Overall Design;
4.2 Scientific Rationale for
Study Design;
5 Study Population;
9.2 Sample Size
Determination
Increased overall sample size to 190 to allow
additional enrollment ofseronegative
participants.
The sample size change does not
impact the primary analysis of
150 seropositive participants
with gMG; the change reflects
only an increase in the cohort of
seronegative participants with
gMG.
1.1 Synopsis, Objectives and
Endpoints;
1.1 Synopsis, Overall
Design Open-label
Extension phase;
1.1 Synopsis, Intervention
Groups and Duration, Open-
label Extension Phase;
1.2 Schema;
1.3 Schedule of Activities,
Table 2, Note, Table 3
Column Headings and Note;
3 Objectives and Endpoints;
4.1 Overall Design, Open-
label Extension Phase;
4.2 Scientific Rationale for
Study Design, Study
To streamline visit schedule and
IMP administration, the OLE
dosing sections are updated to
allow only q2w dosing in the
OLE.
CCI
CCI

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Section Number 
and Name
Description of Change 
Brief Rationale
Phase/Periods Intervention
Group;
4.3 Justification of Dose;
6.1 Study Intervention(s)
Administered, Open-label
Extension Phase;
6.5 Dose Modification
1.1 Synopsis, Objectives and 
Endpoints; 
1.1 Synopsis, Statistical 
Methods;
3 Objectives and Endpoints;
4.2 Scientific Rational for
Study Design;
9.4.2.2 Secondary Endpoints
Changed “symptom remission” to “minimum 
symptom expression” 
To reflect the preferred term
used by clinicians for an MG-
ADL score of 0 or 1.
1.1 Synopsis, Other Efficacy 
Endpoints; 
9.4.2.2 Secondary Endpoints
Added clarifying text for sustainability of 
response for QMG. 
To clarify definition of sustained
response.
1.1 Synopsis, Overall 
Design; 
1.3 Schedule of Activities, 
Table 1 Footnote “b”; 
1.3 Schedule of Activites, 
Table 4; 
4.1 Overall Design; 
7.1 Discontinuation of Study 
Intervention  
Text describing discontinuation of study 
intervention was clarified to indicate when 
participants are eligible to rollover to the OLE 
and when the ET visit must be completed. 
Clarification that participants
who discontinue study
intervention during the double-
blind placebo-controlled phase
for any reason other than
Clinical Deterioration requiring
hospitalization or rescue therapy
must complete the 24 weeks of
study procedures to rollover to
the OLE.
1.1 Synopsis, Statistical 
Methods; 
4.1 Overall Design; 
4.2 Scientific Rationale; 
5 Study Population  
9.4.2.1 Primary Endpoint; 
9.4.2.2 Secondary 
Endpoint(s) 
Added text within protocol to clarify, as 
specified in Inclusion Criterion #4, 
participants must be on stable MG therapy or 
discontinued corticosteroids and/or 
immunosuppressants ≥4 weeks prior to 
screening due to intolerance or lack of 
efficacy. 
Original language from inclusion
Criterion #4 was re-stated within
protocol sections to further
emphasize that study participants
who discontinued prior standard
of care MG therapy due to
intolerance or lack of efficacy
are also permitted in the study as
per the original protocol.
1.1 Synopsis, Statistical
Methods;
9.2 Sample Size
Determination
Deleted text describing sample size 
re-estimation. 
Due to current estimates of the
dropout rate, sample size
re-estimation will not be
performed and has been removed
from the SAP.
1.1 Synopsis, Overall
Design;
1.1 Synopsis, Number of
Participants;
1.1 Synopsis, Sample Size
Determination;
4.1 Overall Design;
4.2 Scientific Rationale for
Study Design;
5. Study Population;
5.1.1 Inclusion Criteria for
Double-blind Placebo
Added footnote to clarify that the study is no 
longer recruiting seronegative participants. 
Enrollment of seronegative
participants has been completed.

