Clinical trial NCT04963270
Conditions: Generalized Myasthenia Gravis
Sponsor: Hoffmann-La Roche
Start date: 2021-10-19; Completion date: 2024-09-02
Enrollment: 188 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of satralizumab compared with placebo in participants with generalized myasthenia gravis (gMG).

Detailed description:

Arms: arm 1: Participants will receive Satralizumab at Weeks 0, 2, 4, and Q4W thereafter. Adolescent patients who first enter the study in the OLE period will receive satralizumab SC loading doses at Week 0, 2, and 4 in the OLE, followed by maintenance doses Q4W thereafter and will remain on stable background therapy until Week 24 of the OLE. arm 2: Participants will receive placebo at Weeks 0, 2, 4, and Q4W thereafter
Interventions: intervention 1: Satralizumab intervention 2: Placebo
Intervention descriptions: intervention 1: Satralizumab will be administered as a subcutaneous injection intervention 2: Satralizumab placebo will be administered as a subcutaneous injection

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
A Phase III, Randomized, Double-Blind, Placebo-Controlled, 
Multicenter Study to Evaluate Efficacy, Safety, Pharmacokinetics, and 
Pharmacodynamics of Satralizumab in Patients with Generalized 
Myasthenia Gravis 
NCT Number: NCT04963270 
Document Date: Protocol Version 5: 21-July-2023 
 
 
 


CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
*Chugai will act as the Sponsor only in Taiwan and Japan.  The specific details of the legal/regulatory
entity within the relevant country are provided within the clinical trial agreement with the 
Investigator/Institution and the Clinical Trial Application with the Competent Authority. 
Satralizumab—F. Hoffmann-La Roche Ltd 
Protocol WN42636, Version 5 
PROTOCOL 
PROTOCOL TITLE: 
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
EVALUATE EFFICACY, SAFETY, 
PHARMACOKINETICS, AND PHARMACODYNAMICS 
OF SATRALIZUMAB IN PATIENTS WITH 
GENERALIZED MYASTHENIA GRAVIS 
PROTOCOL NUMBER: 
WN42636 
VERSION NUMBER: 
5 
TEST PRODUCT: 
Satralizumab (RO5333787) 
STUDY PHASE 
Phase III 
REGULATORY AGENCY 
IDENTIFIER NUMBERS 
IND Number: 151937  
EudraCT Number:  2020-004436-21 
EU CT Number:  2023-507169-24-00 
NCT Number:  NCT04963270 
CO-SPONSOR’S NAMES 
AND LEGAL 
REGISTERED 
ADDRESSES: 
F. Hoffmann-La Roche Ltd
Grenzacherstrasse 124
4070 Basel, Switzerland
Chugai Pharmaceutical Co. Ltd.* 
1-1 Nihonbashi-Muromachi 2-chome
Chuo-ku, Tokyo 103-8324
Japan
APPROVAL: 
See electronic signature and date stamp on the final page 
of this document. 


 
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PROTOCOL HISTORY 
Protocol 
Associated Country-Specific Protocols  
Version 
Date Final 
Country 
Version 
Date Final 
5 
See electronic date 
stamp on the final 
page of this document 
 
 
 
4 
1 March 2023 
France 
5 
30 March 2023 
China 
4 
30 March 2023 
The Netherlands 
4 
10 March 2023 
3 
10 November 2021 
Germany 
5 
17 February 2023 
China 
3 
8 December 2021 
Germany 
4 
6 December 2021 
France 
4 
6 December 2021 
2 
16 February 2021 
France  
3 
24 June 2021 
Germany 
3 
30 March 2021 
China 
2 
19 February 2021 
1 
1 February 2021 
China 
1 
9 February 2021 
 
 


 
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PROTOCOL AMENDMENT, VERSION 5: 
RATIONALE 
Protocol WN42636 has primarily been amended to allow adolescent patients to enroll 
directly into the open-label extension (OLE) period, due to recruitment difficulties related 
to placebo use in the double-blind (DB) period.  In response to the evolving gMG 
treatment landscape, the AChR-antibody seropositive population has been reduced from 
192 to 160 participants (adults and adolescents) as the effect size (difference in mean 
change from baseline in Myasthenia Gravis Activities of Daily Living at Week 24 
between satralizumab and placebo-treated arms) increased from 1.7 to 2.  
Consequently, the total sample size has been reduced from 240 to approximately 
185 patients.   Substantive changes to the protocol, along with a rationale for each 
change, are summarized below: 
• 
The synopsis has been simplified to align with Clinical Trials Regulation (CTR) and 
other guidelines. 
• 
A new section on adolescent enrollment (Section 3.1.3) has been added to reflect 
adolescent patient enrollment into the OLE period at study start, and the protocol 
has been revised throughout (Sections 3.1 [Figure 1], 3.1.4, 3.1.7, 3.2, 3.4.8, 4.2.1, 
4.3.2, 4.5.2, 6,1, 6.4.8, and 6.5; Appendix 2). 
• 
The pharmacokinetic interim analysis has been completed, and the text has been 
revised accordingly (Sections 3.1.1, 3.1.2,3.4.11, 4.3.2.1, 6.1, and 6.11.2).  
• 
The protocol has been revised throughout to reflect the new sample size 
(Sections 3.1.7, 4.1, 6.1 and 9.6). 
• 
Text regarding a China extended enrollment phase has been removed as the 
patient target has been reached. (Sections 3.1.5, 4.1, 4.1.1, 6.1, and 6.12). 
• 
A section describing patient input into the study design has been added to align with 
CTR requirements (Section 3.1.8). 
• 
A section describing duration of participation has been added to align with CTR 
requirements (Section 3.3). 
• 
Studies listed in the Rationale for Secondary Outcome Measures have been 
updated to align with current study status (Section 3.4.6). 
• 
Changes have been made to consolidate the protocols across EU countries to align 
with CTR requirements:  
The enrollment will be limited to adult patients (≥ 18 years old) for all 
participating sites in France (Sections 3.1.6, 3,4,2,3, and 4.1.1). 
An additional exclusionary criterion related to patients with Myasthenia Gravis 
Foundation of America (MGFA) Class IV at screening has been added for 
participants in France.  The study will enroll patients with MGFA Class II or III at 
screening at participating sites in France (Sections 3.4.2.1, 4.1.1, and 4.1.2.1). 
The eligibility criterion in Section 4.1.1 has been consolidated to reflect that 
participating sites in the Netherlands and Germany use pre-existing positive 


 
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serologic test results ordered by a health care professional to support gMG 
diagnosis, instead of using antibody tests performed by the central laboratory 
during screening. Relevant changes have been made throughout the protocol 
(Sections 4.5.2, 4.5.3, and 4.5.6; Appendices 1, 2, and 3). 
• 
The responsibilities of the investigator and the role of the Medical Monitor during 
study conduct have been clarified (Sections 4.2.2, 4.4 and 5.1.4.1). 
• 
A comprehensive list of investigational medicinal products and auxiliary medicinal 
products has been added to align with CTR requirements in the European Economic 
Area (Section 4.3, 4.3.2.3 and Appendix 15).  Additionally, non investigational 
medicinal products (NIMPs) language as per Clinical Trials Directive (CTD) has been 
removed from the protocol. 
• 
Table 7 Recommended Dosage for Delayed or Missed Doses and after Rescue 
Therapy with Plasma Exchange has been amended to include recommendations for 
treatment interruptions (Section 4.3.2.2). 
• 
Language has been added to indicate that sites can confirm that appropriate 
temperature conditions have been maintained during investigational medicinal 
product transit either by time monitoring (shipment arrival date and time) or 
temperature monitoring (Section 4.3.4). 
• 
TSH has been removed from the central laboratory assessments (Section 4.5.6) to 
align with previously amended Section 4.1.2.4 and Appendix 1. 
• 
Language has been added to clarify that adverse events associated with a special 
situation that also qualify as adverse events of special interest should be reported 
within 24 hours (Section 5.3.5.12). 
• 
Language has been added to indicate that the Informed Consent Form will instruct 
female patients to inform the investigator if they become pregnant (Section 5.4.3.1). 
• 
It has been made explicit that expedited safety reports are notified to EudraVigilance 
(Section 5.7). 
• 
Text has been added to define the modified intent-to-treat population (mITT) 
(Sections 6, 6.1, and 6.4.1). 
• 
The hierarchical gatekeeping has been updated to include mean change from 
baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) score in 
MuSK +  and LRP4 +  patients at Week 24 to align with the Statistical Analysis Plan 
(Section 6.4.3).  
• 
The name of a Roche policy on data sharing has been corrected (Section 9.5). 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 


 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM ............................................. 14 
PROTOCOL SYNOPSIS......................................................................................... 15 
1. 
BACKGROUND ................................................................................ 25 
1.1 
Background on Myasthenia Gravis ............................................ 25 
1.2 
Juvenile Myasthenia Gravis ........................................................ 27 
1.3 
Current Treatment and Unmet Medical Need............................ 28 
1.4 
Background on Satralizumab ..................................................... 30 
1.5 
Study Rationale and Benefit−Risk Assessment ........................ 32 
1.5.1 
Rationale for IL-6 Inhibition as a Therapeutic Mode of 
Action in Generalized Myasthenia Gravis .................................. 32 
1.5.2 
Satralizumab Dose Selection ..................................................... 34 
1.5.3 
Study and Primary Analysis Population ..................................... 34 
1.5.4 
Overview of Risks and Safety Measures ................................... 34 
1.5.5 
Benefit−Risk Assessment ........................................................... 36 
2. 
OBJECTIVES AND ENDPOINTS .................................................... 36 
3. 
STUDY DESIGN ............................................................................... 41 
3.1 
Description of the Study .............................................................. 41 
3.1.1 
Double-Blind Period .................................................................... 42 
3.1.2 
Independent Data Monitoring Committee .................................. 43 
3.1.3 
Adolescent Patients........................................................................ 43 
3.1.4 
Open-Label Extension Period..................................................... 44 
3.1.5 
Unscheduled Visits and Rescue Therapy .................................. 44 
3.1.6 
Safety Follow-Up ......................................................................... 45 
3.1.7 
Number of Patients and Study Regions ..................................... 46 
3.1.8 
Patient Input into Study Design .................................................... 46 
3.2 
End of Study and Length of Study.............................................. 46 
3.3 
Duration of Participation ............................................................... 47 
3.4 
Rationale for Study Design ......................................................... 47 
3.4.1 
Rationale for Satralizumab Dose and Schedule........................ 47 
3.4.2 
Rationale for Patient Population ................................................. 49 


 
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3.4.2.1 
Rationale for Choice of Disease Severity and Residual 
Disease Symptoms ..................................................................... 49 
3.4.2.2 
Autoantibody Types and Diagnosis............................................ 50 
3.4.2.3 
Rationale for Inclusion of Adolescent Patients .......................... 50 
3.4.3 
Rationale for Choice of Background Treatment ........................ 51 
3.4.4 
Rationale for Control Group ........................................................ 51 
3.4.5 
Rationale for Primary Outcome Measure:  Myasthenia 
Gravis Activities of Daily Living................................................... 51 
3.4.6 
Rationale for Secondary Outcome Measures............................ 52 
3.4.7 
Rationale for Secondary Responder Analysis ........................... 54 
3.4.7.1 
MG-ADL Responder Definition ................................................... 54 
3.4.7.2 
QMG Responder Definition......................................................... 55 
3.4.7.3 
MGC Responder Definition ......................................................... 55 
3.4.7.4 
Rescue Therapy Handling in the Responder Definition ............ 55 
3.4.8 
Rationale for Open-Label Extension .......................................... 55 
3.4.9 
Rationale for Biomarker Assessments ....................................... 56 
3.4.10 
Rationale for PK Sample Collection Schedule .......................... 57 
3.4.11 
Rationale for Interim PK Analysis ............................................... 57 
3.4.12 
Rationale for Immunogenicity Sample Collection ...................... 59 
4. 
MATERIALS AND METHODS ......................................................... 59 
4.1 
Patients ........................................................................................ 59 
4.1.1 
Inclusion Criteria.......................................................................... 59 
4.1.2 
Exclusion Criteria ........................................................................ 61 
4.1.2.1 
Exclusion Criteria Related to Myasthenia Gravis: ..................... 61 
4.1.2.2 
Exclusion Criteria Related to Previous or Concomitant 
Therapy: ....................................................................................... 61 
4.1.2.3 
General Safety Exclusion Criteria: ............................................. 62 
4.1.2.4 
Laboratory Exclusion Criteria (at Screening): ............................ 64 
4.2 
Method of Treatment Assignment and Blinding ........................ 64 
4.2.1 
Treatment Assignment ................................................................ 64 
4.2.2 
Blinding ........................................................................................ 65 
4.3 
Study Treatment and Other Treatments Relevant to the 
Study Design ............................................................................... 67 
4.3.1 
Study Treatment Formulation and Packaging ........................... 67 


 
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4.3.1.1 
Satralizumab and Placebo .......................................................... 67 
4.3.1.2 
Background Therapy ................................................................... 67 
4.3.2 
Study Treatment Dosage, Administration, and Compliance ..... 67 
4.3.2.1 
Satralizumab and Placebo .......................................................... 68 
4.3.2.2 
Modifications of Dose or Treatment Schedule........................... 70 
4.3.2.3 
Background Therapy ................................................................... 73 
4.3.3 
Rescue Medication...................................................................... 74 
4.3.4 
Investigational Medicinal Product Handling and 
Accountability .............................................................................. 74 
4.3.5 
Continued Access to Satralizumab ............................................ 75 
4.4 
Concomitant Therapy, Prohibited Food, and Additional 
Restrictions .................................................................................. 76 
4.4.1 
Permitted Therapy ....................................................................... 76 
4.4.2 
Cautionary Therapy..................................................................... 76 
4.4.2.1 
Medications Given with Precaution due to Effects Related 
to CYP Enzymes ......................................................................... 77 
4.4.3 
Prohibited Therapy ...................................................................... 78 
4.4.4 
Additional Restrictions................................................................. 79 
4.4.5 
Immunizations and Vaccinations ................................................ 79 
4.5 
Study Assessments..................................................................... 79 
4.5.1 
Informed Consent Forms and Screening Log............................ 80 
4.5.2 
Screening Assessments ............................................................. 80 
4.5.2.1 
Hepatitis B Screening.................................................................. 81 
4.5.2.2 
Hepatitis C Screening ................................................................. 81 
4.5.2.3 
Screening for Tuberculosis ......................................................... 81 
4.5.3 
Medical History, Baseline Conditions, Concomitant 
Medication, and Demographic Data ........................................... 81 
4.5.4 
Physical Examinations ................................................................ 82 
4.5.5 
Vital Signs .................................................................................... 82 
4.5.6 
Laboratory, Biomarker, and Other Biological Samples ............. 83 
4.5.7 
Electrocardiograms ..................................................................... 86 
4.5.8 
Clinical Outcome Assessments .................................................. 86 
4.5.8.1 
Data Collection Methods for Clinical Outcome 
Assessments ............................................................................... 87 


 
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4.5.8.2 
Description of Clinical Outcome Assessment Instruments ....... 88 
4.5.9 
Blood Samples for Whole Genome Sequencing or Whole 
Exome Sequencing ..................................................................... 90 
4.5.10 
Optional Samples for Research Biosample Repository ............ 91 
4.5.10.1 
Overview of the Research Biosample Repository ..................... 91 
4.5.10.2 
Approval by the Institutional Review Board or Ethics 
Committee ................................................................................... 91 
4.5.10.3 
Sample Collection ....................................................................... 92 
4.5.10.4 
Confidentiality .............................................................................. 92 
4.5.10.5 
Consent to Participate in the Research Biosample 
Repository.................................................................................... 93 
4.5.10.6 
Withdrawal from the Research Biosample Repository.............. 93 
4.5.10.7 
Monitoring and Oversight............................................................ 94 
4.6 
Treatment, Patient, Study, and Site Discontinuation................. 94 
4.6.1 
Study Treatment Discontinuation ............................................... 94 
4.6.2 
Patient Discontinuation from the Study ...................................... 95 
4.6.3 
Study Discontinuation ................................................................. 95 
4.6.4 
Site Discontinuation .................................................................... 95 
5. 
ASSESSMENT OF SAFETY ............................................................ 96 
5.1 
Safety Plan .................................................................................. 96 
5.1.1 
Risks Associated with Satralizumab .......................................... 96 
5.1.1.1 
Infections...................................................................................... 96 
5.1.1.2 
Hypersensitivity ........................................................................... 97 
5.1.1.3 
Liver Enzyme and Bilirubin Elevations ....................................... 98 
5.1.1.4 
Neutropenia ................................................................................. 99 
5.1.1.5 
Thrombocytopenia..................................................................... 100 
5.1.1.6 
Elevations in Lipid Levels.......................................................... 100 
5.1.1.7 
Laboratory Abnormalities Associated with the 
Pharmacodynamic Effect of Satralizumab ............................... 101 
5.1.1.8 
CYP450 Enzyme Normalization ............................................... 101 
5.1.2 
Other Risks Associated with Drugs in the Same Class .......... 101 
5.1.2.1 
Gastrointestinal Perforations (Complications of 
Diverticulitis) .............................................................................. 101 
5.1.2.2 
Malignancies.............................................................................. 102 


 
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5.1.2.3 
Demyelinating Disorders ........................................................... 102 
5.1.3 
Concomitant Immunosuppressive Treatment .......................... 102 
5.1.4 
Management of Patients Who Experience Adverse Events ... 102 
5.1.4.1 
Treatment Interruption or Discontinuation ............................... 102 
5.1.4.2 
Management Guidelines for Adverse Events .......................... 103 
5.2 
Safety Parameters and Definitions........................................... 103 
5.2.1 
Adverse Events ......................................................................... 103 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) .................................................................................... 103 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor)....................................................... 104 
5.2.4 
Selected Adverse Events.......................................................... 105 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters..................................................................... 105 
5.3.1 
Adverse Event Reporting Period .............................................. 105 
5.3.2 
Eliciting Adverse Event Information ......................................... 105 
5.3.3 
Assessment of Severity of Adverse Events ............................. 106 
5.3.4 
Assessment of Causality of Adverse Events ........................... 106 
5.3.5 
Procedures for Recording Adverse Events.............................. 107 
5.3.5.1 
Injection Reactions .................................................................... 107 
5.3.5.2 
Diagnosis versus Signs and Symptoms................................... 107 
5.3.5.3 
Adverse Events That Are Secondary to Other Events ............ 107 
5.3.5.4 
Persistent or Recurrent Adverse Events .................................. 108 
5.3.5.5 
Abnormal Laboratory Values .................................................... 108 
5.3.5.6 
Abnormal Vital Sign Values ...................................................... 109 
5.3.5.7 
Abnormal Liver Function Tests ................................................. 109 
5.3.5.8 
Deaths........................................................................................ 110 
5.3.5.9 
Preexisting Medical Conditions ................................................ 110 
5.3.5.10 
Lack of Efficacy or Worsening of Generalized Myasthenia 
Gravis ......................................................................................... 110 
5.3.5.11 
Hospitalization or Prolonged Hospitalization ........................... 111 
5.3.5.12 
Cases of Overdose, Medication Error, Drug Abuse, or 
Drug Misuse............................................................................... 111 
5.3.5.13 
Patient-Reported or Clinician-Reported Outcome Data .......... 113 


 
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5.3.5.14 
Safety Biomarker Data .............................................................. 113 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor...................................................................................... 113 
5.4.1 
Medical Monitors and Emergency Medical Contacts .............. 114 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest .......................................... 114 
5.4.2.1 
Events That Occur prior to Study Drug Initiation ..................... 114 
5.4.2.2 
Events That Occur after Study Drug Initiation ......................... 114 
5.4.3 
Reporting Requirements for Pregnancies................................ 115 
5.4.3.1 
Pregnancies in Female Patients............................................... 115 
5.4.3.2 
Pregnancies in Female Partners of Male Patients .................. 115 
5.4.3.3 
Abortions .................................................................................... 115 
5.4.3.4 
Congenital Anomalies/Birth Defects......................................... 116 
5.4.4 
Reporting Requirements for Medical Device Complaints ....... 116 
5.5 
Follow-Up of Patients after Adverse Events ............................ 116 
5.5.1 
Investigator Follow-Up .............................................................. 116 
5.5.2 
Sponsor Follow-Up.................................................................... 117 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period ....................................................................... 117 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees .............. 117 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN........ 118 
6.1 
Determination of Sample Size .................................................. 118 
6.2 
Summaries of Conduct of Study............................................... 119 
6.3 
Summaries of Treatment Group Comparability ....................... 119 
6.4 
Efficacy Analyses ...................................................................... 120 
6.4.1 
Primary Efficacy Estimand ........................................................ 120 
6.4.2 
Primary Efficacy Estimator........................................................ 121 
6.4.3 
Type I Error Control................................................................... 122 
6.4.4 
Secondary Efficacy Endpoints .................................................. 122 
6.4.5 
Responder Estimand and Estimator ........................................ 123 
6.4.6 
Count Estimand and Estimator ................................................. 124 
6.4.7 
Duration Estimand and Estimator............................................. 125 
6.4.8 
Exploratory Efficacy Endpoints ................................................. 125 


 
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6.5 
Safety Analyses......................................................................... 126 
6.6 
Pharmacokinetic Analyses........................................................ 126 
6.7 
Immunogenicity Analyses ......................................................... 127 
6.8 
Pharmacodynamic Analyses .................................................... 128 
6.9 
Exploratory Biomarker Analyses .............................................. 128 
6.10 
Health Status Utility Analyses................................................... 128 
6.11 
Interim Analysis ......................................................................... 128 
6.11.1 
Optional Interim Analysis .......................................................... 128 
6.11.2 
Interim Pharmacokinetic Analysis ............................................ 129 
6.12 
China Subpopulation Analyses................................................. 129 
7. 
DATA COLLECTION AND MANAGEMENT ................................. 129 
7.1 
Data Quality Assurance ............................................................ 129 
7.2 
Electronic Case Report Forms ................................................. 130 
7.3 
Source Data Documentation..................................................... 130 
7.4 
Use of Computerized Systems ................................................. 131 
7.5 
Retention of Records ................................................................ 131 
8. 
ETHICAL CONSIDERATIONS....................................................... 132 
8.1 
Compliance with Laws and Regulations .................................. 132 
8.2 
Informed Consent ...................................................................... 132 
8.3 
Institutional Review Board or Ethics Committee ..................... 133 
8.4 
Confidentiality ............................................................................ 133 
8.5 
Financial Disclosure .................................................................. 134 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ......................................................................... 135 
9.1 
Study Documentation ................................................................ 135 
9.2 
Protocol Deviations ................................................................... 135 
9.3 
Management of Study Quality .................................................. 135 
9.4 
Site Inspections ......................................................................... 135 
9.5 
Dissemination of Data and Protection of Trade Secrets ......... 135 
9.6 
Administrative Structure ............................................................ 136 
9.7 
Protocol Amendments............................................................... 137 
10. 
REFERENCES................................................................................ 138 


 
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LIST OF TABLES 
 
Table 1 
Classification of Myasthenia Gravis Subgroups............................ 27 
Table 2 
Objectives and Endpoints during the Double-Blind Period .......... 37 
Table 3 
Objectives and Endpoints during the Open-Label Extension 
Period .............................................................................................. 40 
Table 4 
Dosing Regimen for Investigation in Phase III Study of 
Satralizumab for the Treatment of Generalized Myasthenia 
Gravis .............................................................................................. 47 
Table 5 
Precision and Bias for Generalized Myasthenia Gravis 
Clearance Estimate for Different Pharmacokinetic Interim 
Analysis Sample Sizes ................................................................... 58 
Table 6 
Dosing Regimen Switches for Patients Who May Lose or 
Gain Body Weight ........................................................................... 70 
Table 7 
Recommended Dosage for Delayed or Missed Doses and 
after Rescue Therapy with Plasma Exchange .............................. 72 
Table 8 
Management of Patients with Elevated Transaminases 
(ALT and/or AST)............................................................................ 99 
Table 9 
Management of Neutropenia Low Neutrophil Count ................... 100 
Table 10 
Management of Low Platelet Count............................................. 100 
Table 11 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ................................................ 106 
 
 
LIST OF FIGURES 
Figure 1 
Study Design ................................................................................... 42 
Figure 2 
Dependencies of Steady-State Exposure Parameters and 
Receptor Occupancy on Body Weight Following 120mg 
Q4W Dosing (Body Weight Range:  40−100 kg), and 180-mg 
Q4W Dosing (Body Weight Range:  100−160 kg) ........................ 48 
Figure 3 
Dependencies of Steady-State Ctrough and Receptor 
Occupancy on Body Weight following 180-mg Q4W Dosing 
(Body Weight Range:  40−100 kg), and 240-mg Q4W Dosing 
(Body Weight Range:  100−160 kg)............................................... 49 
 
 


 
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LIST OF APPENDICES 
Appendix 1 
 Schedule of Activities:  Screening and Double-Blind Periods ... 144 
Appendix 2 
 Schedule of Activities:  Open-Label Extension Period .............. 151 
Appendix 3 
 Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples ...................................................................... 159 
Appendix 4 
 Anaphylaxis Precautions ............................................................. 162 
Appendix 5 
 Instructions for Tuberculosis Screening and Treatment ............ 163 
Appendix 6 
 Myasthenia Gravis-Activities of Daily Living............................... 165 
Appendix 7 
 Quantitative Myasthenia Gravis .................................................. 166 
Appendix 8 
 Myasthenia Gravis Composite Scale.......................................... 167 
Appendix 9 
 Myasthenia Gravis Quality of Life 15 (revised) (MG-QOL 
15r) ................................................................................................ 169 
Appendix 10 
 EuroQoL EQ-5D-5L ..................................................................... 170 
Appendix 11 
 Columbia-Suicide Severity Rating Scale (C-SSRS)  at 
Baseline......................................................................................... 173 
Appendix 12 
 Columbia-Suicide Severity Rating Scale (C-SSRS)  since 
Last Visit ........................................................................................ 176 
Appendix 13 
 Neuro-QOL Item Bank v1.0−Fatigue Short Form ...................... 179 
Appendix 14 
 Myasthenia Gravis Foundation of America Clinical 
Classification ................................................................................. 180 
Appendix 15 
 Investigational Medicinal Product and Auxiliary Medicinal 
Products Designations (for Use in European Economic Area)........... 181 


 
Satralizumab—F. Hoffmann-La Roche Ltd 
14/Protocol WN42636, Version 5 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
PROTOCOL TITLE: 
A PHASE III RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, MULTICENTER STUDY TO 
EVALUATE EFFICACY, SAFETY, 
PHARMACOKINETICS, AND PHARMACODYNAMICS OF 
SATRALIZUMAB IN PATIENTS WITH GENERALIZED 
MYASTHENIA GRAVIS 
PROTOCOL NUMBER: 
WN42636 
VERSION NUMBER: 
5 
TEST PRODUCT: 
Satralizumab (RO5333787) 
CO-SPONSORS: 
F. Hoffmann-La Roche Ltd 
Chugai Pharmaceutical Co. Ltd.* 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator's Name (print) 
 
 
 
 
 
Principal Investigator's Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local study monitor. 
 