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Section Number 
and Name
Description of Change 
Brief Rationale
Controlled Phase,
Criterion 2
9.2 Sample Size
Determination
1.3 Schedule of Activities, 
Table 1 Footnote “h” 
Table 2 Footnote “e” 
Table 3 Footnote “a”; 
8.1.1 Myasthenia Gravis – 
Activities of Daily Living; 
8.1.2 Quantitative 
Myasthenia Gravis 
Added clarification that the investigator 
should attempt to reschedule the visit within 
the per protocol visit window if 
acetylcholinesterase inhibitors were taken 
<12 hours prior to visits where MG-ADL and 
QMG assessments are performed. 
Clarification added as
acetylcholinesterase inhibitors
can have an impact on the
MG-ADL and QMG assessment.
MG-ADL and QMG are the
primary and key secondary
endpoints of the study and as
such all efforts should be made
to collect objective data with no
confounding factor.
1.3 Schedule of Activities, 
Table 1 Footnote “n” 
Table 1 Footnote “u” 
Table 2 Footnote “i” 
Table 2 Footnote “q”
Text requiring FSH testing was clarified in 
Table 1 footnote “n” and Table 2 footnote “i”. 
Added new footnote to define menopausal
status and clarify required FSH testing.
To clarify when FSH testing is
required.
1.3 Schedule of Activities, 
Table 1 Footnote “m” 
Clarified that lipid labs at screening are not 
required to be non-fasting. 
Lipid labs at screening can be
non-fasting, but are not required
to be.
1.1 Synopsis, Overall 
Design; 
1.1 Synopsis, Open-label 
Extension Phase; 
4.1 Overall Design; 
4.4 End of Study Definition; 
6.6 Continued Access to 
Study Intervention After the
End of Study
Added reference to new Appendix 
(Appendix 10.10.1) for sites in the EU. 
Prior local country amendments
are now consolidated within the
global protocol and aligned with
EU CTR requirements; region-
specific requirements for the EU
have been moved to an
appendix.
6.1 Study Intervention(s) 
Administered 
Added table with descriptions and 
classifications for all medicinal products used 
in the study.
To align with the EU CTR
requirements.
6.1 Study Intervention(s) 
Administered. 
6.8 Concomitant Therapy
Moved text describing standard of care MG 
medications from Section 6.8 to Section 6.1. 
To align with the EU CTR
requirements.
6.3 Measures to Minimize 
Bias: Randomization and 
Blinding 
Text added to last paragraph to clarify when 
the double-blind, placebo-controlled phase is 
complete.
To clarify end of double-blind
phase
6.8.1 Prohibited Therapies 
Added botulinum toxin to list of prohibited 
therapies. 
Botulinum toxin is a product
contraindication in MG and has
been added to the examples of
prohibited medications for
clarity.
6.8.1 Prohibited Therapies 
Added reference to new Appendix 
(Appendix 10.10.2) for sites in France. 
To provide a consolidated
protocol and align with EU CTR
requirements, country-specific
requirements for France have
been moved to an appendix.
6.8.2 Rescue 
Medication/Therapy/Clinical 
Deterioration  
Added clarification that:
IVIg and plasmapheresis are the only
rescue treatments permitted.
For participants who require rescue
treatment during the double-blind,
To provide clarification
regarding permitted rescue
treatments, the potential for
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Section Number
and Name
Description of Change 
Brief Rationale
placebo controlled phase EOP visit 
must be completed prior to OLE 
entry.
For participants requiring rescue
treatment during the OLE, continued
OLE participation must be discussed
with the sponsor’s medical monitor.
nipocalimab, and required study
visits for these participants.
8.1.1 Myasthenia Gravis – 
Activities of Daily Living; 
8.1.2 Quantitative
Myasthenia Gravis
Added clarifying text to circumstances
regarding unavoidable changes in raters.
To clarify circumstances where a
change in rater is unavoidable.
8.2.10 Benefit Risk Balance; 
9.4.6 Other Analyses 
Added sections for benefit-risk balance 
To align with nipocalimab
protocols for other indications
9.2 Sample Size 
Determination  
Removed MSE from sample size 
determination. 