Satralizumab—F. Hoffmann-La Roche Ltd 
15/Protocol WN42636, Version 5 
PROTOCOL TITLE: 
REGULATORY 
AGENCY IDENTIFIERS: 
PROTOCOL SYNOPSIS 
A PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, MULTICENTER STUDY TO EVALUATE 
EFFICACY, SAFETY, PHARMACOKINETICS, AND 
PHARMACODYNAMICS OF SATRALIZUMAB IN PATIENTS WITH 
GENERALIZED MYASTHENIA GRAVIS 
I1D 1XmEer  .....
(XGrD&T 1XmEer  
EU CT Number:  2023-507169-24-00
N&T 1XmEer  1&T
STUDY RATIONALE 
The purpose of this study is to evaluate the efficacy, safety, pharmacokinetics, and 
pharmacodynamics of satralizumab compared with placebo as add-on therapy to standard of 
care (SOC) for the treatment of generalized myasthenia gravis (gMG), which is a chronic 
autoimmune condition that has substantial impact on day-to-day functioning of patients.  In 
addition, the study will assess the long-term safety and efficacy of satralizumab during the open-
label extension (OLE) period.   
OBJECTIVES AND ENDPOINTS 
Table 1 
Objectives and Endpoints during the Double-Blind Period 
Primary Efficacy Objective 
Corresponding Endpoint 
• To evaluate the efficacy of
satralizumab versus placebo on
function in daily life in the AChR +
population
• Mean change from baseline in total MG-ADL score
at Week 24
AChR = acetylcholine receptor; AChR +  = AChR-antibody seropositive (patients/population); 
ADA = anti-drug antibody; AUC = area under the concentration−time curve; CL/F = apparent 
clearance; Ctrough = trough concentration; gMG = generalized myasthenia gravis; IL-6 = interleukin-
6; MG-ADL = Myasthenia Gravis Activities of Daily Living; MGC = Myasthenia Gravis Composite; 
MG-QOL 15r = Myasthenia Gravis Quality of Life 15 Scale (revised); NCI CTCAE v5.0 = National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0; 
Neuro−QoL = Quality of Life in Neurological Disorders; OP = overall population; 
PK = pharmacokinetic; QMG = Quantitative Myasthenia Gravis; QoL = quality of life; sIL-
6R = soluble interleukin-6 receptor; V/F = apparent volume of distribution. 
a  
Patients who receive rescue therapy will be considered non-responders


 
Satralizumab—F. Hoffmann-La Roche Ltd 
16/Protocol WN42636, Version 5 
Table 1 
Objectives and Endpoints during the Double-Blind Period (cont.) 
Secondary Efficacy Objectives 
Corresponding Endpoints 
• To evaluate the efficacy of 
satralizumab versus placebo on 
function in daily life in the OP  
• Mean change from baseline in total MG-ADL score 
at Week 24 
• To evaluate the efficacy of 
satralizumab versus placebo in the 
AChR + population and OP on: 
 
 
– 
Function in daily life 
• 
Percentage of patients with a ≥ 2-point reduction 
from baseline in total MG-ADL score at Week 24a 
– 
QMG, QoL, and Fatigue 
• 
Mean change from baseline in QMG score, 
MG-QOL 15r total score and Neuro−QoL Fatigue 
Subscale total score at Week 24  
• 
Percentage of patients with a ≥ 3-point reduction 
from baseline in QMG score at Week 24a 
– 
Clinical status 
• 
Mean change from baseline in total MGC score at 
Week 24 
• 
Percentage of patients with a ≥ 3-point reduction 
from baseline in total MGC score at Week 24 a 
– 
Disease severity 
• 
Proportion of patients: 
– 
Who have achieved minimal disease 
manifestation (total MG-ADL score of 0 or 1) 
at Week 24 a 
– 
With at least one gMG-related exacerbation 
between baseline and Week 24 
– 
Receiving rescue therapy between baseline 
and Week 24 
• 
Annualized rate of gMG-related exacerbations 
• To evaluate the durability of the 
efficacy of satralizumab versus 
placebo in the AChR + population and 
the OP 
• 
Duration (average number of consecutive months) 
of meaningful improvement, defined as ≥ 2-point 
reduction from baseline in total MG-ADL score a 
AChR = acetylcholine receptor; AChR +  = AChR-antibody seropositive (patients/population); 
ADA = anti-drug antibody; AUC = area under the concentration−time curve; CL/F = apparent 
clearance; Ctrough = trough concentration; gMG = generalized myasthenia gravis; IL-6 = interleukin-
6; MG-ADL = Myasthenia Gravis Activities of Daily Living; MGC = Myasthenia Gravis Composite; 
MG-QOL 15r = Myasthenia Gravis Quality of Life 15 Scale (revised); NCI CTCAE v5.0 = National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0; 
Neuro−QoL = Quality of Life in Neurological Disorders; OP = overall population; 
PK = pharmacokinetic; QMG = Quantitative Myasthenia Gravis; QoL = quality of life; sIL-
6R = soluble interleukin-6 receptor; V/F = apparent volume of distribution. 
a  
Patients who receive rescue therapy will be considered non-responders 
 


 
Satralizumab—F. Hoffmann-La Roche Ltd 
17/Protocol WN42636, Version 5 
Table 1 
Objectives and Endpoints during the Double-Blind Period (cont.) 
Safety Objective 
Corresponding Endpoints 
• To evaluate the safety of satralizumab 
versus placebo 
• Incidence and severity of adverse events, with 
severity determined according to NCI CTCAE v5.0 
grading 
• Change from baseline in targeted vital signs, ECG 
results, physical examination findings, targeted 
clinical laboratory test results, and suicidality 
Pharmacokinetic Objective 
Corresponding Endpoints 
• To investigate the pharmacokinetics of 
satralizumab by evaluating plasma 
exposure over 24 weeks 
• Serum concentrations of satralizumab (mean and 
SD of Ctrough) at specified timepoints 
• Estimates of primary PK parameters (e.g., CL/F and 
V/F) and secondary PK parameters (e.g., AUC) 
derived using population−PK modeling 
Immunogenicity Objective 
Corresponding Endpoint 
• To evaluate the immune response to 
satralizumab  
• 
Prevalence of ADAs at baseline and incidence of 
ADAs during the study 
AChR = acetylcholine receptor; AChR +  = AChR-antibody seropositive (patients/population); 
ADA = anti-drug antibody; AUC = area under the concentration−time curve; CL/F = apparent 
clearance; Ctrough = trough concentration; gMG = generalized myasthenia gravis; IL-6 = interleukin-
6; MG-ADL = Myasthenia Gravis Activities of Daily Living; MGC = Myasthenia Gravis Composite; 
MG-QOL 15r = Myasthenia Gravis Quality of Life 15 Scale (revised); NCI CTCAE v5.0 = National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0; 
Neuro−QoL = Quality of Life in Neurological Disorders; OP = overall population; 
PK = pharmacokinetic; QMG = Quantitative Myasthenia Gravis; QoL = quality of life; sIL-
6R = soluble interleukin-6 receptor; V/F = apparent volume of distribution. 
a  
Patients who receive rescue therapy will be considered non-responders 
 
 


 
Satralizumab—F. Hoffmann-La Roche Ltd 
18/Protocol WN42636, Version 5 
Table 2 
Objectives and Endpoints during the Open-Label Period 
Safety Objective 
Corresponding Endpoints 
• To evaluate the long-term safety and 
tolerability of satralizumab  
• Incidence and severity of adverse events, with 
severity determined according to NCI CTCAE v5.0 
grading 
• Change from baseline in targeted vital signs, ECG 
results, physical examination findings, targeted clinical 
laboratory test results, and suicidality  
Efficacy Objectives 
Corresponding Endpoints 
• To assess the efficacy of 
satralizumab in the AChR + 
population and OP  
• Mean change from active treatment baseline in: 
– 
MG-ADL total score 
– 
QMG score 
– 
MGC score 
– 
MG-QOL 15r score 
• Percentage of responders a based on:  
– 
 ≥ 2-point reduction in total MG-ADL score or 
– 
 ≥ 3-point reduction in QMG score or 
– 
 ≥ 3-point reduction in total MGC score 
• Proportion of time and duration that patients show a 
meaningful improvement, defined as a ≥ 2-point 
reduction from active treatment baseline in total 
MG-ADL score 
• Number and severity of gMG-related exacerbations  
• To assess the effect of satralizumab 
on steroid/IST/AChEI dose 
modification in the AChR + population 
and OP  
• The proportion of patients who maintain clinical 
response without increase in symptomatic medication 
dose and are able to reduce corticosteroid dose or 
withdraw from corticosteroid or IST during the OLE 
AChEI = acetylcholinesterase inhibitor; AChR = acetylcholine receptor; AChR +  = AChR-antibody 
seropositive (patients/population); ADA = anti-drug antibody; AUC = area under the 
concentration−time curve; CL/F = apparent clearance; Ctrough = trough concentration; 
IL-6 = interleukin-6; IST = immunosuppressant; MG-ADL = Myasthenia Gravis Activities of Daily 
Living; MG-QOL 15r = Myasthenia Gravis Quality of Life 15 Scale (revised); NCI CTCAE 
v5.0 = National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0; 
OLE = open-label extension; OP = overall population; PD = pharmacodynamic; 
PK = pharmacokinetic; QMG = Quantitative Myasthenia Gravis; QoL = quality of life; sIL-
6R = soluble interleukin-6 receptor; V/F = apparent volume of distribution. 
 
 


 
Satralizumab—F. Hoffmann-La Roche Ltd 
19/Protocol WN42636, Version 5 
Table 2 
Objectives and Endpoints during the Open-Label Period (cont.) 
Pharmacokinetic Objective 
Corresponding Endpoints 
• To investigate the pharmacokinetics 
of satralizumab by evaluating plasma 
exposure in the OLE 
• Serum concentrations of satralizumab (mean and SD 
of Ctrough)  
• Estimates of primary PK parameters (e.g., CL/F and 
V/F) and secondary PK parameters (e.g., AUC) 
derived using population−PK modeling 
Immunogenicity Objective 
Corresponding Endpoint 
• To evaluate the immune response to 
satralizumab 
• Prevalence of ADAs at baseline and incidence of 
ADAs during the OLE 
Pharmacodynamic Objective 
Corresponding Endpoint 
• To confirm target engagement and 
pathway inhibition in response to 
satralizumab 
• Absolute values and change from baseline in serum 
levels of PD biomarkers IL-6 and sIL-6R 
AChEI = acetylcholinesterase inhibitor; AChR = acetylcholine receptor; AChR +  = AChR-antibody 
seropositive (patients/population); ADA = anti-drug antibody; AUC = area under the 
concentration−time curve; CL/F = apparent clearance; Ctrough = trough concentration; 
IL-6 = interleukin-6; IST = immunosuppressant; MG-ADL = Myasthenia Gravis Activities of Daily 
Living; MG-QOL 15r = Myasthenia Gravis Quality of Life 15 Scale (revised); NCI CTCAE 
v5.0 = National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0; 
OLE = open-label extension; OP = overall population; PD = pharmacodynamic; 
PK = pharmacokinetic; QMG = Quantitative Myasthenia Gravis; QoL = quality of life; sIL-
6R = soluble interleukin-6 receptor; V/F = apparent volume of distribution. 
 
OVERALL DESIGN AND STUDY POPULATION 
This Phase III, randomized, double-blind (DB), placebo-controlled, multicenter study is designed 
to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of satralizumab 
compared with placebo as add-on therapy to SOC for the treatment of gMG.  The study will 
include a 28-day screening period, a 24-week DB treatment period, and approximately 2-year 
OLE period after the last patient initiates open-label treatment.  As of global protocol Version 5, 
adolescent patients enrolled in the study will directly enter the OLE period after completion of the 
screening period. 
 


 
Satralizumab—F. Hoffmann-La Roche Ltd 
20/Protocol WN42636, Version 5 
Several key aspects of the study design and study population are summarized in the table 
below. 
Phase: 
Phase III 
Population Type: 
Adult and pediatric 
patients 
Control Method: 
Placebo (DB period) 
and none (OLE 
period) 
Population Diagnosis 
or Condition: 
gMG 
Interventional 
Model: 
Parallel (DB period) 
and single group 
(OLE period) 
Population Age: 
Adults ≥ 18 years a and 
adolescents ≥ 12 years 
to < 18 years 
Test Product{s}: 
Satralizumab 
Site Distribution: 
Multi-site and multi-
region 
Active Comparator: Not applicable  
Study Treatment 
Assignment Method: 
Randomization and 
stratification 
Number of Arms: 
2 
Number of Participants 
to Be Enrolled: 
Approximately 185 
DB = double-blind; gMG = generalized myasthenia gravis; OLE = open-label extension 
a  
Only adult patients aged ≥ 18 years old will be included at participating sites in France 
STUDY TREATMENT 
Weight-tiered dosing via SC injection will be used in this study. 
Table 3 Dosing Regimen:  Double-Blind Period 
Body Weight at 
Baseline a 
Dose and Regimen 
 ≤ 100 kg 
120 mg satralizumab/placebo administered at 
Weeks 0, 2, 4 (loading doses), and maintenance 
doses Q4W thereafter as a SC injection 
 > 100 kg 
180 mg satralizumab/placebo administered at 
Weeks 0, 2, 4 (loading doses), and maintenance 
doses Q4W thereafter as a SC injection 
SC =  subcutaneous, Q4W = every 4 weeks. 
a Recommendations in case of changes in body weight in an individual 
patient would result in a different dosing band are given in the protocol. 
 
During the OLE period, all patients will receive open-label treatment with 120 mg or 180 mg 
satralizumab, as determined based on body weight (see above).  Adult and adolescent patients 
who receive placebo during the DB period will receive satralizumab SC loading doses at Weeks 
0, 2, and 4 in the OLE, followed by maintenance doses every 4 weeks (Q4W) thereafter during 
the OLE period.  Adult and adolescent patients who receive active treatment during the DB period 
will continue receiving satralizumab SC Q4W during the OLE period, but will receive an additional 
placebo SC injection at Week 2 to maintain blinding to DB treatment assignment.   
Adolescent patients who first enter the study in the OLE period will receive satralizumab SC loading doses 
at Week 0, 2, and 4 in the OLE, followed by maintenance doses Q4W thereafter and will remain on stable 
background therapy until Week 24 of the OLE. 
Information on delayed or missed doses, as well as background therapy and rescue medication, 
can be found in the protocol. 
 


 
Satralizumab—F. Hoffmann-La Roche Ltd 
21/Protocol WN42636, Version 5 
DURATION OF PARTICIPATION 
The total duration of study participation for each individual enrolled in the DB period is expected 
to be approximately 2.5−4 years, depending on when the participant enters the OLE and the 
duration of time the participant spends in this period. 
The total duration of study participation for adolescent patients enrolled directly in the OLE period is 
approximately 2−3.5 years, according to the estimated recruitment timelines. 
 
COMMITTEES 
Independent Committees: Independent Data Monitoring Committee  
Other Committees: 
Not applicable 
 


 
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22/Protocol WN42636, Version 5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AChE 
acetylcholinesterase 
AChEI 
acetylcholinesterase inhibitors 
AChR 
acetylcholine receptor 
AChR +   
AChR-antibody seropositive (patients/population) 
ADA 
anti-drug antibody 
AQP4 
Aquaporin-4 
AUC 
area under the concentration−time curve; 
AxMP 
auxiliary medicinal product 
CL 
total clearance of drug 
CL/F 
apparent clearance 
ClinRO 
clinician-reported outcome 
Cmax 
maximum concentration observed 
COVID-19 
coronavirus disease 2019 
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
trough concentration 
Ctr,ss 
trough concentration at steady state  
C-SSRS  
Columbia Suicide Severity Scale 
CSR 
Clinical Study Report 
DB 
double-blind; 
EAMG 
experimental autoimmune myasthenia gravis 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EEA 
European Economic Area 
EFF 
extended finger flange 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
GI 
gastrointestinal 
gMG 
generalized myasthenia gravis 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HCP 
health care professional 
HIPAA 
Health Insurance Portability and Accountability Act 


 
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Abbreviation 
Definition 
HRQOL 
health-related quality-of-life 
HV 
healthy volunteer 
ICC 
intra-class correlation coefficient 
ICH 
International Council for Harmonisation 
iDCC 
independent Data Coordinating Center 
iDMC 
independent Data Monitoring Committee 
IFN-γ 
interferon-γ 
IL-6 
interleukin-6 
IL-6R 
interleukin-6 receptor 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
IST 
immunosuppressant 
IVIg 
intravenous immunoglobulin 
IxRS 
interactive voice or web-based response system 
JMG 
juvenile myasthenia gravis 
LPLV 
last patient, last visit 
LRP4 
low-density lipoprotein receptor−related protein 4 
MCID 
minimum clinically important difference 
MG 
Myasthenia gravis 
MG-ADL 
Myasthenia Gravis Activities of Daily Living 
MGC 
Myasthenia Gravis Composite 
MGFA 
Myasthenia Gravis Foundation of America 
MG-QOL 15r 
Myasthenia Gravis Quality of Life 15 Scale (revised) 
mIL-6R 
membrane-bound IL-6R 
mITT 
modified intent-to-treat (population) 
MM 
minimal manifestations 
MN 
mobile nurse 
MuSK 
muscle-specific kinase 
NCI 
National Cancer Institute 
Neuro−QoL 
Quality of Life in Neurological Disorders 
NGS 
next-generation sequencing 
NMJ 
neuromuscular junction 
NMOSD 
neuromyelitis optica spectrum disorder 
NSD 
needle safety device 
NSDCR 
not study drug or condition related 
OCS 
oral corticosteroids 


 
Satralizumab—F. Hoffmann-La Roche Ltd 
24/Protocol WN42636, Version 5 
 
Abbreviation 
Definition 
OLE 
open-label extension 
OP 
overall population 
PBMCs 
peripheral blood mononuclear cells 
PD 
pharmacodynamic 
PE 
plasma exchange 
PFS 
prefilled syringe 
PK 
pharmacokinetic 
pop PK 
population PK 
PRO 
patient-reported outcome 
PY 
patient years 
QMG 
Quantitative Myasthenia Gravis score 
QoL 
quality of life 
QTcF 
QT interval corrected through use of Fridericia's 
formula 
Q4W 
every 4 weeks 
RA 
rheumatoid arthritis 
RBR 
Research Biosample Repository 
RO 
receptor occupancy 
ROC 
receiver operating curves 
ROtr,ss 
trough receptor occupancy at steady-state 
SAP 
Statistical Analysis Plan 
SDCR 
study drug or condition related 
SFU 
safety follow-up 
sIL-6R  
soluble interleukin-6 receptor 
SJS 
Stevens-Johnson Syndrome 
SOC 
standard of care 
TB 
tuberculosis 
Treg 
regulatory T cells 
Th17 
T-helper 17 
ULN 
upper limit of normal 
VAS 
visual analogue scale 
WES 
whole exome sequencing 
WGS 
whole genome sequencing 
 
 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON MYASTHENIA GRAVIS 
Myasthenia gravis (MG) is a rare chronic autoimmune disease that affects the 
postsynaptic membrane at the neuromuscular junction (NMJ).  The hallmark of the 
disorder is a fluctuating degree and variable combination of fatigable weakness in 
ocular, facial, bulbar (oropharyngeal), respiratory, trunk (axial), and limb muscles.  
Bulbar weakness results in difficulties with chewing, swallowing (dysphagia), and talking 
(dysarthria).  Fatigability is characterized by worsening of the weakness with exercise 
and repetitive muscle use; as a result, it is typically most pronounced in the evening. 
There are two clinical forms of MG:  ocular MG, present in about 15% of patients, and 
generalized MG (gMG), affecting about 85% of patients (Gilhus et al. 2019).  In ocular 
MG, the weakness is limited to the eyelids and extraocular muscles resulting in drooping 
of the eyelid (ptosis) and double vision (diplopia), respectively.  In gMG, the weakness 
commonly affects ocular muscles in combination with other muscle groups. 
More than 50% of patients with MG experience ocular manifestations as their initial 
symptoms.  In contrast, approximately 15% of patients experience facial and bulbar 
weakness as their initial manifestations.  Less than 5% of patients present with proximal 
limb weakness alone.  Less common presentations include isolated neck weakness, 
isolated respiratory muscle weakness, and distal limb weakness (Gilhus et al. 2019).  
Myasthenia gravis has a variable course.  The disease usually peaks within a few years 
from disease onset.  More than half of the patients who present with ocular 
manifestations at disease onset will develop generalized disease within the first 2 years.  
Many of the patients who have no ocular manifestations at disease onset develop ptosis 
or diplopia at some point in the course of the disease.  Disease worsening (clinical 
exacerbations) can be triggered by infections, surgery, and certain medications.  About 
15% of patients experience myasthenic crisis, characterized by weakness of the 
diaphragm and accessory breathing muscles resulting in respiratory failure.  Myasthenic 
crisis is a neurologic emergency that is managed in the intensive care setting with 
ventilatory support and fast-acting therapies.  MG is not considered a progressive 
disease as permanent muscle damage and resulting irreversible disability rarely occurs. 
The listed MG symptoms substantially influence the daily life of the patients.  Ptosis has 
significant impact on the quality of life (QoL) not only because it impairs vision but also 
because it makes the affected individual self-conscious and thus results in social 
withdrawal (Richards et al. 2014).  Diplopia, fatigue, and weakness hinder the affected 
individual from completing basic daily tasks, including taking care of their hygiene 
(Basta et al. 2012).  Considering the interferences of daily functioning due to the 
symptoms of MG, heightened depression and lowered QoL are common (Leonardi et 
al. 2010; Yang et al. 2016; Koopman et al. 2016). 


 
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Prevalence and incidence of MG ranges substantially across the literature according to 
study methodology, study period, and the sociodemographic distribution of the study 
population.  The majority of studies in the literature report estimated prevalence of MG 
as 15–240 cases per million individuals globally, although some regional European 
studies report a prevalence as high as 329−649 cases per million individuals (Carr et al. 
2010; Montomoli et al. 2012; Leoni et al. 2014; Aragonès et al. 2017). 
As with prevalence, the reported cumulative incidence has increased over time, likely 
due to improvements in diagnosis, more widespread antibody testing, and physician 
awareness.  Studies published during 1950−1994 report an incidence of 2−15 per million 
individuals, while more recent studies report an increased incidence of 9−104 per million 
individuals (Phillips and Torner 1996; Kumar et al. 2020).   
MG is caused by autoantibodies that bind to acetylcholine receptors (AChRs) or to other 
functionally related molecules in the postsynaptic membrane at the NMJ, such as 
muscle-specific kinase (MuSK) or low-density lipoprotein receptor−related protein 4 
(LRP4).  Patients with positive AChR, MuSK, or LRP4 autoantibodies have seropositive 
MG.  Patients in whom currently commercially available tests did not detect presence of 
the three types of autoantibodies are considered seronegative.  Approximately 85% of 
patients with gMG test positive for AChR autoantibodies (AChR + MG), 7%−8% for 
MuSK autoantibodies (MuSK + MG), and 1%−3% for LRP4 autoantibodies (LRP4 + MG), 
whereas about 6% of patients are seronegative.  Autoantibody production in MG is a T-
cell−dependent process, and the thymus is thought to play an important role in the 
dysregulation of self-tolerance and ultimately MG pathogenesis.  The majority of patients 
with AChR antibody−seropositive (AChR +) MG have thymic abnormalities:  hyperplasia 
in 60%−70% and thymoma in 10%−12% of patients. 
MG is classified into subgroups according to clinical manifestations, age at onset, the 
presence of autoantibody pattern, and thymus pathology (see Table 1) (Gilhus and 
Verschuuren 2015; Gilhus 2016).  Ocular MG and LRP4 + MG tend to be milder, 
whereas MuSK + MG and probably thymoma-associated MG tend to be more severe 
(Andersen et al. 2016). 