MSE moved from key secondary
endpoint to a secondary
endpoint.
1.1 Synopsis, Statistical 
Methods; 
9.3 Population Analysis Sets
Revised text and table describing analysis sets 
for consistency with the SAP.
Alignment edit.
10.10.1 Requirements for 
EUR; 
10.10.2 Requirements for 
FRA  
New Appendix (Appendix 10.10.2 ) for 
Country/Territory Specific requirements was 
added to include regional requirements 
specific to EU and country-specific 
requirements for France. 
To provide a consolidated
protocol and align with EU CTR
requirements, region-specific
requirements for the EU and
country-specific requirements
for France have been moved to
an appendix.
10.2 Appendix 2: Clinical 
Laboratory Tests 
Added bicarbonate to clinical chemistry  
Added clarifying text to routine urinalysis 
section of the table.
To include missing protocol
template text.
11 References 
New references added. 
To include additional references.
Throughout the protocol 
Minor grammatical, formatting, or spelling 
changes were made.
Minor errors were noted.
Amendment 1 (21 July 2022)
Overall Rationale for the Amendment: To add an exploratory endpoint for the use of an
actigraphy watch to assess physical activity, mobility, and sleep at selected sites. Two additional
exclusion criteria were added to align with standard language across the nipocalimab program. In
addition, clarifying edits from the latest sponsor protocol template and edits to align with standard
language across the nipocalimab program were made throughout the protocol.
Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis,
Exploratory Objectives;
1.1 Synopsis, Efficacy
Evaluations;
1.1 Synopsis, Statistical
Methods;
1.3. Schedule of Activities
(SoA) Table 1 ;
Added an assessment of physical activity
using actigraphy watch-collected data (at
selected sites) throughout the relevant
sections of the protocol.
This exploratory outcome measure will
allow analysis of changes in digital
parameters in nipocalimab compared to
placebo on daily physical activities in
seropositive gMG participants when
treatment is taken as directed (at
selected sites).

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Section number 
and Name
Description of Change 
Brief Rationale
3. Objectives and
Endpoints;
New section 8.1.9. Digital
Health –Actigraphy
Measurements (at Selected
Sites);
9.4.2.2 Secondary
Endpoint(s)
2.3.1. Risks for Study 
Participation 
Updated risk language in Table 5 and
removed overdose as a potential risk of
clinical significance from the table.
To align with nipocalimab IB.
5.2. Exclusion Criteria, 
Criterion 33 
Added new exclusion criterion
regarding BCG vaccination.
To ensure the safety of participants and
to provide sufficient details and better
guidance to study investigators to
determine whether participants are
eligible for the study. This aligns with
standard language across the
nipocalimab program.
5.2. Exclusion Criteria,
Criterion 34
Added new criterion for granulomatous
infection.
Criterion added to disallow participants
with a history of active granulomatous
infection before screening. This aligns
with standard language across the
nipocalimab program
5.1.1 Inclusion Criteria for
Double-blind Placebo-
Controlled Phase Entry,
Criterion 1 and
Criterion 15;
5.1.2 Inclusion Criteria for
Open-label Extension
Phase Entry, Criterion 6;
10.4.3 Informed Consent
Process
Revised to clarify that participants must
be ≥18 years of age and the legal age of
consent in their jurisdiction.
Clarification that only adult
participants as per the legal age of
consent in that jurisdiction will be
eligible to participate in the study.
5.1.1. Inclusion Criteria for
Double-blind Placebo-
Controlled Phase Entry,
Criterion 9
Criterion removed. 
Male or female is no longer an
inclusion criterion. Standard
requirement for all sponsor protocols.
5.1.1 Inclusion Criteria for
Double-blind Placebo-
Controlled Phase Entry,
Criterion 4
Added clarification to types of
discontinued immuno-agents as well as
timing for changes to background
medications.
To clarify that background medications
must be optimized and unchanged for
the duration specified in Criterion 4
prior to screening and/or baseline
visits.