 
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Table 1 
Classification of Myasthenia Gravis Subgroups 
Subgroup 
Autoantibody 
Age at Onset (years) 
Thymus 
Abnormalities 
Early-onset MG a 
AChR 
< 50  
Hyperplasia common 
Late-onset MG 
AChR 
> 50  
Atrophy common 
Thymoma-associated 
MG 
AChR 
Any 
Type AB and B 
thymoma 
MuSK MG 
MuSK 
Any 
Normal 
LRP4 MG 
LRP4 
Any 
Normal 
Seronegative MG 
None detected 
Any 
Variable 
Ocular MG b 
AChR, MuSK, LRP4, 
or none 
Any 
Variable 
AChR = acetylcholine receptor; LRP4 = low-density lipoprotein receptor−related protein 4; 
MG = myasthenia gravis; MuSK = muscle-specific kinase. 
a Juvenile MG is not considered a separate subgroup and is part of early-onset MG.  All patients 
at one time point can belong only to one subgroup.  
b Ocular MG includes the patients with ocular symptoms only and no clinical weakness in other 
muscles. 
  
The age at onset of AChR MG often has a bimodal pattern, with a lower peak observed 
at around 30 years of age and a higher peak at 70–80 years of age (Heldal et al. 2009; 
Carr et al. 2010; Andersen et al. 2010).  The incidence peak in young adults is mainly 
attributed to women, whereas late-onset MG is slightly more frequent in men 
(Carr et al. 2010; Gilhus and Verschuuren 2015). 
1.2 
JUVENILE MYASTHENIA GRAVIS 
Juvenile, or childhood, MG (JMG), defined by onset before the age of 18 years 
(O’Connell 2020) shares aspects of pathophysiology and most of the clinical features of 
adult early-onset MG (Gilhus et al. 2019).  JMG is distinguished from genetic, 
non-autoimmune forms of neuromuscular transmission defect, the so-called congenital 
myasthenic syndromes. 
The juvenile-onset and adult-onset MG differ with respect to epidemiology, frequency of 
ocular and generalized MG forms, prognosis, and therapeutic approaches. 
A range of 12−80% of patients with JMG have been reported to have gMG (Chung et 
al. 2003; Kalb et al. 2002; Popperud et al. 2017), which is below the estimated frequency 
of 85% in adults.  gMG is relatively uncommon in prepubertal children, regardless of 
race (Chung et al, 2003, O’Connell et al. 2020).  
The pathophysiology of MG in pediatric patients is highly similar to that of adults.  JMG is 
also caused by autoantibodies that bind to AChR or to other functionally relevant 
molecules in the postsynaptic membrane at the NMJ, such as MuSK or LRP4.   


 
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However the percentage of patients seropositive for these molecules differ from 
adult-onset MG:  majority of patients (90%) are AChR +, < 8% are MuSK + , and < 2% are 
LRP4 + , whereas about 10%−30% of patients are seronegative (Finnis and Jayawant 
2011; Takahashi et al. 2012; VanderPluym et al. 2013; Baraud 2018; Vecchio et al. 
2020).   
Diagnosis of JMG is established using the same evaluations and procedures as in 
adult MG.   
1.3 
CURRENT TREATMENT AND UNMET MEDICAL NEED 
The goal of therapy in gMG is to induce pharmacological remission, complete stable 
remission, or minimal manifestations (MM), while minimizing side effects from 
medications (Jaretzki et al. 2000).  The Myasthenia Gravis Foundation of America 
(MGFA) post-intervention status defines MM as a patient who has no symptoms or 
functional limitations from gMG but has some weakness on examination of some 
muscles.  In October 2013, the MGFA appointed a Task Force, a panel of 
15 international experts, who developed consensus-based guidance for the 
management of MG, which was published in 2016 (Sanders et al). 
In contrast to adult MG there are no internationally accepted standards of care for JMG, 
and prospective randomized controlled data to evaluate treatment outcomes and 
efficacy have been difficult to collect.  Most of the current practice on JMG diagnosis and 
treatment is extrapolated from adult trials and experience.  
There are three types of primary therapies used to treat gMG: 
• 
Symptomatic treatment using acetylcholinesterase (AChE) inhibitors (AChEIs; anti-
cholinesterases) 
• 
Immunosuppressive and immunomodulatory therapies 
• 
Thymectomy  
 
Symptomatic treatment using AChEI increases the amount of acetylcholine available at 
the NMJ.  Given its oral route of administration, pyridostigmine bromide is the preferred 
AChEI, and is usually the first-line medication in patients with gMG, including those with 
JMG.  All subgroups of patients with gMG, with the exception of patients with MuSK + 
gMG, respond to AChEIs but with inter-individual variability in the degree of weakness 
relief, optimal dosage, and tolerability (Finnis and Jayawant et al. 2011; O’Connell et al. 
2020).  Muscle strength can be restored to normal levels over long periods in only a few 
patients with mild disease. 
Chronic immunosuppressive therapies (glucocorticoids and non-steroidal 
immunosuppressive agents) target the underlying immune dysregulation.  Patients with 
symptoms that exert functional impairment or reduce QoL when on maximum tolerated 
AChEI treatment should receive immunotherapy.  Commonly used immunosuppressive 
therapies include oral corticosteroids (OCSs), antimetabolites (such as azathioprine, 


 
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mycophenolate mofetil, or methotrexate) and calcineurin inhibitors (such as cyclosporine 
and tacrolimus).  The time of onset of clinical effect of each of these therapies for gMG 
varies considerably ranging from a few weeks for OCSs to approximately 2−12 months 
for mycophenolate mofetil and azathioprine (Sanders et al. 2016).  The time of onset 
plays a large role, in addition to the pace and severity of the disease, in choosing the 
appropriate therapy for a given patient.   
OCSs are first-line immunotherapy drugs for adult-onset and juvenile MG (O’Connell et 
al. 2020); in children, they are used cautiously, at the lowest possible dose because of 
growth retardation and other chronic systemic side effects, including weight gain, 
cushingoid features, hyperglycemia, hypertension, cataracts, glaucoma, behavioral 
changes, and susceptibility to infection.  
Conventional steroid-sparing immunosuppressive agents are used on a limited basis in 
children because of the long-term risk of malignancy and teratogenicity (Munot et al. 
2020); methotrexate, cyclosporine and cyclophosphamide are reserved only for 
refractory cases (see Section 4.5.3 for definition).  
Patients with insufficient response, further disease worsening, or intolerance to the 
above medications may receive treatment with chronic IV immunoglobulin (IVIg), plasma 
exchange (PE), B-cell depletion with rituximab, or terminal complement activation 
inhibition with eculizumab (Soliris U.S. Package Insert; Sanders et al. 2016).  In 
single-arm study reports, rituximab was effective but with varying response rates 
(Anderson et al. 2016; Tandan et al. 2017; Robeson et al. 2017).  Furthermore, in a 
Phase II trial in patients with AChR gMG (NCT02110706) rituximab was safe and well 
tolerated, but the study did not reach the primary endpoint of a 75% reduction in 
glucocorticoid levels.  The use of rituximab in refractory JMG is sparsely documented 
(Zingariello et al. 2020; Barraud et al. 2018).  Many of the therapies used in MG, 
including rituximab, are used off-label. 
Therapeutic PE and IVIg are rapid but short-acting immunomodulating treatments.  
As such, they are typically used in patients with acute severe gMG when a rapid 
response is crucial, and are the mainstay of management of myasthenic crisis.  As their 
effect is short-lived (4−12 weeks), maintenance immunotherapy is usually needed.  
They may be used as chronic, maintenance therapy in patients with refractory gMG 
(see Section 4.5.3 for definition) or in patients for whom immunosuppressive agents are 
relatively contraindicated, such as the pediatric population. 
Thymectomy is indicated for patients with thymoma if resection is feasible and in many 
other AChR antibody−positive patients with non-thymomatous gMG who are 
18−65 years old.  In patients with a non-neoplastic thymus, thymectomy for the 
improvement of gMG has been performed for several decades, and is supported by 
extensive evidence on the pathogenetic role of the thymus in AChR + gMG and by a 
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al. 2010; Wolfe et al. 2016; Gronseth et al. 2020).  The role and timing of thymectomy is 
still not well established or standardized in children.  It is usually considered as a 
therapeutic option in AChR + gMG when the response to pyridostigmine and ISTs is 
incomplete or to avoid the long-term side effects of ISTs, especially corticosteroids.  
Thymectomy does not have an effect in MuSK gMG and has not been systematically 
examined in patients with gMG who have no detectable antibodies.  Thymectomy does 
not cure gMG, and the long-term effect on antibody concentrations, T-cell subsets, and 
immune responses is very modest. 
The majority of treated patients achieve a relatively stable condition allowing them to 
perform daily tasks (Andersen et al. 2016).  However, only a few patients achieve 
remission, i.e., have no symptoms or signs of gMG and no evidence of weakness of any 
muscle on neurological examination.  Even if fully functional, many patients experience 
side effects of the above listed treatments for gMG (Bacci et al. 2019).  While children 
tend to exhibit higher rates of spontaneous or pharmacologic remission than adults, the 
frequency of refractory MG in pediatric population is unknown.  OCSs, the most 
commonly used and fast-acting medications, result in a plethora of adverse effects that 
almost universally limit patients’ QoL.  Steroid-sparing agents are suboptimal 
alternatives because of their non-specific immunosuppressive profile, onset of action 
that may be delayed by more than 6 months, and significant long-term side effects, 
including malignancies.  IVIg and therapeutic PE are associated with considerable 
logistical challenges.  Overall, the unmet need in gMG remains high for disease-specific, 
more effective, safer, and relatively convenient treatments. 
1.4 
BACKGROUND ON SATRALIZUMAB 
Satralizumab (RO5333787) is a humanized anti−interleukin-6 receptor (IL-6R) IgG2 
monoclonal antibody that was constructed by modifying the amino acid sequence of 
tocilizumab to prolong its plasma drug-elimination half-life.  In addition, satralizumab has 
the following distinguishing characteristics:  pH-dependent binding to its antigen (IL-6R) 
(Igawa et al. 2010a), decreased antibody molecule isoelectric point (Igawa et al. 2010b), 
and stronger binding to neonatal Fc receptor (Petkova et al. 2006).  Moreover, its Fc 
region has been modified to minimize antibody-dependent cellular cytotoxicity and 
complement-dependent cytotoxicity effector activity. 
Satralizumab maintains pharmacological effects of IL-6R blockade using a 4-week 
dosing frequency by SC injection due to its prolonged plasma drug-elimination half-life.  
Satralizumab specifically targets the human IL-6R, preventing interleukin (IL)-6 from 
binding to the membrane-bound and soluble IL-6R (mIL-6R and sIL-6R respectively), 
thereby inhibiting IL-6 signaling. 
The clinical pharmacology, safety, and efficacy of satralizumab has been characterized 
in four clinical trials:  a single ascending dose (SA-001JP) trial in healthy subjects (both 
Japanese and Caucasian), a multiple ascending dose (SA-105JP) trial in patients with 


 
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rheumatoid arthritis (RA), and two Phase III clinical studies in patients with neuromyelitis 
optica spectrum disorder (NMOSD; BN40898 [SA-307JG] and BN40900 [SA-309JG).  
Study BN40900 was a randomized (2:1 ratio), placebo-controlled trial in 95 patients 
without concurrent immunosuppressant (IST) therapy, and Study BN40898 was a 
randomized (1:1 ratio), placebo-controlled trial in 83 patients (76 adults and 
7 adolescents, aged 12 to ≤ 17 years) using concurrent IST.  All patients in Study 
BN40898 were receiving either concurrent azathioprine (34.9%), OCS (44.6%), or 
mycophenolate mofetil (14.5%) during the trial.  Five adolescent patients received a 
combination of azathioprine or mycophenolate mofetil with corticosteroids.  Meaningful 
and comparable efficacy based on relative risk of experiencing relapse was 
demonstrated in both Phase III studies in aquaporin-4 (AQP4) IgG−seropositive patients.  
The relative risk of experiencing an adjudicated relapse in AQP4-IgG−seropositive 
patients was reduced by 79% in Study BN40898 (N = 55) and by 74% in Study BN40900 
(N = 64).  Satralizumab 120 mg every 4 weeks (Q4W) given as monotherapy or in 
combination with IST was safe and well tolerated by patients with NMOSD.  
Results from the Phase III clinical Studies BN40898 and BN40900 confirmed the 
adequacy of the selected dosing regimen (doses of 120 mg administered at Weeks 0, 2, 
and 4 followed by 120 mg Q4W).  At this dose, the effective drug-elimination half-life is 
approximately 30 days based on data pooled between the two studies, supporting the 
recommended maintenance dosing interval of Q4W.  Robust sIL-6R stabilization and 
increases in IL-6 levels were seen, indicative of target engagement.  The median 
predicted occupancy at the sIL-6R and mIL-6R in patients with NMOSD was maintained 
at > 95% throughout the dose interval, and for the entire duration of therapy (Week 180 
and Week 204 in Studies BN40898 and BN40900, respectively).   
In Studies BN40898 and BN40900, anti-drug antibodies (ADAs) were observed in 41% 
and 71% of patients receiving satralizumab in the double-blind (DB) period, respectively.  
Apparent correlations between ADA development and higher body weight and lower 
exposure, were not reflected in clinical outcomes.  Meaningful and comparable efficacy 
was demonstrated in all exposure subgroups and in all body weight groups.   
During the Phase III studies BN40898 and BN40900 in NMOSD, satralizumab 
demonstrated a favorable safety profile.  During the DB period, 63 patients were 
exposed to satralizumab monotherapy and 41 patients were exposed to satralizumab in 
combination with IST (please refer to the Satralizumab Investigator’s Brochure for further 
details).  In the DB period, patient median exposure to satralizumab was approximately 
two years in both studies.  The median exposure to placebo was approximately one 
year.  
Overall, satralizumab was well tolerated by patients with NMOSD.  The safety profile of 
satralizumab in combination with OCS (15 mg of prednisolone equivalent per day), 
azathioprine or mycophenolate mofetil was comparable to satralizumab monotherapy.  


 
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The PK and safety profiles of satralizumab in adolescent patients was comparable to 
those in adult patients with NMOSD. 
The most frequently reported adverse drug reactions were headache, arthralgia and 
injection reactions.  The majority of adverse events were of mild or moderate severity 
and resolved without changes to the study drug.  Injection reactions were reported in 
12.5% of the patients treated with satralizumab (monotherapy or in combination with 
IST) and were predominantly of mild to moderate severity.  The incidence rate of 
infections was not higher in the satralizumab group compared to the  placebo group in 
both the monotherapy study (satralizumab:  99.8 events/100 patient years (PY) [95% CI:  
82.4 to 119.8]; placebo:  162.6 events/100 PY [95% CI:  125.8 to 206.9]) and in the add-
on study (satralizumab + IST:  132.5 events/100 PY [95% CI:  108.2 to 160.5]; 
placebo + IST:  149.6 events/100 PY [95% CI:  120.1 to 184.1].  
Laboratory abnormalities including neutropenia, thrombocytopenia, elevations in liver 
enzymes, and lipid elevations have been reported in patients treated with satralizumab. 
Please refer to the Satralizumab Investigator’s Brochure for details on nonclinical and 
clinical studies 
1.5 
STUDY RATIONALE AND BENEFIT−RISK ASSESSMENT 
Satralizumab is being developed for treatment of gMG, which is a chronic autoimmune 
condition that has substantial impact on day-to-day functioning of patients.   
1.5.1 
Rationale for IL-6 Inhibition as a Therapeutic Mode of Action in 
Generalized Myasthenia Gravis  
IL-6 is a pleiotropic inflammatory cytokine produced by T-cells, monocytes, 
macrophages, and fibroblasts that mediates various functions through the IL-6R 
(Kishimoto 2010; Tanaka and Kishimoto 2012).  It acts as a regulator of B- and T-cell 
functions, induces the differentiation of activated B-cells into antibody-producing plasma 
cells and the production of complement components.  Given the pathological relevance 
of autoantibodies, pro-inflammatory T-cell activity, and complement activation in gMG, 
IL-6 inhibition through satralizumab is expected to dampen immune mechanisms that 
underlie the clinical phenotype of gMG. 
A study in IL-6 knockout mice investigated the role of IL-6 in experimental autoimmune 
myasthenia gravis (EAMG) (Deng et al. 2002).  IL-6 gene knockout (IL-6 −/−) mice in the 
C57BL/6 background were immunized with Torpedo californica AChR and evaluated for 
EAMG.  Only 25% of AChR-immunized IL-6 − / − mice developed clinical EAMG compared 
with 83% of C57BL/6 (wild type) mice.  The AChR-specific lymphocyte proliferative 
response, interferon-γ (IFN-γ), and IL-10 production were suppressed in 
AChR-immunized IL-6 − / − mice.  EAMG resistance in IL-6 − / − mice was associated with a 
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levels.  These data provide direct genetic evidence for a key role of IL-6 in the 
autoimmune response to AChR and in EAMG pathogenesis. 
A study in EAMG-induced and healthy control rats assessed if the equilibrium between 
suppressive regulatory T cells (Treg) and pathogenic T-helper (Th) 17 cells is perturbed 
in the disease and showed that Th17 cell-related genes are upregulated and 
Treg-related genes are downregulated in EAMG.  The shift in favor of Th17 cells in 
EAMG could be reversed by antibodies to IL-6 (Aricha et al. 2011).  Administration of 
anti−IL-6 antibodies cross-reactive to rat IL-6 to myasthenic rats suppressed EAMG 
when treatment was started during the acute or the chronic phase of disease.  
Suppression of EAMG by anti−IL-6 antibodies was accompanied by a decrease in the 
overall rat anti-AChR antibody titers and by a reduced number of B-cells compared with 
control treatment. 
The collaboration between T- and B-cells is thought to be critical in the generation of the 
class-switched, affinity-matured pathogenic autoantibodies in gMG.  Dysregulated 
immune processes involving CD4 + T cells such as Th17 and T-follicular helper cells and 
various B-cell subsets have been implicated in the production of autoantibodies and 
secretion of proinflammatory cytokines.  
Satralizumab has proven to be highly efficacious in NMOSD (Section 1.4), another 
chronic autoimmune disease, which shares several common features with MG.  NMOSD 
and MG are mediated by pathogenic autoantibodies against the AQP4 and proteins at 
the postsynaptic portion of the NMJ (AChR, MuSK, and LRP4), respectively.  In both 
diseases the immunopathogenic mechanisms include the breakdown of tolerance, the 
collaboration of T-cells and B-cells, imbalances in Th1, Th2, Th17, and Treg cells, 
aberrant cytokine and antibody secretion, and complement system activation (Wang and 
Yan 2017).  Evidence of increased IL-6 levels has been reported in the cerebrospinal 
fluid of patients with NMOSD (Uzawa et al. 2009) and in the muscle tissue in patients 
with MG (Maurer et al. 2015).  In addition, a recent comparison of peripheral blood B-cell 
subset ratios and B-cell−related cytokine levels showed that serum IL-6 levels were 
significantly higher in patients with gMG (anti-AChR−seropositive MGFA Grade II−IV) 
compared to healthy controls (Hu et al. 2020).  Serum IL-6 levels were shown to be 
significantly increased in AChR + MG and were correlated with MG disease severity, 
suggesting that IL-6 is involved in the pathogenesis of MG (Uzawa et al. 2021).  
Tocilizumab, a blocker of IL-6 signaling, has been shown to have a beneficial effect in 
2 female patients with moderate and severe AChR + MG and insufficient response to 
rituximab (Jonsson et al. 2017).  Both patientswho had failed at least two 
IST/immunomodulatory therapies, including prednisone and maintenance 
IVIgdisplayed a beneficial response to tocilizumab with lowered Quantitative 
Myasthenia Gravis (QMG) scores and improved muscle strength.  The treatment with 
this IL-6 inhibitor was well tolerated without reported adverse events.  


 
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These data identify IL-6 as an important target for modulation of autoimmune response 
in MG and suggest an IL-6 inhibitor may have a therapeutic benefit for patients with 
gMG. 
1.5.2 
Satralizumab Dose Selection 
The 120 mg Q4W dosing regimen was shown to be safe and efficacious in the Phase III 
NMOSD studies.  As expected for a monoclonal antibody, a clear correlation between 
body weight and exposure was observed, and although most patients achieved near 
maximal IL-6R occupancy throughout the dose interval, those patients with lower 
receptor occupancy (RO) values generally weighed > 100 kg.  
The dosing regimen proposed for this study in gMG is therefore 120 mg Q4W for 
patients ≤ 100 kg, and 180 mg Q4W for patients > 100 kg.  The intention of this dosing 
regimen is to achieve exposures associated with near maximal RO across the body 
weight range in gMG.  PK parameters in adolescent patients with NMOSD were similar 
to those in adult patients, and the predicted exposures resulting from this dosing 
regimen are supported by the existing safety profile established in the Phase III studies 
in adult and adolescent patients with NMOSD. 
Please refer to Section 3.4.1 for further details. 
1.5.3 
Study and Primary Analysis Population  
The analysis considers two analysis populations: the AChR antibody seropositive 
(AChR + ) population and the overall population (OP).  The primary analysis will be 
performed in the AChR + population. Each efficacy analysis for the DB period will be 
conducted on all randomized patients that have completed at least one postbaseline 
Myasthenia Gravis Activities of Daily Living (MG-ADL) assessment (modified intent-to-
treat [mITT] population). 
The pleiotropic role of IL-6 suggests that satralizumab may be efficacious in patients with 
gMG irrespective of antibody type.  AChR and LRP4 antibodies are produced by 
long-lived plasma cells, whereas MuSK IgG4 antibodies are presumably secreted by 
short-lived circulating plasmablasts.  IL-6 is a pro-inflammatory cytokine with pleiotropic 
functions including induction of the differentiation and proliferation of pro-inflammatory 
Th17 cells and plasmablasts, and plasma cell maturation.  Therefore, IL-6 blockade has 
the potential to modulate the immunopathogenic mechanisms of gMG irrespective of 
autoantibody type.   
1.5.4 
Overview of Risks and Safety Measures 
The potential risks associated with satralizumab treatment in patients with gMG are 
based on the clinical experience with satralizumab in ongoing and completed studies in 
NMOSD, as well the safety information from other anti-IL-6R antibodies. An overview of 
the anticipated safety risks for satralizumab is provided below.  Additional details on the 


 
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individual risks are provided in Section 5.1.1 and the Satralizumab Investigator’s 
Brochure. 
• 
Infections:  Treatment with IL-6R inhibitor may increase risk of infections, including 
serious infections.  IL6-R inhibitors suppress acute phase reactions (fever, increase 
in C-reactive protein [CRP], etc.) induced by IL-6, which may delay the detection of 
infection 
• 
Serious hypersensitivity reactions:  Anaphylaxis and hypersensitivity reactions are 
considered a potential risk for all biologic medications, including satralizumab 
  
The following lab abnormalities have been observed in patients treated with 
satralizumab: 
• 
Liver enzyme and bilirubin elevations  
• 
Neutropenia 
• 
Thrombocytopenia 
• 
Elevations in lipid levels 
  
Other laboratory abnormalities including decrease in CRP, fibrinogen and complements 
have been observed in patients treated with satralizumab and are anticipated 
pharmacodynamic (PD) effects.  In addition, blockade of IL-6 signaling by satralizumab 
may result in normalization of CYP450 activity and therefore increases the metabolism 
of CYP450 substrates.  Caution should be exercised in patients receiving CYP450 
substrates, as doses may need to be adjusted. 
In addition to the risks above, the following risks are potential risks for drugs in the same 
class: 
• 
Gastrointestinal (GI) perforation (complication of diverticulitis) 
• 
Malignancies 
• 
Demyelinating disorders 
  
Several measures will be taken to manage these risks and to ensure the safety of 
patients participating in this study: 
• 
Patients who may have an increased safety risk will be excluded from the study (see 
Section 4.1.2.3) 
• 
Regular standard safety evaluations (laboratory measures, physical examinations, 
vital sign measurements and ECG) will be performed throughout the study, with a 
special focus on monitoring the risks that have been previously associated with 
satralizumab or other IL-6R inhibitors (see Section 5.1.1). 
• 
An independent Data Monitoring Committee (iDMC) will perform periodic safety data 
review during the DB period in an unblinded manner and, based on the review, will 
make recommendations on study conduct. 
 


 
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1.5.5 
Benefit−Risk Assessment 
Overall, the benefit−risk profile of investigation of satralizumab in a population of patients 
with gMG is considered favorable based on the following: 
• 
Preclinical evidence of a key role of IL-6 in the autoimmune response to AChR and 
in pathogenesis of EAMG 
• 
Similarities between NMOSD and gMG 
• 
Case reports indicating beneficial effects of IL-6R blockade in patients with gMG 
• 
Satralizumab as monotherapy or as a combination with OCS (15 mg of prednisolone 
equivalent per day), azathioprine, or mycophenolate mofetil was efficacious and well 
tolerated in patients with NMOSD in the Phase III clinical Studies BN40898 and 
BN40900 
 
All necessary measures will be taken to closely monitor the safety of the patients 
enrolled in this study.   
An assessment was conducted to determine whether there is any impact of the 
coronavirus disease 2019 (COVID-19) pandemic on the benefit-risk assessment of this 
study protocol, including, but not limited to, the patient population under study, study 
treatment and/or treatment combination being evaluated.  Based on that assessment, 
the safety monitoring, management guidelines, and the risk mitigation measures 
provided in the study protocol are considered adequate. 
With reference to COVID-19 vaccines, an assessment was conducted to determine 
whether there is any impact of the COVID-19 vaccines on the benefit−risk assessment of 
this study protocol.  General information for vaccines provided in Sections 4.4.5 and 
5.1.1.1 are also applicable to COVID-19 vaccines. 
Based on this assessment, no additional risk mitigation measures related to COVID-19 
vaccination are proposed at this time.  The recommendations and management plan 
provided in the study protocol are considered adequate.  
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics 
of satralizumab compared with placebo in patients with gMG on stable background 
therapy.  In addition, the study will assess the long-term safety and efficacy of 
satralizumab during the open-label extension (OLE) period.   
In this protocol, "study treatment" refers to satralizumab or placebo (assigned in addition 
to background therapy). 
Specific objectives and corresponding endpoints of the DB period and the OLE are 
outlined in Table 2 and Table 3, respectively.  The hierarchy of secondary endpoints is 
listed in Section 6.4.3.  


 
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Table 2 
Objectives and Endpoints during the Double-Blind Period 
Primary Efficacy Objective 
Corresponding Endpoint 
• To evaluate the efficacy of 
satralizumab versus placebo on 
function in daily life in the AChR + 
population  
• Mean change from baseline in total MG-ADL score 
at Week 24 
Secondary Efficacy Objectives 
Corresponding Endpoints 
• To evaluate the efficacy of 
satralizumab versus placebo on 
function in daily life in the OP  
• Mean change from baseline in total MG-ADL score 
at Week 24 
• To evaluate the efficacy of 
satralizumab versus placebo in the 
AChR + population and OP on: 
 
 
– 
Function in daily life 
• 
Percentage of patients with a ≥ 2-point reduction 
from baseline in total MG-ADL score at Week 24a 
– 
QMG, QoL, and Fatigue 
• 
Mean change from baseline in QMG score, 
MG-QOL 15r total score and Neuro−QoL Fatigue 
Subscale total score at Week 24  
• 
Percentage of patients with a ≥ 3-point reduction 
from baseline in QMG score at Week 24a 
– 
Clinical status 
• 
Mean change from baseline in total MGC score at 
Week 24 
• 
Percentage of patients with a ≥ 3-point reduction 
from baseline in total MGC score at Week 24 a 
– 
Disease severity 
• 
Proportion of patients: 
– 
Who have achieved minimal disease 
manifestation (total MG-ADL score of 0 or 1) 
at Week 24 a 
– 
With at least one gMG-related exacerbation 
between baseline and Week 24 
– 
Receiving rescue therapy between baseline 
and Week 24 
• 
Annualized rate of gMG-related exacerbations 
• To evaluate the durability of the 
efficacy of satralizumab versus 
placebo in the AChR + population and 
the OP 
• 
Duration (average number of consecutive months) 
of meaningful improvement, defined as ≥ 2-point 
reduction from baseline in total MG-ADL score a 
AChR = acetylcholine receptor; AChR +  = AChR-antibody seropositive (patients/population); 
ADA = anti-drug antibody; AUC = area under the concentration−time curve; CL/F = apparent 
clearance; Ctrough = trough concentration; gMG = generalized myasthenia gravis; IL-6 = interleukin-
6; MG=Myasthenia gravis; MG-ADL = Myasthenia Gravis Activities of Daily Living; 
MGC = Myasthenia Gravis Composite; MG-QOL 15r = Myasthenia Gravis Quality of Life 15 
Scale (revised); NCI CTCAE v5.0 = National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 5.0; Neuro−QoL = Quality of Life in Neurological Disorders; 
OP = overall population; PD = pharmacodynamic; PK = pharmacokinetic; QMG = Quantitative 
Myasthenia Gravis; QoL = quality of life; sIL-6R = soluble interleukin-6 receptor; V/F = apparent 
volume of distribution. 
a  
Patients who receive rescue therapy will be considered non-responders 
 
 


 
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Table 2 
Objectives and Endpoints during the Double-Blind Period (cont.) 
Exploratory Efficacy Objectives 
Corresponding Endpoints 
• To evaluate the efficacy of 
satralizumab versus placebo in the 
AChR + population and OP on: 
 
 
– 
Severity of gMG exacerbations 
 
• Severity of gMG-related exacerbations 
• Proportion of patients with at least one gMG-related 
exacerbation leading to hospitalization between 
baseline and Week 24 
• Annualized rate of gMG-related exacerbations 
leading to hospitalization 
– 
Time-to-event 
• Time to disease improvement as measured by: 
– 
 ≥ 2-point reduction in total MG-ADL score or 
– 
 ≥ 3-point reduction in QMG score or 
– 
 ≥ 3-point reduction in total MGC score or 
– 
MG-ADL score of 0 or 1 
• Time to disease worsening as measured by the 
time from baseline to: 
– 
Start of rescue therapy 
– 
gMG-related exacerbation 
– 
Hospitalizations related to gMG exacerbation 
– 
QoL 
• Mean change from baseline to Week 24 in EuroQoL 
EQ-5D-5L Health Utility Index score 
Safety Objective 
Corresponding Endpoints 
• To evaluate the safety of 
satralizumab versus placebo 
• Incidence and severity of adverse events, with 
severity determined according to NCI CTCAE v5.0 
grading 
• Change from baseline in targeted vital signs, ECG 
results, physical examination findings, targeted 
clinical laboratory test results, and suicidality 
Pharmacodynamic Objective 
Corresponding Endpoint 
• To confirm target engagement and 
pathway inhibition in response to 
satralizumab 
• Absolute values and change from baseline in serum 
levels of biomarkers IL-6 and sIL-6R 
AChR = acetylcholine receptor; AChR +  = AChR-antibody seropositive (patients/population); 
ADA = anti-drug antibody; AUC = area under the concentration−time curve; CL/F = apparent 
clearance; Ctrough = trough concentration; gMG = generalized myasthenia gravis; 
IL-6 = interleukin-6; MG-ADL = Myasthenia Gravis Activities of Daily Living; MGC = Myasthenia 
Gravis Composite; MG-QOL 15r = Myasthenia Gravis Quality of Life 15 Scale (revised); NCI 
CTCAE v5.0 = National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 5.0; Neuro−QoL = Quality of Life in Neurological Disorders; OP = overall population; 
PD = pharmacodynamic; PK = pharmacokinetic; QMG = Quantitative Myasthenia Gravis; 
QoL = quality of life; sIL-6R = soluble interleukin-6 receptor; V/F = apparent volume of 
distribution. 
a  
Patients who receive rescue therapy will be considered non-responders 
 
 


 
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Table 2 
Objectives and Endpoints during the Double-Blind Period (cont.) 
Pharmacokinetic Objective 
Corresponding Endpoints 
• To investigate the pharmacokinetics of 
satralizumab by evaluating plasma 
exposure over 24 weeks 
 
• Serum concentrations of satralizumab (mean 
and SD of Ctrough) at specified timepoints 
• Estimates of primary PK parameters (e.g., CL/F 
and V/F) and secondary PK parameters 
(e.g., AUC) derived using population−PK 
modeling 
Exploratory Pharmacokinetic Objective 
Corresponding Endpoints 
• To evaluate potential relationships 
between drug exposure and the efficacy 
and safety of satralizumab 
• Relationship between selected covariates and 
exposure to satralizumab 
• Relationship between serum concentration or PK 
parameters for satralizumab and efficacy 
endpoints, PD biomarkers and safety endpoints 
Immunogenicity Objective 
Corresponding Endpoint 
• To evaluate the immune response to 
satralizumab  
• Prevalence of ADAs at baseline and incidence of 
ADAs during the study 
Exploratory Immunogenicity Objective 
Corresponding Endpoint 
• To evaluate potential effects of ADAs on 
efficacy, biomarker, safety, and PK 
endpoints 
• Relationship between ADA status and efficacy, 
biomarker, safety or PK endpoints 
Exploratory Biomarker Objective 
Corresponding Endpoint 
• To identify and/or evaluate biomarkers 
that are predictive of response to 
satralizumab, can provide evidence of 
satralizumab activity, or can increase the 
knowledge and understanding of 
disease biology 
• Relationship between biomarkers in blood and 
efficacy endpoints. 
AChR = acetylcholine receptor; AChR +  = AChR-antibody seropositive (patients/population); 
ADA = anti-drug antibody; AUC = area under the concentration−time curve; CL/F = apparent 
clearance; Ctrough = trough concentration; gMG = generalized myasthenia gravis; 
IL-6 = interleukin-6; MG-ADL = Myasthenia Gravis Activities of Daily Living; MGC = Myasthenia 
Gravis Composite; MG-QOL 15r = Myasthenia Gravis Quality of Life 15 Scale (revised); NCI 
CTCAE v5.0 = National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 5.0; Neuro−QoL = Quality of Life in Neurological Disorders; OP = overall population; 
PD = pharmacodynamic; PK = pharmacokinetic; QMG = Quantitative Myasthenia Gravis; 
QoL = quality of life; sIL-6R = soluble interleukin-6 receptor; V/F = apparent volume of 
distribution. 
a  
Patients who receive rescue therapy will be considered non-responders 
 
 


 
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Table 3 
Objectives and Endpoints during the Open-Label Extension 
Period 
Safety Objective 
Corresponding Endpoints 
• To evaluate the long-term safety and 
tolerability of satralizumab  
• Incidence and severity of adverse events, with 
severity determined according to NCI CTCAE v5.0 
grading 
• Change from baseline in targeted vital signs, ECG 
results, physical examination findings, targeted clinical 
laboratory test results, and suicidality  
Efficacy Objectives 
Corresponding Endpoints 
• To assess the efficacy of 
satralizumab in the AChR + 
population and OP  
• Mean change from active treatment baseline in: 
– 
MG-ADL total score 
– 
QMG score 
– 
MGC score 
– 
MG-QOL 15r score 
• Percentage of responders a based on:  
– 
 ≥ 2-point reduction in total MG-ADL score or 
– 
 ≥ 3-point reduction in QMG score or 
– 
 ≥ 3-point reduction in total MGC score 
• Proportion of time and duration that patients show a 
meaningful improvement, defined as a ≥ 2-point 
reduction from active treatment baseline in total 
MG-ADL score 
• Number and severity of gMG-related exacerbations  
• To assess the effect of satralizumab 
on steroid/IST/AChEI dose 
modification in the AChR + population 
and OP  
• The proportion of patients who maintain clinical 
response without increase in symptomatic medication 
dose and are able to reduce corticosteroid dose or 
withdraw from corticosteroid or IST during the OLE 
Exploratory Efficacy Objective 
Corresponding Endpoint 
• To evaluate the efficacy of 
satralizumab versus placebo on 
additional QoL  
• Mean change from baseline in Neuro−QoL Fatigue 
Subscale total score and EuroQoL EQ−5D−5L Health 
Utility Index score 
AChEI = acetylcholinesterase inhibitor; AChR = acetylcholine receptor; AChR +  = AChR-antibody 
seropositive (patients/population); ADA = anti-drug antibody; AUC = area under the 
concentration−time curve; CL/F = apparent clearance; Ctrough = trough concentration; 
IL-6 = interleukin-6; IST = immunosuppressant; MG-ADL = Myasthenia Gravis Activities of Daily 
Living; MG-QOL 15r = Myasthenia Gravis Quality of Life 15 Scale (revised); NCI CTCAE 
v5.0 = National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0; 
Neuro−QoL = Quality of Life in Neurological Disorders; OLE = open-label extension; OP = overall 
population; PD = pharmacodynamic; PK = pharmacokinetic; QMG = Quantitative Myasthenia 
Gravis; QoL = quality of life; sIL-6R = soluble interleukin-6 receptor; V/F = apparent volume of 
distribution. 


 
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Table 3 
Objectives and Endpoints during the Open-Label Extension 
Period (cont.) 
Pharmacokinetic Objective 
Corresponding Endpoints 
• To investigate the pharmacokinetics 
of satralizumab by evaluating plasma 
exposure in the OLE 
• Serum concentrations of satralizumab (mean and SD 
of Ctrough)  
• Estimates of primary PK parameters (e.g., CL/F and 
V/F) and secondary PK parameters (e.g., AUC) 
derived using population−PK modeling 
Immunogenicity Objective 
Corresponding Endpoint 
• To evaluate the immune response to 
satralizumab 
• Prevalence of ADAs at baseline and incidence of 
ADAs during the OLE 
Pharmacodynamic Objective 
Corresponding Endpoint 
• To confirm target engagement and 
pathway inhibition in response to 
satralizumab 
• Absolute values and change from baseline in serum 
levels of PD biomarkers IL-6 and sIL-6R 
Exploratory Biomarker Objective 
Corresponding Endpoint 
• To identify and/or evaluate 
biomarkers that can provide evidence 
of satralizumab activity, can aid in 
characterizing the mechanism of 
action, or can increase the 
knowledge and understanding of 
disease biology 
• Relationship between biomarkers in blood and 
efficacy endpoints 
AChEI = acetylcholinesterase inhibitor; AChR = acetylcholine receptor; AChR +  = AChR-antibody 
seropositive (patients/population); ADA = anti-drug antibody; AUC = area under the 
concentration−time curve; CL/F = apparent clearance; Ctrough = trough concentration; 
IL-6 = interleukin-6; IST = immunosuppressant; MG-ADL = Myasthenia Gravis Activities of Daily 
Living; MG-QOL 15r = Myasthenia Gravis Quality of Life 15 Scale (revised); NCI CTCAE 
v5.0 = National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0; 
Neuro−QoL = Quality of Life in Neurological Disorders; OLE = open-label extension; OP = overall 
population; PD = pharmacodynamic; PK = pharmacokinetic; QMG = Quantitative Myasthenia 
Gravis; QoL = quality of life; sIL-6R = soluble interleukin-6 receptor; V/F = apparent volume of 
distribution. 
  
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This Phase III, randomized, DB, placebo -controlled, multicenter study is designed to 
evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of satralizumab 
compared with placebo as add-on therapy to standard of care (SOC) for the treatment of 
gMG.  The study will include a 28-day screening period, a 24-week DB treatment period, 
and approximately 2-year OLE period after the last patient initiates open-label treatment.  
As of global protocol Version 5, adolescents will be enrolled directly into the OLE period after 
completion of the screening period (see Section 3.1.3 for details).  
During the screening period, patients’ eligibility for study participation will be evaluated.  
The 28-day screening period may be extended, in exceptional circumstances, but cannot 
exceed 42 days.  A complete blood count (e.g., white blood cells, neutrophils, and PK 


 
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platelets) and liver test (ALT, AST and bilirubin) must be within 28 days prior to baseline.  
Figure 1 presents an overview of the study design.  The schedule of activities is provided 
in Appendix 1 and Appendix 2. 
Figure 1 Study Design 
 
DB = double-blind; LA = last assessment; LO = last observation; OLE = open-label extension; 
PK = pharmacokinetic; R = randomization; SOC = standard of care 
a Week 0 baseline assessments will be collected pre-dose. 
b Week 0 of OLE period coincides with Week 24 of DB period. 
c Patients treated with active drug in DB period will be administered a placebo dose at Week 2 
of the OLE period to maintain blinding of treatment assignment in the DB period. 
d The length of OLE period is approximately 2 years after the last patient enters OLE or 
approximately 4 years after the first patient enters the OLE.  Further details are provided in 
Section 3.2.   
e Adolescent patients will be enrolled directly into the OLE period (after completion of screening; see 
Section 3.1.3) and will receive open-label satralizumab SC loading doses at Weeks 0, 2, and 4 in the 
OLE, followed by maintenance doses Q4W thereafter during the OLE period.   
 
3.1.1 
Double-Blind Period 
During the DB treatment period, patients will be randomized in a 1:1 ratio to receive 
either 120 mg or 180 mg satralizumab, as determined on the basis of body weight 
(Group A), or placebo (Group B) for 24 weeks (see Figure 1).  Randomization will be 
stratified based on the following: 
• 
Baseline SOC treatment:  AChEI monotherapy and/or an OCS versus a steroid-
sparing IST monotherapy or a combination of a steroid-sparing IST with other 
treatments (an AChEI and/or an OCS) 
• 
Autoantibody type:  AChR antibody-positive versus AChR antibody-negative 
(includes MuSK antibody- or LRP4 antibody-positive) 
• 
Region:  North America versus Europe versus rest of world. 
 
Blinded study drug will be administered subcutaneously to patients at Weeks 0, 2, 4, and 
Q4W thereafter until the end of the DB period in addition to background treatments at a 
stable dose (see Section 4.1.1). 


 
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An interim analysis of pharmacokinetic (PK) data was performed when approximately 
30 patients completed a minimum of 8 weeks of DB treatment (including approximately 
15 patients from the satralizumab group).  The purpose of the interim analysis was to 
confirm that the achieved exposure to satralizumab (and predicted RO) was within the 
target range. The background therapies permitted in this study are AChEI alone or the 
following therapies (with or without AChEI): OCSs, one IST, and an OCS in combination 
with one IST.  Patients should remain on stable dose of background therapy throughout 
the DB period and until Week 12 of the OLE, with the exception of the last AChEI dose 
taken prior to in-clinic visits.  AChEIs should not be taken for 10 hours prior to 
completion of efficacy assessments at each study visit (except screening visit), including 
QMG and MGC testing, if medically safe to do so.  The permitted IST drugs are 
azathioprine, mycophenolate mofetil, tacrolimus, and cyclosporin A (see Section 4.4.1). 
Following the interim analysis of PK data, the iDMC recommended that the initially proposed 
doses (120 mg ≤ 100 kg > 180 mg) should be retained and that the Sponsor should continue the 
study without dose modification. Further details on the interim analysis of PK data are provided 
in Section 6.11.2. 
3.1.2 
Independent Data Monitoring Committee 
An iDMC will be used during the DB period and until the database lock for the primary 
analysis.  The iDMC will perform periodic (approximately every 3 months) unblinded 
safety reviews and make recommendations on trial continuation or modification.  The 
iDMC was involved in the interim PK analysis as detailed in Section 6.11.2.  All 
summaries and analyses will be prepared by the independent Data Coordinating Center 
(iDCC) and presented by treatment group for the iDMC’s review.  Members of the iDMC 
and iDCC will be external to the Sponsor and the study team and will follow a charter 
that outlines their roles and responsibilities.  The Sponsor will remain blinded.  
Interactions between the iDMC and Sponsor will be carried out as specified in the iDMC 
Charter.  
3.1.3 
Adolescent Patients 
As of global protocol Version 5, all adolescent patients enrolled into the study will directly enter 
the OLE period after completion of screening (see Figure 1). 
Adolescent patients enrolled directly into the OLE will remain on stable background therapy 
until Week 24 of the OLE (Section 3.4.8). 
Adolescent patients enrolled through previous versions of the protocol (prior to global protocol 
Version 5) will continue in the study as follows: 
• 
Adolescent patients randomized in the DB period prior to the randomization of the last adult 
patient in the DB period will continue on randomized, DB study drug for 24 weeks and can 
then enter the OLE period (after completion of the DB period) to start open-label 
satralizumab, remaining on stable background therapy until Week 12 OLE 


 
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• 
Adolescent patients randomized in the DB period after the randomization of the last adult 
patient in the DB period will enter the OLE period (without completion of DB period) to 
start open-label satralizumab, remaining on stable background therapy until Week 12 OLE 
 
3.1.4 
Open-Label Extension Period  
Patients who complete the DB period can enter the OLE period.  As of global protocol 
Version 5, adolescent patients will directly enter the OLE period after completion of screening 
(see Section 3.1.3). Patients who experience a clinical exacerbation that requires rescue 
therapy during the DB period may continue in the study until the end of the DB period 
and can enter the OLE period upon completion of treatment and assessments in the DB 
period. 
For adult and adolescent patients who complete the DB period, the final visit of the DB period 
coincides with the Week 0 visit of the OLE period and is, therefore, considered the OLE 
baseline.  The assessments performed at Week 24 of the DB period will be used as the 
active treatment baseline for the patients who receive placebo during the DB period and 
as the OLE baseline for patients who receive satralizumab during the DB period.  
Upon completion of the Week 24 assessments all patients will receive open-label 
treatment with satralizumab. 
In the OLE period, all patients will receive open-label treatment with 120 mg or 180 mg 
satralizumab, as determined based on body weight.  Patients who receive placebo 
during the DB period will receive satralizumab SC loading doses at Weeks 0, 2, and 4 in 
the OLE, followed by maintenance doses Q4W thereafter during the OLE period.  
Patients who receive active treatment during the DB period will continue receiving SC 
satralizumab Q4W during the OLE period but will receive an additional placebo SC 
injection at Week 2 to maintain blinding to DB treatment assignment.   
For adult and adolescent patients who first enter the study randomized in the DB period, to 
ensure a period of satralizumab treatment stability in patients previously treated with 
placebo, dose reduction (taper) of background therapy (OCS, IST, and/or AChEIs) can 
be started at or after Week 12 of the OLE period at the discretion of the investigator.  
Adolescent patients who first enter the study in the OLE period will receive satralizumab SC 
loading doses at Weeks 0, 2, and 4 in the OLE, followed by maintenance doses Q4W thereafter.   
Further details on adolescent patients in the OLE period are provided in Sections 3.1.3 and 3.4.8.  
3.1.5 
Unscheduled Visits and Rescue Therapy 
Unscheduled visits can be performed at the discretion of the treating neurologist. 
If a suspected gMG exacerbation occurs during the study, the participant should return 
to the study site and undergo the following evaluations before or immediately after any 
administration of the rescue therapy:  MG-ADL, QMG, Myasthenia Gravis Composite 


 
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(MGC), and Myasthenia Gravis Quality of Life 15 Scale (revised) (MG-QOL 15r).  
Additional assessments, such as hematology, chemistry, and urinalysis, will be 
performed if an infection or a metabolic disturbance is suspected to be contributing to 
the clinical presentation necessitating the unscheduled visit. 
MG exacerbation requiring rescue therapy is defined as one of the following: 
• 
MG crisis (Sanders et al. 2016) 
• 
Substantial symptomatic worsening that requires immediate therapy 
• 
Health in jeopardy if rescue therapy is not given, as determined by the treating 
physician. 
 
Rescue therapy includes IVIg and PE with or without high -dose corticosteroids as 
outlined in Section 4.3.3.  The choice of rescue therapy will be determined by the 
investigator on the basis of his or her overall clinical assessment. 
Study drug administration will be continued as scheduled, concurrently with rescue 
therapy, unless the investigator considers it necessary to interrupt or discontinue study 
treatment (see Section 5.1.4).  Patients who receive PE as rescue therapy will receive 
loading doses of study drug as soon as possible post -PE.  Site staff should consult the 
Medical Monitor as to how to schedule dosing in such circumstances. 
Patients who receive rescue therapy during the DB period may receive OLE 
satralizumab after completion of the DB period.  
3.1.6 
Safety Follow-Up 
Patients who discontinue study treatment during the DB period for any reason should 
continue with the remaining assessments defined in the protocol.  All efforts will be made 
to minimize missing data.  However, patients who are unwilling to return to the clinic for 
all assessments will be asked to complete an end of treatment (EOT) visit within 
4 weeks and a safety follow-up (SFU) visit 12 weeks after the final dose of study drug. 
Patients who discontinue study treatment during the OLE period will be asked to 
complete an EOT visit within 4 weeks and a SFU visit 12 weeks after the final dose of 
study drug.  Patients who decide to continue treatment with satralizumab outside of this 
study will have to complete the EOT visit, but they will not have to complete the SFU or 
end of study visit.  
For patients aged ≥ 12 to < 18 years at the time of informed consent, who withdraw from 
the study or complete the extension period, an additional follow-up assessment will be 
conducted at 24 weeks after the final dose of study drug. 


 
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3.1.7 
Number of Patients and Study Regions 
The study will be conducted at approximately 120 sites in about 19 countries, including 
but not limited to, North America, Europe, Latin America, and Asia. 
This study will initially enroll approximately 160 AChR + patients, and up to 
25 MuSK + /LRP4 + patients, including adults and adolescents aged ≥ 12 years to < 18 years 
old with gMG across all sites.  Only adult patients aged ≥ 18 years old will be included at 
participating sites in France.   
After completion of the global enrollment phase, additional adolescent patients may be 
enrolled in the OLE period.  
3.1.8 
Patient Input into Study Design 
Adolescent patients diagnosed with MG and their caregivers from different organizations within 
the patient community were interviewed and asked to provide feedback on the following aspects of 
the study:  
• 
Study design, endpoints, inclusion and exclusion criteria activities, and patient-reported 
outcomes (PROs) 
• 
Recruitment and retention (e.g., inclusivity of underserved patient communities, potential 
recruitment challenges, possible retention challenges). 
 
This feedback was taken into consideration when developing the protocol.  
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when the last patient, last visit (LPLV), 
occurs (i.e., last patient in the global study phase) or the date at which the last data point 
required for statistical analysis or SFU is received from the last patient (global enrollment 
phase), whichever occurs later.  The LPLV is expected to occur approximately 2 years 
after the last patient in the global study phase enters the OLE period.  
For adolescent patients enrolled directly in the OLE, the LPLV is expected to occur 
approximately 2.5 years after the last adolescent patient is enrolled in the adolescent OLE. 
The end of the DB study period is expected to occur 24 weeks after the last patient in 
the global study phase is enrolled.  The duration of the OLE period is estimated to be 
approximately 2 years from the last global study phase patient entering the OLE and 
approximately 4 years from the first patient entering this phase.  The total length of study, 
from screening of the first patient to the end of the adolescent OLE period, is estimated to be 
approximately 6 years.   