5.1.1 Inclusion Criteria for
Double-blind Placebo-
Controlled Phase Entry,
Criterion 8;
5.1.1 Inclusion Criteria for
Open-label Extension
Phase Entry, Criterion 4
Added text regarding recommendation
for COVID-19 vaccination
Aligned with update to sponsor
COVID-19 guidance.
5.1.1 Inclusion Criteria for
Double-blind Placebo-
Controlled Phase Entry,
Criterion 11
Updated the length of time a woman of
childbearing potential must practice a
highly effective method of contraception
to 30 days after last administration of
study intervention.
To align with nipocalimab protocols for
other indications.
Added for clarification

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Section number 
and Name
Description of Change 
Brief Rationale
Added text clarifying that labeling
requirements for concomitant treatment
will supersede if more stringent
5.2. Exclusion Criteria, 
Criterion 17 
Updated language for time for 
administration of live vaccine. 
To align with recommendations
available from the CDC Advisory
Committee on Immunization Practices,
the Infectious Diseases Society of
America, and the half-life of
nipocalimab.
5.2. Exclusion Criteria, 
Criterion 17 
Added language to refer to exclusion 
criterion #33 
For clarity, provided reference to new
criterion
5.2. Exclusion Criteria, 
Criterion 1 
Revised to provide further detail to 
excluded disease history. 
To align with nipocalimab protocols for
other indications.
5.1.1 Inclusion Criteria for 
Double-blind Placebo- 
Controlled Phase Entry, 
Inclusion Criterion 13;
10.6 Appendix 6:
Contraceptive and Barrier
Guidance
Revised instructional text regarding 
contraception 
Incorporation of clarifying edits from
the latest sponsor protocol template
update
5.2 Exclusion Criteria, 
Criterion 3 
Clarified that to be eligible for the study, 
participants should not meet the
definition of Clinical Deterioration as
noted in Section 6.8.2.
Clarification of exclusion criteria
5.2 Exclusion Criteria, 
Criterion 15 
Added eculizumab or other novel 
therapeutic agents to prohibited
therapies.
Provided for clarification.
5.2 Exclusion Criteria 
Criterion 31  
Criterion deleted. 
Criterion is redundant with text added
to exclusion criterion #1.
5.2 Exclusion Criteria 
Added note following exclusion 
criterion #29 to clarify appropriate 
medical interventions and measures to 
be followed should a participant meet 
criterion #29.
Clinical findings based on C-SSRS
should be reported as adverse
events/serious adverse events as
applicable.
8.2.9 Suicidal Ideation and 
Behavior Risk Monitoring 
Added text to clarify appropriate 
medical interventions and measures to 
be followed should a participant’s 
C-SSRS results indicate active suicidal 
ideation and/or a plan/intent.
Clarified that clinical findings based on
C-SSRS should be reported as AEs or
SAEs, as applicable.
Clinical findings based on C-SSRS
should be reported as adverse
events/serious adverse events as
applicable.
1.1 Synopsis; 
4.1 Overall Design; 
8. Study Assessments and 
Procedures; 
8.3.1 Time Period and
Frequency for Collecting
Adverse Event and Serious
Adverse Event
Information;
9.4.5 Safety Analyses;
10.4.6 Committee Structure
Added text related to major adverse 
cardiovascular events (MACE) and the 
Event Adjudication Committee (EAC). 
Potential MACE events will undergo
review by an event adjudication
committee in alignment with the
overall nipocalimab program
5.2 Exclusion Criteria 
Criterion 31  
Criterion deleted. 
Criterion is redundant with text added
to exclusion criterion #1.

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Section number 
and Name
Description of Change 
Brief Rationale
5.2 Exclusion Criteria 
Added note following exclusion 
criterion #29 to clarify appropriate 
medical interventions and measures to 
be followed should a participant meet 
criterion #29.
Clinical findings based on C-SSRS
should be reported as adverse
events/serious adverse events as
applicable.