 
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3.3 
DURATION OF PARTICIPATION 
The total duration of study participation for each individual enrolled in the DB period is expected 
to be approximately 2.5−4 years, depending on when the participant enters the OLE and the 
duration of time the participant spends in this period. 
The total duration of study participation for adolescent patients enrolled directly in the OLE is 
expected to be approximately 2−3.5 years, according to the estimated recruitment timelines. 
3.4 
RATIONALE FOR STUDY DESIGN 
3.4.1 
Rationale for Satralizumab Dose and Schedule 
Weight-tiered dosing via SC injection will be used in this study for the investigation of 
efficacy and safety of satralizumab in gMG as shown in Table 4.  
Table 4 
Dosing Regimen for Investigation in Phase III Study of 
Satralizumab for the Treatment of Generalized Myasthenia Gravis 
Body Weight at Baseline a 
Dose and Regimen 
 ≤ 100 kg 
120 mg administered at Weeks 0, 2, 4, and Q4W thereafter as 
a SC injection 
 > 100 kg 
180 mg administered at Weeks 0, 2, 4, and Q4W thereafter as 
a SC injection 
Q4W = every 4 weeks. 
a Recommendations in case of changes in body weight in an individual patient would result in a 
different dosing band are given in Table 6.  
  
The dose regimen is based on a combination of sources of information, including: 
• 
PK, PD, and safety data for satralizumab for the initial development in NMOSD 
• 
Consideration of differences in population demographics, particularly the greater 
incidence of males in the gMG population compared to NMOSD, resulting in greater 
representation of higher body weights. 
 
The 120-mg fixed dose regimen investigated in the Phase III studies in NMOSD was 
associated with high predicted median trough receptor occupancy (≥ 95%) at 
steady-state (ROtr,ss) values in most patients, and was shown to be safe and efficacious 
in all body weight groups.  The few patients with predicted ROtr,ss values < 80% generally 
had baseline body weights > 100 kg. 
Real-world data from a large U.S. emergency room-based dataset of 58,860 patients 
having an MG code suggest that approximately 30% of patients in this population may 
have body weights > 100 kg.  Exposure similar to that in NMOSD is expected to be 
effective also in gMG, and therefore the Sponsor has performed simulations using the 
existing population-PK (pop PK) model, to estimate the dose required to achieve the 
same near-maximal ROtr,ss values achieved in patients with NMOSD throughout the 
dose interval for patients across the expected gMG body weight range.   




 
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[67.5 to 124.1]).  PK simulation has therefore been used to explore potentially useful 
regimens in the case that CL in the gMG population is more representative of that 
observed in HV.  The simulations presented in Figure 3 indicate that if that is the case, a 
dosing regimen of 180 mg and 240 mg for patients ≤ 100 kg and > 100 kg, respectively, 
would be expected to maintain the target level of RO across the body weight ranges.  
Provision is therefore made to adapt the dose to this higher dosing regimen if CL values 
in gMG are found to be reflective of those in HV.   
Figure 3 Dependencies of Steady-State Ctrough and Receptor Occupancy 
on Body Weight following 180-mg Q4W Dosing (Body Weight 
Range:  40−100 kg), and 240-mg Q4W Dosing (Body Weight 
Range:  100−160 kg) 
 
Ctrough = steady-state trough concentration; RO = receptor occupancy. 
  
PK simulations will be used as part of the interim PK analysis to either confirm that the 
initially proposed doses achieve target exposures, or that the dose should be adapted to 
180/240 mg regimen.  In either case, the chosen dosing regimen will be associated with 
exposures that do not significantly exceed the existing exposure−safety coverage. 
3.4.2 
Rationale for Patient Population  
3.4.2.1 
Rationale for Choice of Disease Severity and Residual Disease 
Symptoms  
This study will investigate the efficacy and safety of satralizumab in patients with 
generalized MG Class II, III, or IV1 disease according to the MGFA classification system 
(see Appendix 14).  Patients with MGFA Class V MG will be excluded from the study 
due to the severity and instability of the disease. 
This Phase III study will enroll patients who are receiving a stable SOC treatment with 
suboptimal disease control, irrespective of their prior exposure and response to 
treatment with ISTs, including those who are newly diagnosed or treatment refractory 
(see Section 4.5.3 for definition).  The aim of the study is to recruit a representative and 
generalizable population across the disease severities and treatment histories. 
                                              
1 Patients with MG Class IV at participating sites in France are excluded from the study.  


 
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The residual disease symptoms are defined by having a total score of ≥ 5 on the 
MG-ADL at screening with more than 50% of this score attributed to non-ocular items.  
This criterion was selected to allow for enrollment of gMG patients with sub-optimal 
disease control who may benefit from additional therapy. 
3.4.2.2 
Autoantibody Types and Diagnosis 
The patients must be positive for anti-AChR, anti-MuSK or anti-LRP4 autoantibodies.  
The majority of patients with gMG have detectable antibodies against AChR (~85%), 
MuSK (~7%) or LRP4 (~ 3%) (Gilhus et al. 2019).  Therefore, inclusion of all three 
serotypes allows for inclusion of the majority of patients with gMG.  The study is 
expected to enroll approximately 80% AChR + patients.  
3.4.2.3 
Rationale for Inclusion of Adolescent Patients 
Clinical phenotypes in JMG and especially in post-pubertal patients are similar to adults.  
The main types of treatment for gMG are symptomatic treatment using AChEIs, 
immunosuppressive and immunomodulatory therapies, and thymectomy, which are also 
being used for treatment of juvenile gMG. 
This Phase III study requires patients to be reliable witnesses in terms of assessment of 
disability and general health.  Adolescents are considered capable of cooperating with 
trial procedures without invalidating study results. 
Satralizumab has been studied in 9 adolescent patients with NMOSD aged 12 to < 18 
years (6 out of 9 patients aged < 17 years) of age at the time of informed consent (mean 
age 15 years), of whom 7 were randomized in BN40898 prior to the clinical cut-off date 
of the Clinical Study Report (CSR).  The safety profile of satralizumab in these pediatric 
patients with NMOSD (12 to < 18 years of age) was generally consistent with the profile 
observed in the adult population.  All adverse events reported in adolescent patients 
were of mild or moderate severity and resolved.  None of the adolescent patients 
discontinued the study due to an adverse event.  Data obtained in patients with NMOSD 
patients aged 12 to < 18 years who received the adult dosing regimen (120 mg Q4W) 
show that popPK parameters for satralizumab are not significantly different from those in 
the adult population.  
There is precedent for the use of an anti−IL-6R monoclonal antibody to treat pediatric 
patients, with and without concomitant immunosuppressant therapies.  Tocilizumab is 
licensed for the treatment of systemic juvenile idiopathic arthritis and polyarticular 
juvenile idiopathic arthritis internationally and also for the treatment of Castleman's 
disease in Japan.  The safety profile in clinical trials (approximately 519 pediatric 
patients < 18 years) and post-marketing setting (over 7500 pediatric patients) has been 
consistent with that in adults, and there have been no specific safety concerns identified 
in pediatric patients treated with tocilizumab.   
Only adult patients aged  ≥  18 years old will be included at participating sites in France.   


 
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3.4.3 
Rationale for Choice of Background Treatment 
Patients on a stable dose of background therapy will be enrolled.  The background SOC 
therapies permitted in the proposed study are:   
• 
AChEI 
• 
OCS 
• 
One IST  
• 
OCS in combination with one IST 
 
Use of AChEI is permitted as monotherapy or concomitant treatment for patients on a 
stable dose with OCS, one IST, and OCS in combination with one IST.  For detailed 
requirements on background therapy stable dose please refer to Section 4.4.1. 
The combination treatment regimen of ISTs and/or OCS was chosen on the basis of 
being the most common treatment choice for gMG worldwide and in accordance with the 
international consensus guidance for management of MG (Sanders et al. 2016).  
3.4.4 
Rationale for Control Group  
In this study placebo will be used as comparator to provide objective evidence of safety 
and efficacy data from patients exposed to the experimental therapy.  Use of placebo will 
be in addition to SOC background therapy to avoid withholding of established treatment. 
3.4.5 
Rationale for Primary Outcome Measure:  Myasthenia Gravis 
Activities of Daily Living  
The primary objective for this study is to compare the efficacy of satralizumab added to 
SOC versus placebo added to SOC using the MG-ADL as a primary outcome measure.   
The MG-ADL was developed by Wolfe and colleagues (1999) to assess the degree of 
gMG symptoms (six items:  diplopia, ptosis, difficulties with chewing, swallowing, talking, 
and respiratory problems) and functional limitations in carrying out activities of daily 
living (two items:  ability to brush teeth or comb hair and impairment in the ability to arise 
from a chair) that have been shown to be present and clinically relevant in gMG patients.  
Each of the eight items is ranked on a 0−3 scale yielding a total score that ranges from 0 
to 24, with higher scores indicating greater disease severity (see Appendix 6).  The 
items of the MG-ADL were all derived from the original 13-item symptom list that 
comprises the clinician-rated QMG scale. 
The psychometric properties of the MG-ADL have been characterized.  Construct validity 
has been demonstrated by showing correlations with the QMG (r=0.58; 
Wolfe et al. 1999), MGC measure (r=0.85), and the MG-QOL 15r measure (r=0.76) 
(Muppidi et al. 2011).  Test−retest reliability was determined in a small sample (n = 26) of 
patients queried on two repeated assessments separated by 2−4 days and showed a 
high degree of reproducibility (r = 0.94) (Muppidi et al. 2011).  


 
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The importance of patient feedback given the fluctuating nature of the disease combined 
with the established psychometric properties, including good content validity associated 
with patients’ functioning in daily life, renders MG-ADL an appropriate primary outcome 
measure.  
This scale has been commonly used as primary objective in the recently completed 
studies of eculizumab (Howard et al. 2017), efgartigimod (Howard et al. 2021), 
rozanolixizumab (Bril et al. 2023), zilucoplan (Howard et al. 2023), ravulizumab (Vu et 
al. 2022), and amifampridine phosphate (NCT03304054) for gMG. 
3.4.6 
Rationale for Secondary Outcome Measures 
The QMG, MG-QOL15r, NeuroQOL-Fatigue scale, and the MGC have been selected as 
secondary endpoints in order to compare the efficacy of satralizumab added to SOC 
versus placebo added to SOC. 
The QMG is a 13-item assessment of gMG symptom severity based on clinical 
examination (Tindall et al. 1987).  It has been used in clinical trials since 1983, when it 
was first developed to study the relationship between AChR-Ab binding and disease 
severity (Besinger et al. 1983).  More recently, the QMG has been used as a key 
secondary efficacy outcome measure in the recently completed studies of eculizumab 
(Howard et al. 2017), efgartigimod (Howard et al. 2021), rozanolixizumab (Bril et al. 2023), 
zilucoplan (Howard et al. 2023), ravulizumab (Vu et al. 2022), and amifampridine 
phosphate (NCT03304054) for gMG.  
The QMG items assess severity of symptoms ranging from 0−3 for ptosis, diplopia, 
orbicularis oculi weakness, swallowing, speech disruption, percent forced vital capacity, 
arm and leg endurance (four items), grip strength (two items), and neck flexion strength, 
resulting in a total score that ranges from 0 to 39 with higher values indicating worse 
symptoms (Tindall et al. 1987).  
The psychometric properties of the QMG have been studied using both observational 
and clinical trial data.  The QMG has acceptable internal consistency 
(Cronbach’s α  = 0.74) and test−retest reliability (intra-class correlation coefficient 
[ICC] = 0.88) in clinically stable patients (Barnett et al. 2015).  Construct validity studies 
of the QMG have found correlations with the MGFA score (r2 = 0.54) and the MG-QOL 
15r (r = 0.41) (Barnett et al. 2012).   
This study will evaluate the efficacy of satralizumab added to SOC versus placebo 
added to SOC by comparing the change from baseline in the QMG score at Week 24 
(the end of the DB period). 
The MGC is an additional secondary efficacy outcome measure in this trial.  As the 
name implies, the MGC is a composite measure consisting of items drawn from the 
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Manual Muscle Test (hip, neck, facial, and deltoid strength) in an effort to include both 
clinician- and patient-reported elements in a single measure (Burns et al. 2008).  Each of 
the ten items contribute to a total score ranging from 0 to 50, with higher values 
indicating increasing symptom severity.  
The psychometric properties of the MGC were evaluated in a primary care setting in 
175 patients spread across 11 sites (Burns et al. 2010).  Test−retest reliability was found 
to be high (0.98 correlation coefficient) in a small sample of patients from a single site 
(n = 38).  The MGC exhibited moderate to strong convergent validity with the MG-ADL 
total score (r = 0.85), MG-QOL 15 total score (r = 0.68), and the Manual Muscle Test 
(r = 0.8).  
Given that the MGC has fair psychometric properties and draws on both physician- and 
patient-reported items, the Medical Scientific Advisory Board of the Myasthenia Gravis 
Foundation of America has recommended its use in randomized clinical trials of potential 
new gMG therapies (Benatar et al. 2012). 
As one of the secondary efficacy objectives, this study will evaluate the efficacy of 
satralizumab added to SOC versus placebo added to SOC by comparing the change 
from baseline in the MGC score at Week 24 (the end of the DB study period). 
The MG-QOL-15 is a disease-specific health-related quality of life measure that consists 
of 15 items:  mobility (9 items), symptoms (3 items), and contentment and emotional 
well-being (3 items).  Items are scored on a Likert scale from 0 to 4 with the total score 
ranging from 0 to 60, where higher scores indicate worse HRQoL (Burns et al. 2008) 
The MG-QOL-15 has strong internal consistency reliability (Cronbach’s α  = 0.89) and 
test−retest reliability (ICC = 0.98) (Burns et al. 2011).  In a recent trial of mycophenolate 
mofetil in gMG, the MG-QOL-15 correlated well with the physical and mental summary 
components of the 36-Item Short Form Survey, as well as with MG-specific measures 
(QMG, MG-ADL) (Burns et al. 2008).   
The MG-QOL-15 also demonstrated to be responsive in a randomized, controlled study 
of IVIg versus PE, where responders to treatment improved in average by nine points 
compared with non-responders, who changed by two points, thereby suggesting that a 
decrease MG-QOL-15 of seven or more points is correlated with improvement in the 
subgroup with moderate to severe MG (QMG score ≤ 11) (Barnett et al. 2013).  The 
minimal important difference has not been fully determined.  Based on its extensive use, 
the MG-QOL has been recently modified, to improve the performance of certain items 
(Burns et al. 2016).  In the modified version (MG-QOL 15r) the 15 items were rescored 
from a 0−4 to a 0−2 scale, based on Rasch analysis.  The resulting measure scores 
ranges from 0 to 30, and higher scores indicate worse health-related quality of life.  
When compared with the original scale, the modified version had better psychometric 
properties than the original and it is very easy to use (Burns et al. 2016).  


 
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The Neuro−QOL Fatigue scale is a short form that is part of a collection of instruments 
and item banks, developed through a National Institute of Neurological Disorders and 
Stroke–sponsored initiative to evaluate the HRQoL of adults and children diagnosed with 
neurological disorders (Cella et al. 2012).  It consists of eight items, each using a 5‐level 
Likert scale ranging between 1 = never to 5 = always, with a 7‐day recall period.  
The measure has demonstrated strong internal consistency reliability (Chronbach’s 
α  = 0.97) and construct validity (see Cella et al. 2012 for examples). 
The scale has recently been validated in patients with MG using an observational cohort 
of 257 patients receiving either IVIg/PE or prednisone (Tran et al. 2018).  The results 
demonstrated a positive relationship between fatigue and MG severity.  Patients in 
MGFA Classes II−III exhibited mild to moderate fatigue, while those in Class IV 
experienced severe fatigue.  Fatigue scores also correlated positively with MG 
Impairment Index, QMG, MGC, and MG‐ADL (Pearson’s r  =  0.52–0.69), indicating 
acceptable convergent validity (Tran et al., 2018).  All treatment groups showed a 
significant decrease in fatigue at Week 4 compared to baseline, with a standardized 
response mean for the overall population of 0.49, suggesting that the measure has good 
responsiveness (Tran et al. 2018).  
The Neuro−QOL Fatigue scale was also used in the recent REGAIN study of eculizumab 
in patients with MG (Andersen et al. 2019). 
3.4.7 
Rationale for Secondary Responder Analysis 
As part of the secondary efficacy objectives, the following supportive responder analyses 
for the MG-ADL, QMG, and MGC total scores will be performed. 
The efficacy of satralizumab versus placebo at Week 24 based on percentage of 
patients with: 
• 
A ≥ 2point reduction from baseline in total MG-ADL score with no rescue therapy 
received  
• 
A ≥ 3point reduction from baseline in QMG score with no rescue therapy received  
• 
A ≥ 3point reduction from baseline in total MGC score with no rescue therapy 
received  
Additionally, the efficacy of satralizumab will be assessed by the durability and the onset 
of response using the above responder definitions.  
3.4.7.1 
MG-ADL Responder Definition 
As noted in Section 3.4.5, the primary efficacy objective of this study will be evaluated by 
comparing the mean change from baseline in total MG-ADL score at Week 24.  
In an evaluation of the responsiveness of the MG-ADL to changes in disease status, 
Muppidi and colleagues (2011) assessed gMG patients (n = 76) at two visits, 6 months 
apart, who underwent variable interventions.  A gold standard was derived on the basis 


 
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of combined improvement in both the MG-QOL 15r and a 7-point physician global 
impression of change.  Receiver operating curves (ROC) were derived based on the 
gold standard used to determine responsiveness, resulting in an area under the curve of 
0.9 and suggesting a high degree of accuracy of the MG-ADL to predict clinical 
improvement.  Sensitivity and specificity were calculated systematically for different 
thresholds of change in MG-ADL to determine the most accurate cut-off point for 
predicting clinical improvement based on the gold standard.  A responder threshold of a 
2-point reduction in the MG-ADL was found to be the most accurate predictor of 
improved clinical status (sensitivity = 77 and specificity = 82) (Muppidi et al. 2011). 
3.4.7.2 
QMG Responder Definition 
The responsiveness of the QMG to changes in gMG clinical status has been shown in 
several clinical trials, yielding statistically significant differences between patients treated 
with active drug versus placebo (Tindall et al. 1987; Zinman et al. 2007).  Katzberg and 
colleagues (2014) used data from a randomized clinical trial of gMG patients who 
received either placebo or IVIg therapy to derive estimates of the minimum clinically 
important difference (MCID) that can be used to classify responders 
(Katzberg et al. 2014).  Using a combination of anchor- and distribution-based methods 
that showed strong convergence, they found an MCID threshold of ≥ 2 for QMG baseline 
severity between 0 and 16 and ≥ 3 for QMG baseline severity above 16.  
3.4.7.3 
MGC Responder Definition 
The responsiveness of the MGC to changes in disease status was studied in 11 primary 
care centers with 151 patients receiving SOC as determined by their treating physician.  
Subsequent visits were separated by an average of 4.7 months (Burns et al. 2010).  
A gold standard was defined as improvement in both the physician’s global impression 
of change and the MG-QOL 15r.  ROC curve analysis using this gold standard, showed 
that a 3-point improvement in the MGC had optimal sensitivity and specificity (Burns et 
al. 2010). 
3.4.7.4 
Rescue Therapy Handling in the Responder Definition 
As stated in Section 3.1.4 , the rescue therapies available will be IVIg, PE, and high-
dose IV corticosteroids.  Starting a rescue therapy constitutes a significant stand-alone 
event that would be triggered only by an exacerbation.  Consequently, patients who 
receive rescue therapy will be considered non-responders.  
3.4.8 
Rationale for Open-Label Extension 
Following the 24-week DB period, the study will include an OLE period of approximately 
2 years from last patient in the global study.  Adolescent patients will be enrolled directly in 
the OLE after completion of screening (see Section 3.1.3).  The objectives of the OLE are to 
evaluate satralizumab long-term safety and efficacy, including steroid/IST sparing, in 
patients with gMG.  


 
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The adolescent OLE aims to evaluate pharmacokinetics, pharmacodynamics, safety, and efficacy 
of satralizumab in adolescents aged  ≥ 12 years to < 18 years old with gMG. 
This study will enroll patients on stable background therapy, including OCSs and ISTs as 
indicated in Section 3.1.   
Long-term steroid treatment is associated with numerous adverse effects on many organ 
systems, including bone (osteoporosis, avascular necrosis), muscle (myopathy), 
metabolism and endocrine organs (weight gain, impaired glucose tolerance, 
hypothalamic-pituitary-adrenal suppression), skin (skin atrophy, acne, striae), eyes 
(glaucoma, cataract), behavior and mood (mood disorders, insomnia), cardiovascular 
system (hypertension, fluid retention, perturbations of serum lipoproteins), GI system 
(gastritis, peptic ulcer disease), and immune system (increased risk of infection).  One of 
the key treatment goals in MG is to reduce exposure to steroids (Sanders et al. 2016; 
Jaretzki et al. 2000).  The adverse event profile of the steroid-sparing ISTs that 
constitute the background therapy in this study includes renal toxicity with the use of 
cyclosporine, myelosuppression, infections, liver toxicity, and malignancies 
(Vodopivec et al. 2014; Collins et al. 2019) 
At or after Week 12 of the OLE, tapering of steroids and IST background treatment will 
be allowed based on clinical judgement for adult and adolescent patients randomized in the 
DB period at study start.  Satralizumab dosing until Week 12 of the OLE is required to 
ensure that patients treated with placebo during the DB period have reached steady-
state satralizumab concentrations.   
Adolescent patients enrolled directly in the OLE will remain on stable background therapy until 
Week 24 of the OLE period.   
The ability of patients to successfully taper steroids or ISTs while concurrently taking 
satralizumab will be evaluated in the OLE period based on analyses that will be pre-
specified in the statistical analysis plan (SAP). 
3.4.9 
Rationale for Biomarker Assessments  
This study will assess whether biomarkers, measured at baseline, can be used to 
identify patients with enhanced clinical benefit when treated with satralizumab or 
differential disease progression.  The study will also assess whether biomarkers can aid 
in characterizing the mechanism of action of satralizumab in gMG, provide evidence of 
satralizumab activity in gMG, or increase the knowledge and understanding of gMG 
disease biology.  Exploratory biomarker samples for research purposes to identify 
pathway and/or disease biomarkers may include, but may not be limited to, those 
reflective of inflammation, B- and T-cell subsets, activities, and products (e.g., serum 
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PD biomarker samples will be collected for the assessment of target engagement 
(e.g., IL-6 and sIL-6R) in response to satralizumab treatment.   
3.4.10 
Rationale for PK Sample Collection Schedule 
Samples to assess serum concentration of satralizumab will be taken prior to each 
administration during the DB period, and up to Week 24 of the OLE, followed by every 
12 weeks for the remaining duration of treatment to explore the pharmacokinetics of 
satralizumab in the gMG population following longer term treatment.  This assessment 
will include the impact of a range of covariates on exposure (e.g., gender, race, age, and 
body weight), and relationships between exposure and PD, efficacy, immunogenicity, 
and safety endpoints.   
3.4.11 
Rationale for Interim PK Analysis 
Satralizumab PK- and PD-data collected from the Phase I study in patients with RA were 
used to inform dose-selection for Phase III studies in patients with NMOSD, and this 
regimen was shown to be safe and efficacious.  While a similar approach to 
dose-selection is now proposed for this Phase III study in gMG, the Sponsor is mindful 
that population differences in the pharmacokinetics for satralizumab are possible.  
Therefore, the proposed Phase III design in gMG makes provision for an interim analysis 
of PK data, to ensure that patients are achieving target exposures while the Sponsor 
remains blinded, maintaining the integrity of this pivotal study. 
An interim analysis of PK data was performed when approximately 30 patients completed 
a minimum of 8 weeks of DB treatment (including approximately 15 patients from the 
satralizumab group).  The purpose of the interim analysis was to assess whether the 
achieved exposure to satralizumab (and predicted RO) is within the predicted range.  
The use of the existing PK model as the basis for prediction of RO in this interim 
analysis was considered appropriate given that the target is the same in both indications, 
and similar target expression is expected for gMG.  
The proposed sample size for this PK interim analysis is supported by PK simulation.  
Simulation was performed assuming a CL parameter estimate similar to that observed in 
either NMOSD or in HV (the fastest CL observed in any population to date, and therefore 
associated with potentially the lowest absolute exposure).  Two different scenarios for 
enrollment rate were also simulated and the sample size was varied between n = 12−30.  
The simulated data set contained the cumulative PK data available up to the time that 
the last patients completed 8 weeks of treatment.  For each evaluated scenario, the 
percent of times with relative standard error on CL >20%, percent of times with the CL 
estimate outside of 0.8−1.25 of the true value, and percent of times with the CL estimate 
outside of 0.6−1.44 of the true value were reported.  The results are reported Table 5.  
The simulations indicate that PK data from approximately 15 patients could be expected 
to provide adequate precision (< 20%) and that the population clearance would be 
estimated to a value which is within 0.8−1.25 of true clearance more than 80% of the 


 
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cases (see results for n = 16).  This takes into account that the PK interim analysis 
dataset will include all cumulative PK data available up to the time that the 15th patient 
receiving active drug completes 8 weeks of treatment.  In the case that CL cannot be 
estimated with adequate precision (see above) on the basis of the cumulative dataset at 
this point, the PK interim analysis could be repeated based on the cumulative dataset 
after an additional 10 patients (to include approximately 5 receiving satralizumab) have 
completed 8 weeks of treatment.   
Table 5 
Precision and Bias for Generalized Myasthenia Gravis Clearance 
Estimate for Different Pharmacokinetic Interim Analysis Sample 
Sizes 
 
Number 
of 
Patients 
Percent of Estimation Runs with: 
RSE > 20% a 
CL Estimate Outside 
ratio of 0.8−1.25 of 
NMOSD Reference b 
CL Estimate Outside 
Ratio of 0.6−1.44 of 
NMOSD Reference b 
12 
26.3 
20.0 
2 
16 
8.7 
15.0 
1.3 
20 
2.7 
10.7 
0.7 
24 
0 
6.3 
0.3 
30 
0 
0.7 
0 
CL =  total clearance of drug; NMOSD = neuromyelitis optica spectrum disorder; RSE= residual 
standard error. 
a Estimate of precision, % of simulations with a RSE > 20% are displayed. 
b Estimate of bias, % of simulations with an estimated value outside the specified ranges of the 
true value. 
  