8.2.9 Suicidal Ideation and 
Behavior Risk Monitoring 
Added text to clarify appropriate 
medical interventions and measures to 
be followed should a participant’s 
C-SSRS results indicate active suicidal 
ideation and/or a plan/intent.
Clarified that clinical findings based on
C-SSRS should be reported as AEs or
SAEs, as applicable.
Clinical findings based on C-SSRS
should be reported as adverse
events/serious adverse events as
applicable.
1.1 Synopsis; 
4.1 Overall Design; 
8. Study Assessments and 
Procedures; 
8.3.1 Time Period and
Frequency for Collecting
Adverse Event and Serious
Adverse Event
Information;
9.4.5 Safety Analyses;
10.4.6 Committee Structure
Added text related to major adverse 
cardiovascular events (MACE) and the 
Event Adjudication Committee (EAC). 
Potential MACE events will undergo
review by an event adjudication
committee in alignment with the
overall nipocalimab program
5.2 Exclusion Criteria 
Criterion 31  
Criterion deleted. 
Criterion is redundant with text added
to exclusion criterion #1.
5.2 Exclusion Criteria 
Added note following exclusion 
criterion #29 to clarify appropriate 
medical interventions and measures to 
be followed should a participant meet 
criterion #29.
Clinical findings based on C-SSRS
should be reported as adverse
events/serious adverse events as
applicable.
8.2.9 Suicidal Ideation and 
Behavior Risk Monitoring 
Added text to clarify appropriate 
medical interventions and measures to 
be followed should a participant’s 
C-SSRS results indicate active suicidal 
ideation and/or a plan/intent.
Clarified that clinical findings based on
C-SSRS should be reported as AEs or
SAEs, as applicable.
Clinical findings based on C-SSRS
should be reported as adverse
events/serious adverse events as
applicable.
1.1 Synopsis; 
4.1 Overall Design; 
8. Study Assessments and 
Procedures; 
8.3.1 Time Period and
Frequency for Collecting
Adverse Event and Serious
Adverse Event
Information;
9.4.5 Safety Analyses;
10.4.6 Committee Structure
Added text related to major adverse 
cardiovascular events (MACE) and the 
Event Adjudication Committee (EAC). 
Potential MACE events will undergo
review by an event adjudication
committee in alignment with the
overall nipocalimab program
Synopsis, Statistical 
Methods; 
9.4.2.1. Primary Endpoint 
Multiple imputation methods for the 
primary estimand for EU were revised. 
To specify multiple imputation
methods that are more consistent with
the treatment policy estimand.

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Section number 
and Name
Description of Change 
Brief Rationale
9.4.2.1. Primary Endpoint 
Corrected text under the primary 
estimand for EU for intercurrent events 
due to change in background MG 
medication to ‘Treatment Policy’
Intercurrent events due to change in
background MG medication will be
handled by Treatment Policy.
1.1 Synopsis; 
3. Objectives and 
Endpoints 
Removed the outcome measure: 
evaluate the potential relationship 
between change in QMG scores. 
For consistency in outcomes for
exploring the effects of nipocalimab on
MG disease biomarkers
1.3 Schedule of Activities, 
Table 2 
Added urine drug screen at screening 
visit 
The lab is supportive information for
the determination of eligibility per
exclusion criterion #14; was present in
Double-blind screening but missing in
OLE screening.
1.3 Schedule of Activities 
Table 4 
Added urine pregnancy test, Ig, serum 
for nipocalimab concentrations, ADA, 
and NAb to safety follow-up
assessments.
Consistency across nipocalimab
protocols.
1.1 Synopsis; 
4.1 Overall Design; 
8. Study Assessments and 
Procedures; 
8.3.1 Time Period and
Frequency for Collecting
Adverse Event and Serious
Adverse Event
Information;
9.4.5 Safety Analyses;
10.4.6 Committee Structure
Added text related to major adverse 
cardiovascular events (MACE) and the 
Event Adjudication Committee (EAC). 