Throughout the study, and therefore for the PK interim analysis, patients of a range of 
bodyweights in proportions approximately representative of the overall gMG population 
is expected to be recruited. 
A dose decision framework (including provision for a pre-specified alternative higher 
dose) was defined in a pharmacometric analysis plan prior to study start.  This plan set 
out the criteria for predicted exposure and RO (derived using the existing pop PK model 
based on HV and NMOSD, updated following incorporation of the new data in gMG) with 
which decisions for selection of an adapted dose will be made.  In case target exposures 
(based on those associated with near-maximal receptor occupancy in patients with 
NMOSD) were not achieved, the dose adaptation option was to increase the dose to the 
pre-defined dose regimen of 180 mg and 240 mg for patients ≤ 100 kg and > 100 kg, 
respectively.  The rationale for this higher dose, in the case that CL values in gMG are 
reflective of those in HV (higher than those in the NMOSD population), is presented in 
Section 3.4.1. 
Further details on the PK interim analysis are provided in Section 6.11.2. 


 
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3.4.12 
Rationale for Immunogenicity Sample Collection  
Anti-satralizumab antibodies (hereinafter referred to as ADAs) were detected in a large 
proportion of patients with NMOSD enrolled in the Phase III studies, with available data 
indicating that the probability of developing ADAs was positively correlated with low 
exposure and higher body weight.  However, similar clinically-meaningful efficacy was 
demonstrated in all body weight groups in both Phase III studies.  
Serum samples for ADAs will be taken in parallel to PK samples, with the objective of 
assessing the incidence and titer-time profile of ADAs in the gMG population, and the 
impact on exposure to satralizumab.  ADA data will be included in the blinded review of 
PK data at Week 8, for the purpose of interpretation of the satralizumab concentration 
data, in addition to the subsequent analysis based on the full study dataset.  
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
This study includes patients with gMG who are seropositive for anti-AChR, anti-MuSK or 
anti-LRP4 antibodies.  The proportion of patients who are negative for anti-AChR 
antibodies at screening is estimated to be approximately 10-15% of the total number of 
screened patients.  Recruitment will be managed closely and if proportions of anti-AChR 
antibody positive or anti-AChR antibody negative (anti-MuSK or anti-LRP4 antibody-
positive) exceed expected rates an operational cap may have to be introduced. 
Approximately 185 patients will be enrolled during the global enrollment phase of this 
study.   
4.1.1 
Inclusion Criteria 
Patients must meet the inclusion criteria below to be eligible for study entry. 
• 
Signed Informed Consent Form 
• 
Age ≥ 12 years (or  ≥ 18 years in France) at time of signing Informed Consent Form  
• 
For adolescent patients:  Informed Consent Form for study participation signed by 
the parents or a legal guardian, and patient assent obtained, as per local 
requirements  
• 
Ability to comply with the study protocol 
• 
Confirmed diagnosis of gMG meeting the following criteria: 
– 
Documented history of myasthenic weakness 
– 
MG severity of MGFA Class II, III, or IV2 at screening 
– 
The confirmation of the diagnosis has to be documented and supported by 
positive serologic test for one of the three antibody types:  anti--AChR, 
anti--MuSK or anti--LRP4 at screening (antibody status must be confirmed by 
                                              
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the central laboratory for all antibody types).  For sites in Germany and the 
Netherlands, confirmation of the diagnosis has to be documented and supported by pre-
existing positive serologic test results for one of the three antibody types (anti-AChR, 
anti-MuSK, or anti-LRP4), which must have been ordered by a health care professional 
(HCP) for the patient as part of the patient’s historical SOC.   
• 
A total MG-ADL score of ≥ 5 points at screening with more than 50% of this score 
attributed to non-ocular items 
• 
Ongoing gMG treatment at a stable dose and not exceeding the maximum allowed 
doses specified in Section 4.3.2.3, as defined below: 
– 
For patients receiving azathioprine, treatment for at least 6 months and a dose 
that has been stable for at least 2 months prior to screening 
– 
For patients receiving other ISTs (i.e., mycophenolate mofetil, cyclosporine, 
tacrolimus), treatment for at least 3 months and a dose that has been stable for 
at least 4 weeks prior to screening 
– 
For patients receiving OCS, treatment for at least 3 months and a dose that has 
been stable for at least 4 weeks prior to screening 
– 
For patients receiving an AChEI, treatment with a dose that has been stable for 
at least 2 weeks prior to screening 
• 
No contraindication to at least one of the rescue treatments:  IVIg, PE, or high-dose 
corticosteroids 
• 
For female patients of childbearing potential:  agreement to remain abstinent (refrain 
from heterosexual intercourse) or use adequate contraception during the treatment 
period and for at least 3 months after the final dose of satralizumab.   
A female patient is considered to be of childbearing potential if she is 
postmenarchal, has not reached a postmenopausal state (≥ 12 continuous 
months of amenorrhea with no identified cause other than menopause), and is 
not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations. 
The following are examples of adequate contraceptive methods:  bilateral tubal 
ligation; male sterilization; hormonal contraceptives; hormone-releasing 
intrauterine devices; copper intrauterine devices; male or female condom with 
or without spermicide; and cap, diaphragm, or sponge with spermicide. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not adequate methods of contraception.  
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methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form. 
The contraception requirements specified above only relate to satralizumab and 
are the minimum requirements for contraception during to the study.  Some of 
the allowed background treatments have additional contraceptive requirements, 
including measures for male partners participating in the study. 
Please refer to the local prescribing information of the background treatment(s) 
for additional details on pregnancy related risks.  If a patient is receiving a 
background therapy with specific contraceptive requirements, these additional 
contraceptive measures should be followed as described in the local 
prescribing information. 
  
4.1.2 
Exclusion Criteria 
Patients who meet any of the exclusion criteria listed below will be excluded from study 
entry. 
4.1.2.1 
Exclusion Criteria Related to Myasthenia Gravis: 
Patients who meet any of the following MG-related criteria will be excluded from the 
study: 
• 
History of thymic cysts, thymoma, thymic carcinoma or other neoplasm of the 
thymus as defined by the 2015 WHO classification of tumors of the thymus (Marx et 
al. 2015) unless deemed cured by adequate treatment with no evidence of 
recurrence for ≥ 5 years before screening.   
• 
History of thymectomy within 6 months prior to screening  
• 
Ocular MG (MGFA Class I)  
• 
In France, MGFA Class IV MG at screening 
• 
Myasthenic crisis within the last 3 months prior to screening (MGFA Class V)  
• 
Known disease other than gMG that would interfere with the course and conduct of 
the study (such as severe RA or symptomatic [overt] hyperthyroidism or 
hypothyroidism) 
 
4.1.2.2 
Exclusion Criteria Related to Previous or Concomitant 
Therapy: 
Patients who meet any of the following criteria related to previous or concomitant 
therapies will be excluded from the study: 
• 
Use of IVIg or subcutaneous immunoglobulin (SCIg) within 6 weeks prior to 
randomization/Day 1 
• 
Use of PE within 8 weeks prior to randomization/Day 1 
• 
Treatment with IL-6 inhibitory therapy (e.g., tocilizumab) at any time 
• 
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• 
Treatment with B and/or T cell−depleting agents (except anti-CD20 agents) 
including, but not limited to, inebilizumab and alemtuzumab at any time 
• 
Treatment with anti-CD20 within 6 months prior to screening, unless CD19 counts 
are within normal range, as assessed by the central laboratory at screening  
• 
Treatment with C5 complement inhibitors (e.g., eculizumab or ravulizumab) within 
6 months prior to screening 
• 
Treatment with neonatal Fc receptor antagonists within 6 months prior to screening 
• 
Treatment with anti−B-lymphocyte stimulator monoclonal antibody (e.g., belimumab) 
at any time 
• 
Treatment with cyclophosphamide IV within 6 months prior to screening 
• 
Treatment with oral cyclophosphamide at any time 
• 
Treatment with methotrexate within 8 weeks prior to screening 
• 
Treatment with any investigational agent within 24 weeks prior to screening or 
5 drug-elimination half-lives of the investigational drug (whichever is longer) 
• 
Use of more than one IST (azathioprine, mycophenolate mofetil, cyclosporine A, 
tacrolimus) as background therapy except for the combination of an OCS with 
another permitted IST drug  
 
4.1.2.3 
General Safety Exclusion Criteria: 
Patients who meet any of the following safety-related criteria will be excluded from the 
study: 
• 
Any surgical procedure (except for non-ophthalmic minor surgeries*) within 4 weeks 
prior to screening 
• 
Planned surgical procedure (except for non-ophthalmic minor surgeries*) during the 
study 
* Note:  A minor surgical procedure is considered a procedure that requires only 
local anesthesia or conscious sedation (does not require general, neuraxial or 
regional anesthesia) and is done on an ambulatory/outpatient basis 
(e.g., toenail surgery, mole surgical excision, wisdom tooth extraction).  
Note:  All ophthalmic surgical procedures, major or minor, including strabismus 
surgeries, are prohibited within 4 weeks prior to screening and should not be 
planned during the study. 
• 
Evidence of progressive multifocal leukoencephalopathy 
• 
Evidence of serious uncontrolled concomitant diseases that may preclude patient 
participation, such as other nervous system disease, cardiovascular disease, 
hematologic/hematopoiesis disease, respiratory disease, muscular disease, 
endocrine disease, including thyroid disease, renal/urologic disease, digestive 
system disease 
• 
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• 
Active or recurrent bacterial, viral, fungal, mycobacterial infection, or other infection 
(excluding fungal infection of nail beds or dental caries) at baseline 
• 
Infection requiring hospitalization or treatment with IV anti-infective agents within 
4 weeks prior to baseline visit or oral anti-infective agents within 2 weeks prior to 
baseline visit  
• 
Positive screening tests for hepatitis B, defined as either of the following: 
o Positive hepatitis B surface antigen [HBsAg]  
o Positive total hepatitis B core antibody [total HBcAb] confirmed by a 
positive viral DNA PCR 
• 
Positive screening test for hepatitis C (defined as positive hepatitis C virus [HCV] 
antibody and detectable HCV RNA) 
Participants with positive HCV antibody and undetectable HCV RNA 12 weeks 
after HCV treatment completion are eligible to participate in the study. 
• 
History of drug or alcohol abuse within 1 year prior to baseline 
• 
History of diverticulitis or concurrent severe GI disorders (such as symptomatic 
diverticulosis) that, in the investigator’s opinion, may lead to increased risk of 
complications such as GI perforation 
• 
Evidence of latent or active tuberculosis (TB), excluding patients receiving 
chemoprophylaxis for latent TB infection   
A TB test (tuberculin skin test and/or an interferon-gamma release assay [e.g., 
QuantiFERON-TB Gold In-Tube assay, T-SPOT TB assay]) should be 
conducted according to local guidance.  If a patient is positive for latent TB, 
then the patient must be treated with appropriate anti-mycobacterial therapy for 
at least 4 weeks prior to initiating study treatment administration.  Refer to 
Appendix 5 for details on TB screening and treatment.  
• 
Receipt of live or live attenuated vaccine within 6 weeks prior to baseline 
• 
History of blood donation (one unit or more), plasma donation or platelet donation 
within 90 days prior to screening and Day 1 
• 
History of malignancy within the last 5 years, including solid tumors, hematologic 
malignancies and in situ carcinoma (except basal cell and squamous cell 
carcinomas of the skin, or in situ carcinoma of the cervix uteri that have been 
completely excised and cured) 
• 
History of severe allergic reaction to a biologic agent (e.g., shock, anaphylactic 
reactions)  
• 
Active suicidal ideation within 6 months prior to screening or history of suicide 
attempt within 3 years prior to screening 
• 
Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator's judgment, precludes the patient's safe participation in and completion 
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• 
Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 3 months after the final dose of satralizumab 
Female patients of childbearing potential must have a negative serum 
pregnancy test result at screening prior to initiation of study drug. 
 
4.1.2.4 
Laboratory Exclusion Criteria (at Screening): 
Patients who have any of the following laboratory abnormalities at screening will be 
excluded from the study: 
• 
WBC < 3.0 × 103/µL 
• 
ANC < 2.0 × 103/µL 
• 
Absolute lymphocyte count < 0.5 × 103/µL 
• 
Platelet count < 10 × 104/µL 
• 
AST or ALT > 1.5 × upper limit of normal (ULN) 
 
If retest is conducted because the initial result meets an exclusion criterion, it must be 
conducted at a central laboratory and the last value obtained determines the patient’s 
eligibility for randomization/Day 1, otherwise local laboratory can be used. 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
Randomization and blinding will be employed to minimize bias in treatment assignment 
in the DB period and to provide the basis for valid statistical inference.  
4.2.1 
Treatment Assignment  
This is a randomized, DB study (except for adolescent patients enrolled directly in the OLE 
period of the study).  After initial written informed consent has been obtained, all screening 
procedures and assessments have been completed, and eligibility has been established 
for a patient, the study site will obtain the patient's identification number and treatment kit 
assignment from an interactive voice or web-based response system (IxRS). 
Patients will be randomly assigned to one of two treatment groups: placebo or 
satralizumab.  Eligible patients must be randomized through the IxRS prior to receiving 
any study drug.  Randomization will occur in a 1:1 ratio through use of a permuted-block 
randomization method to ensure a balanced assignment to each treatment group.  
Randomization will be stratified according to the following criteria: 
• 
Baseline SOC treatment:  AChEI monotherapy and/or an OCS versus a steroid-
sparing IST monotherapy or a combination of steroid-sparing IST with other 
treatments (an AChEI and/or an OCS) 
• 
Autoantibody type:  AChR positive versus AChR negative (includes MuSK gMG and 
LRP4 gMG) 
• 
Region:  North America versus Europe versus rest of world 
 


 
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Adolescent patients enrolled in the study will directly enter the OLE period after completion of 
screening and receive open-label satralizumab.  For information on adolescents that have been 
enrolled through previous versions of the protocol (prior to global protocol Version 5), refer to 
Section 3.1.3.  
The IxRS system will also take into account patients’ weight at baseline to allocate to the 
correct dose. 
4.2.2 
Blinding 
Study site personnel and patients will be blinded to treatment assignment during the 
study.  The Sponsor and its agents will also be blinded to treatment assignment, with the 
exception of individuals who require access to patient treatment assignments to fulfill 
their job roles during a clinical trial.  These roles include the unblinding group 
responsible, clinical supply chain managers, central laboratory sample handling staff, 
operational assay group personnel, IxRS service provider, and iDMC members. 
To maintain integrity of the trial results and to prevent potential unblinding of the 
assigned group during the DB treatment phase as a result of adverse events or changes 
to laboratory results, the following additional measures will be implemented until the time 
of the primary analysis: 
• 
To prevent potential unblinding as a result of adverse events or laboratory changes, 
a “dual assessor” approach will be used to evaluate efficacy and safety.  Each site 
will have two separate investigators:  a treating investigator and a rating or 
examining investigator. 
The treating investigator will be the safety assessor and should be a 
neurologist with experience in the care of patients with MG.  The Treating 
Investigator will have access to all patient data and will make all treatment 
decisions on the basis of a patient’s clinical response and laboratory findings. 
This role may be conducted by the principal investigator. 
The examining investigator will be the efficacy assessor and should be a 
qualified HCP trained and experienced in administering and scoring the MG-
ADL, QMG, and MGC.  The examining investigator (or designee, fulfilling the 
same criteria) will complete the QMG and MGC assessments.  During the DB 
treatment period, the examining investigator and his or her qualified designees 
(if applicable) will not be involved with any aspect of medical management of 
the patient and will not be allowed access to patient data.  The roles of the 
treating and examining investigator need to be documented in the Investigator’s 
Site File for each patient.  The treating investigator and the examining 
investigator should not switch roles for a specific patient.  It is recommended 
that the same examining investigator assesses a specific patient throughout the 
DB treatment period.  This role cannot be conducted by the principal 
investigator. 
The dual assessor approach should be applied until the database lock for the 
primary analysis for the study has been achieved. 


 
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• 
Patient education:  During the DB treatment period, prior to being examined by the 
examining investigator, patients should be instructed not to discuss with the 
examining investigator what (if any) adverse effects they may be experiencing. 
• 
Blinding of laboratory parameters:  Selected laboratory parameters that may lead to 
unblinding of the treatment assignment, such as fibrinogen, CRP, immunoglobulins, 
and complement levels, will be blinded until the primary analysis is complete.  The 
iDMC will perform periodic unblinded safety reviews, which include the blinded 
laboratory parameters.  
 
While PK and immunogenicity samples must be collected from patients assigned to the 
placebo group to maintain the blinding of treatment assignment, PK and ADA assay 
results for these patients are generally not needed for the safe conduct or proper 
interpretation of the study data.  Laboratories responsible for performing study drug PK 
and ADA assays will be unblinded to patient treatment assignments to identify 
appropriate samples for analysis.  PK samples from patients assigned to the placebo 
group will not be analyzed for study drug PK concentration except by request (e.g., to 
evaluate a possible error in dosing).  Baseline immunogenicity samples will be analyzed 
for all patients.  Post-baseline immunogenicity samples from patients assigned to the 
placebo group will not be analyzed for ADAs except by request.   
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The treatment code should not be broken except in emergency 
situations.  The investigator is not required to contact the Medical Monitor prior to 
breaking the treatment code.  However, the investigator should inform the Medical Monitor 
that the treatment code has been broken. 
If the investigator wishes to know the identity of the study drug for any reason other than 
a medical emergency, he or she should contact the Medical Monitor directly.  The 
investigator should document and provide an explanation for any non-emergency 
unblinding.  If the Medical Monitor agrees to patient unblinding, the investigator will be 
able to break the treatment code by contacting the IxRS. 
As per health authority reporting requirements, the Sponsor's Drug Safety representative 
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the investigator or Sponsor to be related to 
study drug.  The patient may continue to receive treatment, and the investigator, patient, 
and Sponsor personnel, with the exception of the drug safety representative and 
personnel who must have access to patient treatment assignments to fulfill their roles 
(as defined above) will remain blinded to treatment assignment. 


 
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4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The investigational medicinal product (IMP) for this study is satralizumab.  Background 
therapy and rescue therapy are considered auxiliary medicinal products (AxMPs).  
Appendix 15 identifies all IMPs and AxMPs for this study (for use in European Economic Area 
[EEA]). 
In this protocol, "study treatment" refers to satralizumab or placebo (assigned in addition 
to background therapy). 
4.3.1 
Study Treatment Formulation and Packaging 
4.3.1.1 
Satralizumab and Placebo 
IMP will be supplied by the Sponsor as prefilled syringe (PFS) assembled with a plunger 
rod, needle safety device (NSD), and extended finger flange (EFF) filled with 1.0 mL of 
solution for SC injection corresponding to 120 mg satralizumab.  Satralizumab placebo 
PFS is identical in composition to satralizumab PFS, but does not contain the 
satralizumab active ingredient.  It will be identical in appearance and packaging to 
satralizumab.  A PFS (assembled with an NSD/EFF) filled with 0.5 mL of solution, 
corresponding to 60 mg satralizumab, will be used in the OLE period (after the second 
OLE dose) once it becomes available at the study site.  
For information on the formulation and handling of satralizumab, see the pharmacy 
manual. 
4.3.1.2 
Background Therapy 
Oral Corticosteroids  
For information on the formulation and packaging of OCSs, see the local prescribing 
information for OCSs. 
Immunosuppressive Therapy 
For information on the formulation and packaging of azathioprine, mycophenolate 
mofetil, cyclosporine A, tacrolimus, see the local prescribing information for the 
respective treatment. 
Acetylcholinesterase Inhibitors 
For information on the formulation and packaging of AChEI (pyridostigmine, 
neostigmine, ambenonium), see the local prescribing information. 
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.1. 
Details on treatment administration (e.g., dose and timing) should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Cases of accidental 


 
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overdose, medication error, drug abuse, or drug misuse, along with any associated 
adverse events, should be reported as described in Section 5.3.5.12. 
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Section 5.1.4.1. 
4.3.2.1 
Satralizumab and Placebo 
Patients will receive satralizumab or placebo at Weeks 0, 2, 4 (loading doses) and 
maintenance doses Q4W thereafter during the DB period.  Patients will receive the 
second and the third loading dose (administered at Weeks 2 and 4) within a ± 3-day 
window for both dosing visits and all subsequent doses within a ± 7-day window for each 
dosing visit.  The minimal dosing interval between two loading doses is 8 days.  It should 
be noted that the second loading dose and the Week 2 assessments should coincide 
and occur 14 (±3) days after Study Day 1. 
Study drug will be administered by SC injection in the abdominal or femoral region by 
the investigator or designated person after all other study-related procedures have been 
performed at a site visit.  For the first 5 doses of study drug in the DB and OLE periods, 
all patients should be observed for the signs and symptoms of hypersensitivity reactions 
at the study site for at least 1 hour after administration of study treatment.  
In case of disease exacerbation that requires rescue therapy, study drug administration 
will be continued as scheduled, concurrently with rescue therapy, unless the investigator 
considers it necessary to discontinue study treatment.  Patients who receive PE as 
rescue therapy will receive loading doses of study drug as soon as possible post-PE. 
The dose of study treatment will be determined on the basis of body weight.  
Patients with a body weight ≤ 100 kg will receive 120 mg SC satralizumab or the 
matching volume of placebo.  Patients with a body weight > 100 kg will receive 180 mg 
SC satralizumab or the matching volume of placebo, given as two injections (one 1-mL 
PFS, and one additional 0.5-mL injection).   
An interim PK analysis was included to confirm that the achieved exposures are within 
the target range (see Section 6.11.2).  Based on the results of this analysis and 
pre-specified criteria, the dosing regimen could be modified from 120 mg to 180 mg and 
from 180 mg to 240 mg for patients ≤ 100 kg and > 100 kg, respectively, if needed to 
achieve target concentrations.  For further details on the interim analysis, see Section 6.11.2. 
For preparation and administration of the 180-mg or 240-mg doses of study drug 
(in case of dose modification), please refer to the pharmacy manual.  
In the OLE period, all patients can receive open-label treatment with satralizumab, as 
determined on the basis of body weight, as described above.  Adult and adolescent 
patients who receive active treatment during the DB period (Group A) will continue to 


 
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receive OLE satralizumab subcutaneously Q4W, with a dose of placebo administered at 
Week 2 of the OLE period in order to maintain blinding to DB treatment assignment.  
Adult and adolescent patients who receive placebo treatment during the DB period 
(Group B) will be administered loading doses of satralizumab subcutaneously at Weeks 
0, 2, 4, and maintenance doses Q4W thereafter of the OLE period. After Week 24 of the 
OLE period and in accordance with local regulations, administration of satralizumab 
outside of the study site (e.g., mobile nursing by a qualified HCP or home treatment 
[self-administration or administration by a trained caregiver]) may be allowed on 
scheduled study drug administration days if no on-site assessments are scheduled for 
that dosing date (see Appendix 2).  The investigator will assess if it is appropriate for a 
given patient to receive study drug by self-administration or administration by a caregiver 
outside of the study site.  If administration outside the study site is appropriate, patients 
will be required to give written informed consent to participate in mobile nursing visits or 
home treatment.  Patients and their caregivers will be provided with emergency contact 
information by the site.   
Adolescent patients enrolled directly in the OLE period will receive satralizumab treatment at 
Weeks 0, 2, and 4 (loading doses) and maintenance doses Q4W thereafter.  Patients will receive 
the second and the third loading dose (administered at Weeks 2 and 4) within a ± 3-day window 
for both dosing visits and all subsequent doses within a ± 7-day window for each dosing visit.  
The minimal dosing interval between two loading doses is 8 days.  It should be noted that the 
second loading dose and the Week 2 assessments should coincide and occur 14 (±3) days after 
Study Day 1. 
If eligible for and willing to participate in self-administration, patients and their caregivers 
will be trained how to administer study drug.  After the patient or caregiver signs the 
Informed Consent for Optional Home Treatment, training of the patient or caregiver can 
begin from the Week 16 OLE visit and should continue until the patient or caregiver has 
demonstrated competence in administering the injection of the study drug correctly.  
The assessment to determine the patient's or caregiver's competence in performing the 
injection needs to be made by the Principal Investigator (or delegate) and should be 
documented in the patient’s medical records. After the patient or the patient’s caregiver 
has demonstrated competence in giving the injection correctly, SC injections may be 
administered by the patient or the patient’s caregiver at home.  Patients should be 
followed up by the study site personnel through phone calls around the scheduled study 
drug administration dates to monitor compliance, concomitant medications, and adverse 
events.  If a patient is unable or does not wish to administer study drug at home, clinic 
staff will continue to administer injections to the patient at the study site.  
Patients and their caregivers will be instructed in how to recognize any signs and 
symptoms of hypersensitivity reaction and to identify when to seek emergency medical 
care in case of an extreme reaction.  Patients will record details of their 
home -administered study drug injections in a diary.  Site personnel will monitor the 
study medication records from the diary at the in-clinic visits.  An HCP who is trained on 


 
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study drug preparation, storage and administration should perform the preparation and 
SC administration of any dose that is not in a form of PFS.  
Refer to the pharmacy manual for detailed instructions on drug storage, and 
administration. 
4.3.2.2 
Modifications of Dose or Treatment Schedule 
In the event that an enrolled patient gains or loses weight during the study such that they 
would fall into a different dosing band, the following instructions apply (see Table 6)  
Table 6 
Dosing Regimen Switches for Patients Who May Lose or Gain 
Body Weight 
Body Weight at Baseline 
Dosing Regimen Switches 
 ≤ 100 kg 
Increase dose of study drug to higher dose (180 mg) if a 
patient’s weight increases to ≥ 105 kg, confirmed at two 
consecutive measurements minimum 6 weeks apart 
 > 100 kg 
Reduce dose of study drug to 120 mg if a patient’s weight 
decreases to ≤ 95 kg, confirmed at two consecutive 
measurements minimum 6 weeks apart 
  
The dosage may be modified based on the results of the interim PK analysis (see 
Section 6.11.2). 
Delayed Dosing Visits and Missed Doses  
Delayed dosing visits may be scheduled if the study drug cannot be administered at the 
timepoints defined in the schedule of activities (see Appendix 1 and Appendix 2).  
Thus, a patient who has all assessments of a dosing visit performed but could not 
receive his or her dose of study drug, should be rescheduled for the SC drug 
administration.  At the delayed dosing visit, minimum safety pre-dosing assessments, 
including physical examination and vital signs measurements, ECG, PK, PD, and ADA 
sampling and study drug administration will be performed.  Other pre-dosing 
assessments are listed in the schedule of activities.  Additional tests or assessments, 
such as routine safety laboratory tests, may be performed when the investigator judges 
that these are warranted, and should be recorded in the CRF. 
Patients with active infection during the study should be promptly evaluated and treated 
appropriately; study drug injection should be delayed until the infection is controlled.  For 
serious infections or Grade ≥ 3 infections, study drug injection should be delayed until 
the infection has completely resolved. 
If a patient cannot come to the site for a scheduled visit, every effort should be made to 
collect all the missing data.  Additionally, the site staff should follow up with patients 


 
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around the time of the scheduled visit by telephone to collect any information on safety 
and/or neurological worsening the patient might experience. 
If study drug cannot be administered within the scheduled visit window and is 
subsequently administered outside the visit window, the next dose of study drug should 
be administered on schedule (minimum dosing interval should be 8 days (for loading 
dose) and 14 days (for maintenance dose).   
Site staff should consult with the Medical Monitor if in doubt as to how to schedule 
dosing in such circumstances.  
Missed Doses 
If the delay in dosing is such that the minimum allowable interval between doses cannot 
be maintained within the acceptable dosing windows defined, or dosing cannot be 
completed prior to the date of the next planned dose, then the dose is considered to 
have been missed.  If a study drug injection is missed, it should be administered as 
described in Table 7 provided there are no safety-related reasons for further interruption 
or discontinuation of study treatment (see Section 5.1). 
 
 


 
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Table 7 
Recommended Dosage for Delayed or Missed Doses and after 
Rescue Therapy with Plasma Exchange 
Last Dose Administered 
Recommended Dosage for Delayed or Missed Doses 
Less than 8 weeks during the 
maintenance period or missed 
a loading dose 
Administer study drug by SC injection as soon as possible.  If 
the delayed dosing falls within the next visit window, no 
delayed dosing visit entry needs to be recorded on the eCRF.  
The site should enter data for all assessments and study drug 
administration on the next scheduled visit eCRF page. 
Loading period 
• 
If the second loading dose (Week 2 of DB period or 
Week 2 of OLE period) is delayed or missed, administer 
dose as soon as possible and administer the third and 
final loading dose 14 ( ± 3) days later.  The minimal 
dosing interval between the second and the third loading 
dose is 8 days. 
• 
If the third loading dose (Week 4 of DB or Week 4 of 
OLE period) is delayed or missed, administer dose as 
soon as possible and administer the next dose 4 weeks 
( ± 7 days) later. 
 weeks to less than 12 weeks 
Administer study drug by SC injection at 0 a and 2 weeks 
( ± 3 days), followed by administration every 4 weeks 
( ± 7 days).  
The assessments specified for RLDs 1 and 2 should be 
completed.  Study assessments should then resume as per 
the schedule of activities (see Appendix 1 and Appendix 2) 
12 weeks or longer 
or 
After rescue therapy with PE 
Administer study drug by SC injection at 0 a, 2 weeks 
( ± 3 days), and 4 weeks ( ± 3 days) followed by administration 
every 4 weeks ( ± 7 days) (For treatment interruptions of 
≥ 12 weeks, during which safety assessments have not been 
conducted, at RLD 1 visit it is recommended to perform a 
laboratory assessment and review of the safety labs including LFTs 
[Table 8], ANC [Table 9] and platelets [Table 10] prior to 
administering study drug. Patients should be carefully examined 
for any signs of active infection and if required, additional tests 
should be performed at the discretion of the principal investigator 
prior to study drug administration). 
The assessments specified for RLDs 1, 2, and 3 Visits are to 
be completed.  Study assessments should then resume as 
per the schedule of activities (see Appendix 1 and 
Appendix 2). 
ANC = absolute neutrophil count; DB = double-blind; eCRF = electronic Case Report Form; 
LFT=  liver function test; OLE = open-label extension, PE = plasma exchange; RLD = re-loading dose  
a “0 weeks” refers to time of the first administration after the missed dose. 
  


 
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Site staff should discuss with the Medical Monitor how to schedule dosing in such 
circumstances. 
4.3.2.3 
Background Therapy  
In the DB period (in addition to satralizumab or placebo) patients will receive background 
treatment with OCSs and/or IST and/or AChEIs at a stable dose not exceeding the 
following doses:  
• 
Azathioprine:  3 mg/kg/day for adults, 2.5 mg/kg/day for adolescents (O’Connell et 
al. 2020) 
• 
Mycophenolate mofetil:  3000 mg/day for adults, 2000 mg/day for adolescents  
• 
Cyclosporin A:  5 mg/kg/day 
• 
Tacrolimus:  0.2 mg/kg/day for adults, 0.1 mg/kg/day for adolescents (Ponseti et al. 
2008) 
• 
Oral glucocorticoids:  30 mg/day (prednisone equivalent)  
• 
Pyridostigmine:  600 mg/day for adults, up to 1.5 mg/kg 5 times per day for 
adolescents (maximum 450 mg/day) (O’Connell et al. 2020) 
• 
Neostigmine:  375 mg/day 
• 
Ambenonium:  300 mg/day 
 
These are considered AxMPs (for use in the EEA), see Appendix 15.   
In addition to OCSs, only one IST or immunomodulatory drug at a stable dose is allowed 
during the DB period (see Section 4.1.1). 
AChEIs should not be taken for 10 hours prior to completion of efficacy assessments 
including QMG and MGC testing at each study visit (except screening visit) if medically 
safe to do so. 
In the DB period and the first 12 weeks of the OLE period a dose decrease of baseline 
treatments is permitted only for safety reasons.  Dose increase or change of background 
treatment is strongly discouraged. 
In the OLE period, background treatment, for all adult and adolescent patients randomized 
in the DB period at the start of the study, should be maintained stable for at least the first 
12 weeks to allow satralizumab levels to reach steady state in the patients who received 
placebo during the DB period.  Patients can be tapered off steroids, ISTs, and AChEIs 
after Week 12 of the OLE period based on the investigator’s judgment.   
For adolescent patients enrolled directly into the OLE, stable background therapy should be 
maintained until Week 24 of the OLE period (see Section 3.1.3). 


 
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4.3.3 
Rescue Medication  
Patients may receive rescue therapy in case of MG clinical deterioration/exacerbation on 
any study day.  Exacerbation of MG is defined in Section 3.1.4. 
Rescue therapy includes IVIg (2 g/kg administered over a 2- to 5- day period), or PE with 
or without high-dose corticosteroids (500−1000 mg/day IV methylprednisolone or 
equivalent for 2−5 days).  High-dose corticosteroid therapy should always be 
administered in combination with IVIg or PE. 
The choice of rescue therapy will be determined by the investigator on the basis of his or 
her overall clinical assessment. 
Study drug administration will be continued as scheduled, concurrently with rescue 
therapy, unless the investigator considers it necessary to discontinue study treatment. 
Patients who receive PE as rescue therapy will receive re-loading doses of study drug 
as soon as possible post-PE (see Section 4.3.2.2, Table 7). 
All efforts should be made by the investigator to keep patients in the study during the DB 
period and continue study drug administration even after experiencing a MG 
exacerbation requiring rescue therapy.   
4.3.4 
Investigational Medicinal Product Handling and Accountability 
All IMPs required for completion of this study will be provided by the Sponsor.  The study 
site (i.e., investigator or other authorized personnel [e.g., pharmacist or mobile nurse]) is 
responsible for maintaining records of IMP delivery to the site, IMP inventory at the site, 
IMP use by each patient, and disposition or return of unused IMP, thus enabling 
reconciliation of all IMP received, and for ensuring that patients are provided with doses 
specified by the protocol. 
The study site should follow all instructions included with each shipment of IMP.  The 
study site will acknowledge receipt of IMPs supplied by the Sponsor using the IxRS to 
confirm the shipment condition and content.  Any damaged shipments will be replaced.  
The investigator or designee must confirm that appropriate temperature conditions have 
been maintained during transit, either by time monitoring (shipment arrival date and time) or 
temperature monitoring, for all IMPs received and that any discrepancies have been 
reported and resolved before use of the IMPs.  All IMPs must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions, with access limited to the investigator and 
authorized staff. 
Only patients enrolled in the study may receive IMPs. 


 
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IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor with the appropriate 
documentation.  The site's method of destroying Sponsor-supplied IMPs must be agreed 
to by the Sponsor.  The site must obtain written authorization from the Sponsor before 
any Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on 
the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the drug accountability log. 
Refer to the pharmacy manual and/or the Satralizumab Investigator's Brochure for 
information on IMP handling, including preparation and storage, and accountability.  
4.3.5 
Continued Access to Satralizumab 
The Sponsor will offer continued access to Roche IMP satralizumab free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below. 
A patient will be eligible to receive Roche IMP satralizumab after completing the study if 
all of the following conditions are met: 
• 
The patient has a life-threatening or severe medical condition and requires 
continued Roche IMP treatment for his or her well-being. 
• 
There are no appropriate alternative treatments available to the patient. 
• 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them. 
 
A patient will not be eligible to receive Roche IMP satralizumab after completing the 
study if any of the following conditions are met: 
• 
The Roche IMP is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient). 
• 
The Sponsor has discontinued development of the IMP or data suggest that the IMP 
is not effective for gMG.  
• 
The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
gMG. 
• 
Provision of the Roche IMP is not permitted under the laws and regulations of the 
patient's country. 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 


 
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Patients may be eligible to receive satralizumab as part of an OLE study, as described in 
Section 3.1.2. 
4.4 
CONCOMITANT THERAPY, PROHIBITED FOOD, AND 
ADDITIONAL RESTRICTIONS 
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-
counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used 
by a patient in addition to protocol-mandated treatment from screening visit to end of 
study visit.  All such medications should be reported to the investigator and recorded on 
the Concomitant Medications eCRF. 
The Medical Monitor may be consulted if there are any questions related to concomitant or prior 
therapy. 
4.4.1 
Permitted Therapy  
Patients are permitted to use the following therapies during the study: 
• 
Oral contraceptives (see Section 4.1.1) 
• 
Hormone-replacement therapy 
• 
Background treatment with any of the drugs listed in Section 4.3.2.3 
The dose must not exceed the dose defined in Section 4.3.2.3.  In the DB 
period, a dose decrease of baseline treatments is permitted only for safety 
reasons.  Dose increase or change of background treatment is strongly 
discouraged. 
• 
Rescue therapy in case of acute MG exacerbation defined as IVIg and/or PE 
administered with or without pulse IV corticosteroids (see Section 4.3.3) 
The choice of rescue therapy will be determined by the investigator on the basis 
of his or her overall clinical assessment. 
Study drug administration will be continued as scheduled, concurrently with 
rescue therapy, unless the investigator considers it necessary to discontinue 
study treatment. 
• 
Treatment with topical (e.g., ophthalmic, nasal, otic, cutaneous) corticosteroids for 
adverse events (i.e., indications other than background MG therapy), provided that 
the duration of treatment is kept as short as possible.  
• 
Pain medications (including topical agents, antiepileptic drugs [e.g., pregabalin, 
gabapentin, carbamazepine], antidepressants [tricyclic antidepressants and 
serotonin norepinephrine reuptake inhibitors, e.g., duloxetine], and non-opioid 
analgesics [e.g., acetaminophen, non-steroidal anti-inflammatory drugs]). 
 
4.4.2 
Cautionary Therapy 
Medications that have the strongest evidence for worsening MG should be avoided 
(Sanders et al. 2016; Myasthenia Gravis Foundation 2020) and include the following: 


 
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• 
Magnesium:  potentially dangerous if given intravenously, i.e., for eclampsia during 
late pregnancy or for hypomagnesemia.  Use only if absolutely necessary and 
observe for worsening.  
• 
Macrolide antibiotics (e.g., erythromycin, azithromycin, clarithromycin):  commonly 
prescribed antibiotics for gram-positive bacterial infections.  Use cautiously, if at all.  
• 
Aminoglycoside antibiotics (e.g., gentamycin, neomycin, tobramycin):  used for 
gram-negative bacterial infections.  Use cautiously if no alternative treatment 
available. 
• 
Procainamide:  used for irregular heart rhythm.  Use with caution.  
• 
Desferrioxamine:  a chelating agent used for hemochromatosis.  
• 
β-blockers:  commonly prescribed for hypertension, heart disease and migraine 
headaches but potentially dangerous in MG.  May worsen MG.  Use cautiously. 
• 
Statins (e.g., atorvastatin, pravastatin, rosuvastatin, simvastatin):  used to reduce 
serum cholesterol.  Statins may worsen or precipitate MG.  Use cautiously if 
indicated and at the lowest dose needed.  
• 
Iodinated radiologic contrast agents:  older reports document increased MG 
weakness, but modern contrast agents appear to be safer.  Use cautiously and 
observe for worsening. 
• 
In addition, all drugs that are respiratory depressants (e.g., benzodiazepines, 
opioids, sedatives) should be used with caution. 
The use of cautionary therapies defined above must be recorded on the eCRF.  Adverse 
events related to the administration of these therapies must be documented on the 
appropriate eCRF. 
4.4.2.1 
Medications Given with Precaution due to Effects Related to 
CYP Enzymes  
No drug-drug interaction studies have been performed.  Pop PK analyses did not detect 
any effect of azathioprine, mycophenolate mofetil, or OCS on the clearance of 
satralizumab. 
Both in vitro and in vivo studies have shown that the expression of specific hepatic 
CYP450 enzymes (CYP1A2, CYP2C9, CYP2C19, and CYP3A4) is suppressed by 
cytokines such as IL-6.  Modestly elevated IL-6 levels have been reported in patients 
with gMG. 
Caution should be exercised when starting or discontinuing satralizumab treatment in 
patients who are receiving substrates of CYP450 3A4, 1A2, 2C9 or 2C19, particularly 
those with a narrow therapeutic index (such as warfarin, carbamazepine, phenytoin, and 
theophylline), and/or background ISTs (including tacrolimus and cyclosporine) and 
doses adjusted if needed. 


 
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Given the prolonged terminal half-life of satralizumab (approximately 30 days), the effect 
of satralizumab may persist for several months after stopping therapy. 
The above lists of medications are not necessarily comprehensive.  The investigator 
should consult the prescribing information when determining whether a concomitant 
medication can be safely administered with study treatment.  In addition, the investigator 
should contact the Medical Monitor if questions arise regarding medications not listed 
above. 
4.4.3 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited during the study as described 
below: 
• 
Use of chronic IVIg (defined as more than 2 consecutive treatments administered at 
4- to 6-week intervals) or chronic SCIg during the study  
• 
Use of chronic PE (more than two treatment cycles performed at 4- to 8-week 
intervals) during the study  
• 
Treatment with alternative IL-6/ IL-6-R inhibitory therapy (e.g., tocilizumab) 
• 
Treatment with total body irradiation, or bone marrow transplantation  
• 
Treatment with B- and/or T-cell depleting agents including but not limited to 
rituximab, inebilizumab and alemtuzumab  
• 
Treatment with complement inhibitors (e.g., eculizumab), neonatal Fc receptor 
antagonists, or anti−B-lymphocyte stimulator monoclonal antibody (e.g., belimumab)  
• 
ISTs except for background therapy permitted per protocol (i.e., OCSs, azathioprine, 
mycophenolate mofetil, cyclosporine, tacrolimus) 
• 
Antibiotics telithromycin and fluoroquinolones (e.g., ciprofloxacin, moxifloxacin and 
levofloxacin)  
• 
Botulinum toxin 
• 
D-penicillamine 
• 
Quinine (e.g., chloroquine)  
• 
Treatment with any investigational agent within 24 weeks prior to screening or 
5 drug-elimination half-lives of the investigational drug (whichever is longer) and 
until the end of the study 
• 
Immunization with live or live attenuated vaccine within 6 weeks prior to baseline 
and until the end of the study 
• 
Chinese herbal medicine preparations 
 
Participants who receive any of these prohibited therapies may be required to 
permanently discontinue study treatment (see Section 4.6.1).  The Medical Monitor 
should be contacted to discuss permanent discontinuation of study treatment.  


 
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The use of prohibited therapies defined above must be recorded on the eCRF.  Adverse 
events related to the administration of these therapies must be documented on the 
appropriate eCRF. 
4.4.4 
Additional Restrictions 
AChEIs should not be taken for 10 hours prior to completion of efficacy assessments 
including QMG and MGC testing at each study visit (except screening visit) if medically 
safe to do so. 
4.4.5 
Immunizations and Vaccinations 
It is recommended for all patients to keep up to date with all immunizations according to 
local immunization guidelines prior to randomization/Day 1 in the study. 
• 
The use of any live and live attenuated vaccines is not allowed within 6 weeks prior 
to randomization/Day 1 and during the entire duration of the study.  
• 
Vaccines (including COVID-19 vaccines) other than live or live attenuated are 
permitted during the study.  Vaccines may be less effective in immunocompromised 
patients, however, the effect of satralizumab upon the efficacy of vaccinations is 
currently unknown.  It is recommended that vaccines should be given in accordance 
with the approved/authorized vaccine label and official local immunization guidance. 
 
Refer to the current Satralizumab Investigator’s Brochure for further details regarding 
vaccinations. 
Please contact the Medical Monitor for questions on vaccinations in patients participating 
in this study. 
4.5 
STUDY ASSESSMENTS  
The schedule of activities to be performed during the study is provided in Appendix 1 
(DB period) and Appendix 2 (OLE period).  All activities should be performed and 
documented for each patient.   
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable. 
At applicable sites, certain study assessments, including study drug administration, may 
be performed by a mobile nurse (MN) professional at the patient's home or another 
suitable location, to improve access and convenience for patients participating in the 
study.  The Sponsor will select a healthcare company that will be responsible for 
providing MN services for participating sites (the MN vendor).  The MN vendor is 
responsible for ensuring that all MN professionals are licensed, qualified, and in good 
standing, as per applicable regulations, and that appropriate background checks have 
been performed.  If the investigator at a participating site determines that MN services 
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in MN visits, the MN network will communicate with the patient and the patient's site.  
MN visits will be scheduled on specified visit days, to allow for relevant assessments to 
be performed by the MN professional.  The schedule of activities (see Appendix 1 and 
Appendix 2) will specify the assessments that may be performed by an MN professional. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomization/Day 1.  The investigator will maintain a detailed 
record of all patients screened and to document eligibility or record reasons for 
screening failure, as applicable.  
4.5.2 
Screening Assessments 
Once informed consent is obtained, screening assessments can occur.  Screening tests 
and evaluations will be performed within 28 days prior to Day 1, unless otherwise 
specified. The 28-day screening period may be extended, in exceptional circumstances, 
but cannot exceed 42 days.  If the screening period is extended, the safety laboratory 
assessments specified in Section 4.1.2.4 must be completed within 28 days prior to 
randomization/Day 1.   
If a patient does not meet any laboratory inclusion or exclusion criteria at screening, the 
test can be repeated within 42 days of screening (i.e., retest).  A retest is defined as any 
assessment repeated within 42 days of screening. 
If a patient has not met all of the inclusion/exclusion criteria within 42 days (screen 
failure) of the original screening visit, re-screening (which refers to repeating the whole 
screening process) can be conducted once.  Each patient must be re-consented before 
re-screening occurs.  As part of the re-screening process, a TB test and hepatitis tests, 
MG autoantibody (AChR, MuSK, LRP4 serotype confirmation by the central laboratory) 
testing3 are not required if each of them is conducted within 12 weeks prior to baseline.  
Screen failures are defined as patients who sign the Informed Consent Form but are not 
subsequently enrolled.  If a patient is a considered a screen failure, the investigator will 
maintain a record of reasons for screen failure.  
If a patient experiences myasthenic crisis during the screening period, the patient should 
be treated as a screen failure and should receive rescue medication as outlined in 
                                              
3 For sites in the Netherlands and Germany, the central laboratory autoantibody tests at screening to 
confirm gMG diagnosis is not required.  


 
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Section 4.3.3.  The patient can be re-screened and must re-sign the Informed Consent 
Form. 
Please see Appendix 1 for the schedule of screening assessments for adult and 
adolescent patients who enter the DB period and Appendix 2 for adolescent patients who enter 
directly in the OLE period. 
4.5.2.1 
Hepatitis B Screening 
Patients who are HBsAg positive will be excluded from the study.   
If total HBcAb status is positive, hepatitis B virus (HBV) DNA will be measured at a 
central laboratory.  If HBV DNA is undetectable, the patient may be enrolled.  In these 
cases, HBV DNA measurements must be performed regularly at approximately 
12-weekly intervals during the study.  If HBV DNA is detectable, the patient must be 
excluded. 
4.5.2.2 
Hepatitis C Screening 
Patients with negative hepatitis C serology can be enrolled.  Patients with positive 
hepatitis C serology will be excluded from the study.  However, if HCV RNA is 
undetectable ≥ 12 weeks after HCV treatment completion, the patient can be enrolled. 
4.5.2.3 
Screening for Tuberculosis 
For entry into this study, patients should be screened for TB at the site according to the 
instruction for TB screening (see Appendix 5).  The results of the screening tests will be 
reported on the eCRF.  If the patient is positive for latent TB, appropriate 
anti-mycobacterial therapy must be administered for at least 4 weeks before initiating 
study drug administration in this study.  For further details on screening for TB, see 
Appendix 5. 
4.5.3 
Medical History, Baseline Conditions, Concomitant Medication, 
and Demographic Data 
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking 
history, and use of alcohol and drugs of abuse, will be recorded at baseline.  The 
investigator will record on the eCRF: 
• 
The date of MG diagnosis, 
• 
Diagnostic criteria used to establish the diagnosis of gMG (clinical presentation, 
autoantibody presence, abnormal neuromuscular transmission demonstrated by 
either single-fiber electromyography or repetitive nerve stimulation, positive 
edrophonium chloride test result, response to AChEI), 
• 
Antibody type, titer levels, and the date of testing 
• 
MGFA Class at time of diagnosis and at time of screening 
• 
History of thymectomy with the date of the procedure 


 
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• 
History of MG exacerbations and crisis 
• 
History of IST/immunomodulatory therapy use (including anti-CD20 agents, 
complement inhibitors, acute and maintenance IVIg, and PE therapies), inclusive of 
drug name, prescribed maximum dose, treatment duration, and reason for treatment 
failure 
• 
History of refractory MG defined as: 
– A failure to respond to treatment with OCS and two or more 
immunosuppressive/immunomodulatory therapies either in combination or as 
monotherapy, used in adequate doses for an adequate duration, with persistent 
symptoms or side effects that limit functioning, as defined by patient and 
physician for AChR + and LRP4 + patients (Sanders et al. 2016). 
– A failure to respond to rituximab used as a monotherapy or in combination with 
OCS after more than 6 months.  Treatment failure is defined either by persistent 
symptoms or side effects that limit functioning, as defined by patient and 
physician for MuSK + patients. 
• 
History of any hospital admissions for MG since diagnosis and within the last 2 
years 
• 
All medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements) used by the patient from screening  
At the time of each follow-up physical examination, adverse events and any changes in 
medications and allergies should be recorded. 
Demographic data will include age, sex, and self-reported race/ethnicity.  
4.5.4 
Physical Examinations 
A complete physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat, cardiovascular, 
respiratory, GI, dermatologic, musculoskeletal, and neurologic systems; genitourinary 
examinations may be performed if clinically indicated.  The neurologic examination, 
performed as part of the complete physical examination, should include an assessment 
of the mental status, cranial nerve function, motor function, sensory function, reflexes, 
coordination, and gait.  Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF. 
Limited, symptom-directed physical examinations should be performed at specified 
post-baseline visits and as clinically indicated.  Changes from baseline abnormalities 
should be recorded in patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF. 
4.5.5 
Vital Signs  
Vital signs will include measurements of respiratory rate, pulse rate, body temperature, 
and systolic and diastolic blood pressure while the patient is in a seated position.  Vital 


 
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signs will be measured just before dosing and 15 ( ± 5) minutes and 60 ( ± 5) minutes 
after dosing during the first five dosing visits of the DB, and OLE periods (i.e., if no 
missed doses, Week 0 to Week 12 of the DB and Week 0 to Week 12 of the OLE).  After 
the fifth study drug dose, vital signs should be measured only before study drug 
administration. 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions (e.g., television, cell phones). 
Record abnormalities observed at baseline on the General Medical History and Baseline 
Conditions eCRF.  At subsequent visits, record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF. 
4.5.6 
Laboratory, Biomarker, and Other Biological Samples 
Samples for the following laboratory tests will be sent to the central laboratory for 
analysis.  Instruction manuals and supply kits will be provided for all central laboratory 
assessments.  
• 
Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
absolute differential count (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, other cells) 
• 
Coagulation:  INR and fibrinogen 
• 
Serum chemistry:  sodium, potassium, chloride, calcium, phosphorous, ferritin, BUN, 
creatinine, total bilirubin, total protein, albumin, ALT, AST, ALP, gamma-glutamyl 
transpeptidase, lactate dehydrogenase, CRP, CK, lipase, and uric acid 
• 
Lipids:  total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides 
• 
Quantitative immunoglobulins:  IgA, IgG, IgM, and IgE 
• 
IgG subclass (IgG1, IgG2, IgG3 and IgG4) 
• 
T-, B- (defined by CD19 + ) and natural killer cells (TBNK panel)  
• 
Complement C3, C4 and CH50 
• 
Screening for HBV infection:  HBsAg, total HBcAb, and (if HBsAg test is negative 
and total HBcAb test is positive) HBV DNA.   
• 
Screening for HCV infection:  HCV antibody and (if HCV antibody test is positive) 
HCV RNA.  If a patient has a positive HCV antibody test at screening, an HCV RNA 
test must also be performed to determine if the patient has an HCV infection.  
• 
Serum pregnancy test at screening 
  
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
• 
Urinalysis (urinary glucose, urinary protein, urinary occult blood, urobilinogen) will be 
conducted at each site by dipstick.  If any abnormalities are detected on urine 


 
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dipstick tests, a complete urinalysis (including microscopic of examination of urine) 
and/or urine culture is to be performed (at local laboratory) as deemed necessary.  
• 
Interferon Gamma Release Assay as part of TB screening 
• 
Cortisol and low-dose ACTH stimulation test (if deemed necessary after Week 12 of 
the OLE period) 
• 
Pregnancy test: 
All female patients of childbearing potential (including those who have had a 
tubal ligation) will have a serum pregnancy test done centrally at the screening 
visit.  During the study, serum or urine pregnancy tests will be performed at the 
study site at subsequent visits.  For adolescent patients at the time of informed 
consent, urine β-human chorionic gonadotropin will be recommended during 
the study except screening in order to reduce the blood volume taken.  If a 
urine pregnancy test is positive, it must be confirmed by a serum pregnancy 
test. 
A female patient is considered to be of childbearing potential if she is 
postmenarcheal, has not reached a postmenopausal state ( ≥ 12 continuous 
months of amenorrhea with no identified cause other than menopause), and 
has not undergone surgical sterilization (removal of ovaries and/or uterus).  The 
definition of childbearing potential may be adapted for alignment with local 
guidelines or requirements. 
 