Potential MACE events will undergo
review by an event adjudication
committee in alignment with the
overall nipocalimab program
Synopsis, Statistical 
Methods; 
9.4.2.1. Primary Endpoint 
Multiple imputation methods for the 
primary estimand for EU were revised. 
To specify multiple imputation
methods that are more consistent with
the treatment policy estimand.
9.4.2.1. Primary Endpoint 
Corrected text under the primary 
estimand for EU for intercurrent events 
due to change in background MG 
medication to ‘Treatment Policy’
Intercurrent events due to change in
background MG medication will be
handled by Treatment Policy.
1.1 Synopsis; 
3. Objectives and 
Endpoints 
Removed the outcome measure: 
evaluate the potential relationship 
between change in QMG scores. 
For consistency in outcomes for
exploring the effects of nipocalimab on
MG disease biomarkers
1.3 Schedule of Activities, 
Table 2 
Added urine drug screen at screening 
visit 
The lab is supportive information for
the determination of eligibility per
exclusion criterion #14; was present in
Double-blind screening but missing in
OLE screening.
1.3 Schedule of Activities 
Table 4 
Added urine pregnancy test, Ig, serum 
for nipocalimab concentrations, ADA, 
and NAb to safety follow-up
assessments.
Consistency across nipocalimab
protocols.
1.1. Synopsis; 
1.3 Schedule of Activities; 
3. Objectives and 
Endpoints
Added footnotes to clarify that in China, 
anti-LRP4 autoantibody collection will
only be tested at screening.
To consider local practice feasibility
1.3 Schedule of Activities 
Table 4; 
8.6.1. Pharmacodynamics 
Added a footnote to clarify that 
exploratory biomarker is not applicable
in China.
To consider local practice feasibility

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Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis; 
1.3 Schedule of Activities, 
Table 1 Footnote “r” 
Table 2 Footnote “n”
Table 3 Footnote “j”
3 Objectives and
Endpoints;
4.2 Scientific Rationale for
Study Design
Modified the footnote to clarify that 
exploratory biomarker is not applicable 
in China. 
To provide additional clarification
regarding exploratory biomarker
collection.
1.3. Schedule of Activities, 
Table 1 Footnote “j” 
Table 2 Footnote “f” 
Table 3 Footnote “b”
Added abdomen or skin to list of 
focused physical examination body 
systems
Correction to align with text in Section
8.2.1.
1.3 Schedule of Activities, 
Table 1 Footnote "k", 
Table 2 Footnote "g", and 
Table 3 Footnote "c"; 
8.2.2 Vital Signs; 
9.4.5 Safety Analyses 
Respiratory rate added to vital signs. 
"Immediately" was removed from vital 
sign collection time in the SoA 
footnotes 
Correction to add respiratory rate to list
of vital signs to be collected.
Additionally, "immediately" was
removed from the vital sign collection
time in the SoA footnotes for
consistency with Section 8.2.2
1.3. Schedule of Activities, 
Tables 1, 2, and 3 
A statement regarding requirements to 
confirm a woman is menopausal to 
determine whether a pregnancy test is 
required (Table 1 and Table 2), and that
additional serum pregnancy testing is at
the discretion of the investigator or if
required by local regulations was added.
Clarification and further information on
when pregnancy tests are required in
women of childbearing potential.
8.2.2. Vital Signs 
Text “oral” has been removed from
temperature collection requirement.
There are other preferred alternatives
and the study eCRF accommodates
other anatomical locations for
temperature collection.
1.3. Schedule of Activities
Table 1
Removed exploratory biomarker sample
during Screening.
Exploratory biomarker samples are not
required at the Screening phase.
1.3. Schedule of Activities,
Table 1 and Table 2.
Added collection of serum Ig sample at
Screening.
Total IgG should be measured at
Screening.
1.3. Schedule of Activities,
Table 2
Added ECG at week 24 of the OLE
phase.
To make the OLE ECG schedule
consistent with the double-blind phase.
1.3. Schedule of Activities,
Table 2 Footnote “h”
Table 3 Footnote “d”
Footnote observation time after infusion
in OLE was updated.
Clarification that all participants
receiving their first 3 infusions will
need to be monitored for safety 1-hour
post-infusion, regardless of being in the
DB or OLE phase (as some would have
come from placebo arm).
1.3. Schedule of Activities,
Table 1 Footnote “p”
8.4.1. Evaluations
Added text to clarify that postdose
samples will be collected 45 minutes
(± 15 minutes) after the end of infusion.
Clarification on the time windows for
the post dose samples collection
Synopsis, Overall Design;
Synopsis, Intervention
Groups and Duration;
1.3. Schedule of Activities
Tables 2 and 3;
4.1 Overall Design;
4.2 Scientific Rationale for
Study Design;
6.1 Study Intervention(s)
Administered;
Corrected Title and statement in note of
Table 2, Table 3 to Week 24 and added
clarifying text.
Correction of the time after which a
change in dosing is permitted and to
clarify that the new dosing schedule
must align with the original
q12w/q24w visit schedule as well as to
match the participant’s visit schedule

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Section number 
and Name
Description of Change 
Brief Rationale
6.5 Dose Modification;
3. Objectives and 
Endpoints
Modified text to “could use”. 
For consistency with Section 8.6.
4.2.1. Study-Specific 
Ethical Design 
Considerations; 
8. Study Assessments and 
Procedures
Added text to clarify volume of blood 
collected covers the full duration of the 
double-blind placebo-controlled phase
and 2 years of OLE.
To provide clarification of total volume
of blood to be collected.
5.3 Lifestyle 
Considerations 
Added third criterion regarding timing 
of live vaccines (including BCG). 
For consistency with the exclusion
criteria.
5.4 Screen Failures 
Added text to clarify rescreening is 
permitted once with approval of 
sponsor’s medical monitor.
To clarify when rescreening is
permitted.
6.1 Study Intervention(s) 
Administered 
Additional language to describe how 
nipocalimab and placebo are sourced 
and supplied centrally and locally.
Consistency across nipocalimab
protocols
6.3 Measures to Minimize 
Bias: Randomization and 
Blinding 
Updated masking information for select 
laboratory parameters, including the 
study phases where the parameters
remain masked. Added clarifying text.
To clarify the masking of selected
laboratory data.
6.8.3 Vaccinations 
(Including COVID-19) 
New section added. 
To provide guidance for timing of
non-live vaccine administration
6.8.1 Prohibited Therapies 
Deleted text requiring mandatory 
discontinuation of study intervention. 
Added text to clarify the medical 
monitor and/or sponsor should be 
consulted prior to starting any biologic 
or other advanced therapies. 
The original intent of the prohibited
medications section 6.8.1 is unchanged.
The text was deleted, because the
decision on whether a participant can
continue study participation or must be
discontinued if they take a prohibited
medication may depend on the reason a
medication was given, whether this was
a single-use or sustained treatment, and
the half-life of the prohibited
medication.
5.1.2 Inclusion Criteria for 
Open-label Extension 
Phase; 
6.5 Dose Modification; 
6.8.2 Rescue 
Medication/Therapy/Clinic 
al Deterioration  
Added text to clarify that in instances 
where participants who require rescue 
treatment during the double-blind phase 
and enter the OLE phase based on 
investigator’s discretion after 
completion of an EOP Visit. Also 
clarified, the EOP visit assessments
must not be combined with those of the
OLE Day 1 assessments and while there
is no fixed duration limit between EOP
and OLE Day 1, in instances where the
interval is greater than 4 weeks, the
investigator should assess if it is
appropriate to continue treatment in the
OLE phase in consultation with the
sponsor’s medical monitor.
To inform the investigator on how to
classify completion of double-blind
treatment for participants who require
rescue medication and to assess
whether treatment should be continued
in the OLE.
7.1 Discontinuation of 
Study Intervention  
The list of reasons for discontinuation is 
revised to include a description of 
severe allergic reaction and/or severe 
infusion reaction related to the study
intervention.
To address severe allergic reaction
and/or severe infusion reaction as a
reason for study discontinuation

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Section number 
and Name
Description of Change 
Brief Rationale
8.1.1 Myasthenia Gravis- 
Activities of Daily Living; 
8.1.2 Quantitative
Myasthenia Gravis
Added information regarding 
unavoidable changes in raters. 
To address circumstances where a
change in rater is unavoidable.
8.3.1 Time Period and 
Frequency for Collecting 
Adverse Event and Serious 
Adverse Event 
Information; 
10.2 Appendix 2 Clinical
Laboratory Tests;
10.7 Appendix 7 Liver
Safety: Suggested Actions
and Follow-up
Assessments, Footnote “2”
Corrected the definition of possible 
Hy’s Law cases and added text to clarify 
safety reporting. Revised terminology to 
clarify and align with the rest of the 
protocol. 
Incorporation of clarifying edits from
the latest sponsor protocol template
update and consistency of the
description of "possible Hy's Law"
within the protocol.
8.3.6 Adverse Events of 
Special Interest 
Revised first numbered bullet point. 
To align definitions with nipocalimab
protocols for other indications.
8.4 Pharmacokinetics 
Added text to clarify PK samples should 
be collected at the end of treatment visit 
from participants who discontinued
study intervention or were withdrawn
from the study.
To provide clarification regarding
collection of PK samples.
8.6.1 Pharmacodynamics 
Added clarification that anti-LRP4 will 
also be collected and used to assess 
seropositivity.
To provide clarification regarding
autoantibody testing.
8.7 Immunogenicity 
Assessments 
Removal of language describing the 
storage time (up to 1 month) after 
approval of the final Clinical Study 
Report
Removal of language to maintain
consistency with storage time
mentioned in Section 10.4.5
10.2 Appendix 2 
Clinical Laboratory Tests 
Added glucose as a parameter for 
collection for clinical chemistry  
Glucose has been added as a laboratory
parameter
10.4.3 Informed Consent 
Process 
Added language to inform participants 
who have received previous treatment 
with rituximab that they may be at an
increased risk of infection during the
study.
To provide consistency for all
nipocalimab protocols
10.4.4 Data Protection 
Updated the text on Privacy of Personal 
Data based on EU CTR. 
To align with sponsor protocol
template update.
10.8 Appendix 8 Study 
Conduct During a Natural 
Disaster 
Updated to include latest guidance 
regarding study conduct regarding
COVID-19.
To enhance participant safety.
10.10 Appendix 10: 
Criteria for Assessing 
Potential Cases of
Anaphylaxis
Added an appendix for criteria for 
assessing potential cases of anaphylaxis 
To provide criteria for determining and
assessing cases of anaphylaxis
6.4 Study Intervention 
Compliance 
Removed reference to visiting nurse. 
For consistency within the protocol.
Home infusion is not permitted in the
study.
2. Introduction 
Updated text 
Added information and additional
references
Throughout the protocol 
Added territory(ies) to country(ies). 
To align with sponsor protocol
template update.
Throughout the protocol 
The term “should” was replaced with 
“must” where the text has an intrinsic 
To enhance scientific rigor by
incorporation of clarifying edits where
the text has an intrinsic mandatory

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Section number 
and Name
Description of Change 
Brief Rationale
mandatory component instead of a 
probability or expectation. 
component instead of a probability or
expectation.
Throughout the protocol 
Minor editorial changes including 
grammar, spelling and formatting were
made
Minor errors were noted.

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11. 
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M281/ JNJ-80202135  (nipocalimab)
Clinical Protocol MOM-M281-011 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
150
Status: Approved, Date:  15 August 2024
INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study.
I will conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to
me who assist in the conduct of this study. I will discuss this material with them to ensure that they
are fully informed regarding the study intervention, the conduct of the study, and the obligations
of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Janssen Research & Development
Signature: 
electronic signature appended at the end of the protocol 
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the study, written notification will be
provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD

Signature
User 
Date 
Reason
 
15-Aug-2024
13:16:01
(GMT)
Document Approval
PPD