The following samples will be sent to the Sponsor or a designee for analysis: 
• 
PK/PD assessments:  serum samples for satralizumab concentration, IL-6, and 
sIL-6R 
• 
Immunogenicity assessments:  serum sample for ADA analysis 
• 
Serum samples for determination of autoantibodies at screening, e.g., anti-AChR, 
anti-MuSK, and anti-LRP4 4 
• 
Serum, plasma, blood, and peripheral blood mononuclear cells (PBMCs) samples 
for exploratory research on biomarkers potentially related to disease, drug, or 
clinical response and biomarker assay development 
  
Exploratory biomarker research may include, but will not be limited to, the following: 
• 
gMG-associated autoantibodies during the DB and OLE periods (e.g., anti-AChR, 
anti-MuSK, and anti-LRP4) 
• 
Biomarkers associated with inflammation and T- and B-cell function (e.g., IL-17 and 
B-cell subsets) 
• 
Live-cell assays in PBMCs, e.g., T- and B-cell activation and proliferation  
 
Research may involve extraction of DNA or RNA; analysis of mutations, single 
nucleotide polymorphisms, and other genomic variants; and genomic profiling through 
                                              
4 For sites in the Netherlands and Germany, the central laboratory autoantibody tests at screening to 
confirm gMG diagnosis are not required. 


 
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use of next-generation sequencing (NGS) of a comprehensive panel of genes. Genomic 
research will be aimed at exploring inherited characteristics.  NGS methods may include 
whole genome sequencing (WGS) or whole exome sequencing (WES) of blood 
samples, but only at participating sites (see Section 4.5.9). 
Screening serum, blood, plasma, and PBMC samples, including those collected from 
patients who do not enroll in the study, may be used for future research and/or 
development of disease-related tests or tools. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.10), biological samples will be destroyed 
no later than the time of completion of the final Clinical Study Report (CSR), with the 
following exceptions: 
• 
Serum samples collected for PK or immunogenicity analysis may be needed for 
additional immunogenicity characterization and for PK or immunogenicity assay 
development and validation; therefore, these samples will be destroyed no later than 
5 years after the final CSR has been completed. 
• 
Blood, serum, plasma, and PBMC samples collected for autoantibodies, biomarker 
research, and biomarker assay development will be destroyed no later than 10 
years after the final CSR has been completed.  However, the storage period will be 
in accordance with the Institutional Review Board/Ethics Committee (IRB/EC) 
approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis, including data on genomic variants, will be subject to 
the confidentiality standards described in Section 8.4. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication. 
Assessment of CRP, fibrinogen, satralizumab pharmacokinetics, IL-6, sIL-6R, ADAs, 
immunoglobulins, and complement (C3, C4, and CH50) will be performed in a blinded 
manner and results will not be available to site and Sponsor until database lock for 


 
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analysis of the DB period.  The iDMC will perform periodic unblinded safety reviews, 
which will include the laboratory parameters that are blinded to the sponsor and site.  
4.5.7 
Electrocardiograms 
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of activities (see Appendix 1 and Appendix 2), and may be obtained at 
unscheduled timepoints as indicated.  
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.  
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws).  Circumstances that may induce changes 
in heart rate, including environmental distractions (e.g., television, radio, conversation) 
should be avoided during the pre-ECG resting period and during ECG recording. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  The following should be recorded in the appropriate eCRF:  heart 
rate, RR interval, QRS interval, PR duration, uncorrected QT interval, and QT interval 
corrected through use of Fridericia’s formula (QTcF) on the basis of the machine 
readings of the individual ECG tracings.  Any morphologic waveform changes or other 
ECG abnormalities must be documented on the eCRF.  New or worsened abnormalities 
should be recorded as adverse events if clinically significant. 
If at a particular timepoint the mean QTcF is > 500 ms and/or > 60 ms longer than the 
baseline value, another ECG must be recorded, ideally within the next 5 minutes, and 
ECG monitoring should continue until QTcF has stabilized on two successive ECGs.  
The Medical Monitor should be notified.  SOC treatment may be instituted per the 
discretion of the investigator.  If a PK sample is not scheduled for that timepoint, an 
unscheduled PK sample should be obtained.  The investigator should also evaluate the 
patient for potential concurrent risk factors (e.g., electrolyte abnormalities, 
co-medications known to prolong the QT interval, severe bradycardia). 
4.5.8 
Clinical Outcome Assessments  
PRO and clinician-reported outcome (ClinRO) instruments will be completed to assess 
the treatment benefit of satralizumab.  In addition, PRO instruments will enable the 
capture of each patient's direct experience with satralizumab. 
PRO data will be collected through use of the following instruments:   
• 
MG-ADL 
• 
MG-QOL 15r 
• 
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• 
EuroQoL EQ-5D-5L (EuroQoL 5-Dimension Questionnaire) 
 
ClinRO data will be collected through use of the following instruments:   
• 
QMG  
• 
MGC 
 
Efficacy assessments scheduled on designated visits should be completed pre-dose on 
each dosing day and should be performed prior to any other study specific 
assessment, except for obtaining informed consent at screening.  It is recommended 
that patients complete the efficacy assessments in the morning.  If the clinical efficacy 
assessments cannot be performed in the morning, they should be performed at the 
same time of the day throughout the study.  Efficacy assessments should be performed 
in the following sequence (at each study visit including these assessments):  MG-ADL, 
MG-QOL 15r, Neuro−QoL Fatigue subscale, EuroQoL EQ-5D-5L, QMG, and MGC.  
AChEIs must be held for at least 10 hours before the QMG, and MGC assessments 
(consistent with the revised manual for the QMG test as recommended by the MGFA). 
4.5.8.1 
Data Collection Methods for Clinical Outcome Assessments 
Clinical outcome assessments will be self-administered (MG-QOL 15r, Neuro−QoL 
Fatigue Subscale, EuroQoL EQ-5D-5L) or interviewer-administered (MG-ADL, QMG, 
MGC) at specified timepoints during the study (see the schedule of activities in 
Appendix 1 and Appendix 2).  Instruments will be administered before the patient 
receives any information on disease status, prior to the performance of non-PRO 
assessments, and prior to the administration of study treatment, unless otherwise 
specified. 
PRO instruments, translated into the local language as appropriate, will be provided by 
the Sponsor to enable the appropriate instruments to be administered, in the correct 
order, at each specified timepoint.   
During clinic visits, PRO instruments should be administered as outlined below. 
• 
Patients' health status should not be discussed prior to administration of the 
instruments. 
• 
Sites must administer the official version of each instrument, as provided by the 
Sponsor.  Instruments must not be copied from the protocol. 
• 
Sites should allow sufficient time for patients to complete the instruments, estimated 
to be 20 minutes.  
• 
Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions. 
• 
MG-ADL will be administered by an examining investigator. 
• 
Patients should be instructed to answer questions to the best of their ability; there 
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• 
Site staff should not interpret or explain questions, but may read questions verbatim 
upon request. 
• 
Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments. 
• 
Site staff should review all completed instruments and should ask the patient to 
rectify any response that is not clearly marked in the appropriate location.  If a 
response is missing, site staff should ask the patient to complete the item or confirm 
that the item was intentionally left blank. 
 
ClinRO instruments will be completed at the clinic by the examining investigator at 
specified timepoints during the study (see the schedule of activities in Appendix 1 and 
Appendix 2).  ClinRO instruments will be administered prior to completion of the 
physical examination, prior to any safety assessments, and prior to the 
administration of study treatment.  The instruments will be provided by the Sponsor.  
The examining investigator must complete the official version of each ClinRO instrument 
provided by the Sponsor.  Instruments must not be copied from the protocol. 
4.5.8.2 
Description of Clinical Outcome Assessment Instruments 
Myasthenia Gravis Activities of Daily Living (MG-ADL) 
This instrument was developed for the trial of IVIg by Wolfe and colleagues (Wolfe et al. 
2019).  This is a PRO that combines two items on daily life activities—ability to brush 
teeth or comb hair, and limitations in the ability to rise from a chair—with six items 
reflecting other MG symptoms:  diplopia, ptosis, difficulty chewing, difficulty swallowing, 
voice/speech problems, and respiratory symptoms.  Each item is scored between 0 and 
3, and total scores range from 0 to 24, with higher scores indicating more disease 
severity.  The recall period should be the last 7 days prior to MG-ADL assessment.  An 
examining investigator (or designee) will administer the MG-ADL instrument. 
A sample of the MG-ADL questionnaire is included in Appendix 6. 
Quantitative Myasthenia Gravis (QMG) Score 
The QMG score was developed in the context of a clinical trial in MG and originally had 
eight items (Besinger et al. 1983); it was subsequently modified increasing the number 
of items to 13 (Tindall et al. 1987).  The QMG has several items that measure endurance 
or fatigability, taking into account the fluctuating nature of the disease.  These are as 
follows:  ptosis, diplopia on lateral gaze, eye closure (orbicularis oculi) weakness, 
swallowing 1/2 cup of water, speech during or following counting aloud from 1 to 50, 
percent predicted forced vital capacity, grip strength (two items), arm endurance (two 
items), leg endurance (two items), and neck flexion endurance.  All items are scored on 
a scale from 0 to 3, and total scores range from 0 to 39; higher scores indicate greater 
disease severity.  The test should be performed by the examining investigator as 
described in the QMG Manual. 
A sample of the QMG questionnaire is included in Appendix 7. 


 
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Myasthenia Gravis Composite (MGC) 
The MGC was developed recently aiming for a simple yet comprehensive measure of 
MG severity.  It was developed by combining items from other MG measures, on the 
basis of their performance in two clinical trials of mycophenolate in MG (Sanders et al. 
2008; Muscle Study Group 2008).  The final measure has ten items:  two ocular (diplopia 
and ptosis); four manual muscle test items (facial, neck, shoulder abduction, and hip 
flexion strength), and four patient-reported items (chewing, swallowing, breathing, and 
speech).  The patient-reported items have to be read to the patients, and the whole 
scale is completed by the examining investigator.  Total scores range from 0 to 50 for 
which higher scores indicate greater disease severity. 
Patients (adult and adolescent patients randomized in the DB period at study start) on AChEI 
should remain on stable doses throughout the DB period and until Week 12 of the OLE.  
AChEI should not be taken for at least 10 hours prior to QMG and MG composite testing 
at each visit (except screening visit), in order to reduce fluctuations in performance on 
functional tests due to the temporary symptomatic effects associated with AChEI use. 
A sample of the MGC questionnaire is included in Appendix 8. 
Myasthenia Gravis Quality of Life 15 revised version (MG-QOL15r) 
The MG-QOL15r was developed by simplifying the MG-QOL60 (Burns TM, Muscle 
Nerve 2008).  The instrument contains 15 items assessing the mobility (nine items), 
symptoms (three items), and general contentment and emotional well-being (three 
items).  Individual items are scored from 0 to 2 and the resulting measure scores ranges 
from 0 to 30, and higher scores indicate worse health-related quality of life (HRQoL). 
A sample of the MG-QOL15r questionnaire is included in Appendix 9. 
Neuro−QoL Fatigue Subscale 
The Neuro−QoL is a validated tool designed to evaluate the HRQoL in patients with 
chronic neurological disease (Gershon et al. 2012).  The Fatigue Subscale is 
implemented as an eight-item, stand-alone short form that assesses the multi-
dimensional aspects of fatigue ranging from general tiredness to debilitating exhaustion 
that Impacts activities of daily living.  Raw scores range from 8 to 40 with higher values 
indicating greater fatigue.  
A sample of the Neuro−QoL Fatigue Subscale is included in Appendix 13. 
EuroQoL EQ-5D-5L  
The EuroQoL EQ-5D-5L is a validated self-report health status questionnaire that is 
used to calculate a health status utility score for use in health economic analyses 
(EuroQoL Group 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013) 
(see Appendix 10).  There are two components to the EQ-5D-5L:  a five-item health 
state profile that assesses mobility, self-care, usual activities, pain/discomfort, and 


 
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anxiety/depression, as well as a Visual Analogue Scale (VAS) that measures health 
state.  The EQ-5D-5L is designed to capture the patient's current health status.  
Published weighting systems allow for creation of a single composite score of the 
patient's health status.  The EQ-5D-5L takes approximately 3 minutes to complete.  It will 
be used in this study for informing pharmacoeconomic evaluations. 
A sample of the EQ-5D-5L questionnaire is included in Appendix 10. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a tool used to assess the lifetime suicidality of a patient and to track 
suicidal events throughout treatment.  The scale will be administered at the time points 
indicated in the schedule of activities (see Appendix 1 and Appendix 2) for prompt 
recollection of suicidal ideation, including the intensity of the ideation, behavior and 
attempts with actual and potential lethality.  The "C-SSRS at baseline" will be collected 
at baseline, and the "C-SSRS since last visit" will be collected at subsequent visits.   
Examples of the C-SSRS forms are included in Appendix 11 and Appendix 12. 
4.5.9 
Blood Samples for Whole Genome Sequencing or Whole 
Exome Sequencing  
At participating sites, blood samples will be collected for DNA extraction to enable WGS 
or WES to identify variants that are predictive of response to study drug, are associated 
with progression to a more severe disease state, are associated with susceptibility to 
developing adverse events, can lead to improved adverse event monitoring or 
investigation, or can increase the knowledge and understanding of disease biology and 
drug safety.  Research will be aimed at exploring inherited characteristics.  The samples 
may be sent to one or more laboratories for analysis. 
Collection and submission of blood samples for WGS or WES is contingent upon the 
review and approval of the exploratory research by each site's IRB/EC and, if applicable, 
an appropriate regulatory body.  If a site has not been granted approval for WGS or 
WES, this section of the protocol (Section 4.5.9) will not be applicable at that site. 
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS and WES provide a comprehensive characterization of the genome and exome, 
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches or new methods for monitoring 
efficacy and safety or predicting which patients are more likely to respond to a drug or 
develop adverse events.  Data will be analyzed in the context of this study but may also 
be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 


 
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For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
Blood samples collected for WGS or WES are to be stored until they are no longer 
needed or until they are exhausted.  However, the storage period will be in accordance 
with the IRB/EC -approved Informed Consent Form and applicable laws (e.g., health 
authority requirements). 
Refer to Section 4.5.6 for details on use of samples after patient withdrawal, 
confidentiality standards for data, and availability of data from biomarker analyses. 
4.5.10 
Optional Samples for Research Biosample Repository  
4.5.10.1 
Overview of the Research Biosample Repository  
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR samples will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future. 
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be analyzed to achieve one or 
more of the following objectives: 
• 
To study the association of biomarkers with efficacy or disease progression 
• 
To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation 
• 
To increase knowledge and understanding of disease biology and drug safety 
• 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
• 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.10.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for RBR sampling, this section of the protocol (Section 4.5.10) 
will not be applicable at that site. 


 
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4.5.10.3 
Sample Collection 
The following samples will be stored in the RBR and used for research purposes and 
assay development, including, but not limited to, research on biomarkers related to 
satralizumab, diseases, or drug safety: 
• 
Leftover blood, serum, plasma, PBMCs, and any derivatives thereof (e.g., DNA, 
RNA, proteins, peptides)  
• 
Serum and plasma samples collected at baseline and subsequent visits for RBR 
 
The above samples may be sent to one or more laboratories for analysis, which may 
include proteins, metabolites, and immune cell assessment and/or profiling.  DNA 
samples may be used for the analysis of germline or somatic variants via WGS, WES, or 
other genomic analysis methods.  Genomics is increasingly informing researcher's 
understanding of disease pathobiology.  WGS and WES provide a comprehensive 
characterization of the genome and exome, respectively, and, along with clinical data 
collected in this study, may increase the opportunity for developing new therapeutic 
approaches or new methods for monitoring efficacy and safety or predicting which 
patients are more likely to respond to a drug or develop adverse events. 
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the IRB/EC 
approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
4.5.10.4 
Confidentiality 
RBR samples and associated data will be labeled with a unique patient identification 
number. 
Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication. 


 
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Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
4.5.10.5 
Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR samples.  Patients 
who decline to participate will not provide a separate signature. 
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research. 
4.5.10.6 
Withdrawal from the Research Biosample Repository 
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  However, if RBR samples 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 
his or her RBR samples during the study, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and must enter the date of withdrawal on the RBR Research Sample 
Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent to the 
testing of his or her RBR samples after closure of the site, the investigator must inform 
the Sponsor by emailing the study number and patient number to the following email 
address: 
global.rcr-withdrawal@roche.com 
A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study. 


 
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4.5.10.7 
Monitoring and Oversight 
RBR samples will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, IRB/EC review, 
and health authority inspections by providing direct access to source data and 
documents related to the RBR samples. 
4.6 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment if they experience any of the 
following: 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment 
• 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient 
• 
Pregnancy 
• 
Malignancy 
• 
Severe hypersensitivity or anaphylactic reaction to satralizumab 
• 
GI perforation 
• 
Unacceptable toxicity 
• 
Significant non-compliance with protocol procedures 
• 
Meets the discontinuation criteria in the risk mitigation and dose modification 
strategy (see Section 5.1) 
 
Patients may need to permanently discontinue study treatment if they receive prohibited 
therapy. 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
It is important to distinguish between "withdrawal from treatment / discontinue treatment" 
and "withdrawal from study."  Patients who withdraw from treatment should be 
encouraged to remain in the study for the full duration of the SFU. 
Patients who discontinue study treatment during the DB period for any reason should 
continue with all remaining assessments defined in the protocol.  However, patients who 


 
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are unwilling to return to the clinic for all assessments will be asked to complete an EOT 
visit within 4 weeks and a SFU visit 12 weeks after the final dose of study drug.  
Patients who discontinue study treatment during the OLE period will be asked to 
complete the EOT visit within 4 weeks and a SFU visit 12 weeks after the final dose of 
study drug.  
4.6.2 
Patient Discontinuation from the Study 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time. 
Reasons for patient discontinuation from the study may include, but are not limited to, 
the following: 
• 
Patient withdrawal of consent 
• 
Study termination or site closure 
• 
Adverse event 
• 
The participant enrolls into another interventional clinical study in which an 
investigational treatment or approved therapy for investigational use is administered. 
• 
Loss to follow-up 
• 
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor 
 
Every effort should be made to obtain a reason for patient discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  Patients 
who withdraw from the study will not be replaced. 
4.6.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients 
• 
Patient enrollment is unsatisfactory 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.   
4.6.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 


 
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• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
• 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
Satralizumab is not approved for the treatment of gMG.  The safety plan for patients in 
this study is based on clinical experience with satralizumab in completed and ongoing 
studies, and safety risks observed with medicines in the same class (i.e., anti−IL-6R 
antibodies).  The anticipated important safety risks for satralizumab are outlined below.  
Please refer to the most recent Satralizumab Investigator's Brochure for a complete 
summary of safety information.  
Several measures will be taken to ensure the safety of patients participating in this 
study.  Eligibility criteria have been designed to exclude patients at higher risk for 
toxicities (see Section 4.1.2).  Patients will undergo safety monitoring during the study, 
including assessment of the nature, frequency, and severity of adverse events.  In 
addition, guidelines for managing adverse events, including criteria for treatment 
interruption or discontinuation, are provided below. 
5.1.1 
Risks Associated with Satralizumab 
5.1.1.1 
Infections 
Treatment with IL-6R inhibitors may increase the risk of infections, including serious 
infections.  Treatment with IL-6R inhibitors suppresses acute-phase reactions (fever, 
increase in CRP, etc.) induced by IL-6 and accordingly suppresses signs and symptoms 
associated with infection, which may delay the detection of infection. 
Reactivation of chronic hepatitis B has been observed with other treatments that affect 
the immune system.  TB reactivation has also been reported with other anti−IL-6R 
antibodies. 
The allowed IST background treatments (OCSs, azathioprine, mycophenolate mofetil, 
cyclosporin A, tacrolimus) for patients with gMG participating in this study have been 
associated with serious infections. 
The following participants will be excluded from this study (see Section 4.1.2): 
• 
Participants with active or recurrent bacterial, viral, fungal, mycobacterial infection, 
or other infection (excluding fungal infection of nail beds or dental caries) at baseline 
• 
Participants with infection requiring hospitalization or treatment with IV anti--infective 
agents within 4 weeks prior to baseline visit or oral anti-infective agents within 2 
weeks prior to baseline visit  


 
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• 
Participants with evidence of latent or active tuberculosis (excluding patients 
receiving chemoprophylaxis for latent TB infection) 
• 
Participants with positive screening tests for hepatitis B or hepatitis C  
• 
Participants who received any live or live attenuated vaccine within 6 weeks prior to 
baseline 
 
Management of Infections and Serious Infections 
• 
Patients should be closely monitored for the development of signs and symptoms of 
infection, because signs and symptoms of acute inflammation may be lessened as a 
result of suppression of the acute phase reactants. 
• 
Patients must be instructed to contact their physician immediately when any 
symptoms suggesting infection appear, in order to ensure rapid evaluation and 
appropriate treatment. 
• 
If a patient develops an infection, administration of the study drug is to be 
interrupted until the infection is controlled.  
• 
If a patient develops a serious infection or Grade ≥ 3 infection, administration of the 
study drug is to be interrupted until the infection is resolved.  Upon resolution of the 
infection, the treating physician should conduct a benefit−risk assessment before 
resuming treatment with the study drug.  
• 
If a participant develops hepatitis B infection (new onset or reactivation), the study 
drug should be discontinued. 
• 
Live or live attenuated vaccines are not to be given during the course of the study 
and within 6 weeks prior to baseline as clinical safety has not been established. 
 
Treatment of Infections and Serious Infections 
Treatment with the following antibiotics should be avoided if possible, because they have 
been associated with exacerbations of MG (see Section 4.4.2 for cautionary therapy):  
• 
Macrolide antibiotics (e.g., erythromycin, azithromycin, clarithromycin) 
• 
Aminoglycoside antibiotics (e.g., gentamycin, neomycin, tobramycin)  
• 
Treatment with antibiotics telithromycin and fluoroquinolones (e.g., ciprofloxacin, 
moxifloxacin and levofloxacin) is prohibited during the study (see Section 4.4.3 for 
Prohibited Therapy)  
  
5.1.1.2 
Hypersensitivity 
Anaphylaxis and hypersensitivity reactions are considered a potential risk for all biologic 
medications, including satralizumab.   
The symptoms or signs of hypersensitivity include, but are not limited to, blood pressure 
decrease, dyspnea, loss of consciousness, dizziness, nausea, vomiting, fever, chills, 
urticaria, itchiness, flushing, etc.  


 
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Management of Possible Hypersensitivity Reactions to Satralizumab 
• 
SC injections should be administered at the study sites.  Patients should stay in the 
clinic/hospital for at least one hour after study drug administration for the first five 
doses of study drug in order to receive treatment immediately in case anaphylaxis 
occurs.  Study sites should have medications (e.g., corticosteroid, antihistamine, 
and epinephrine) and access to resuscitation facilities. 
• 
Administration of the study drug outside of the study site might be allowed during 
the OLE period, from OLE Week 24 onward (see Section 4.3.2), if the investigator 
determines that it is appropriate.   
• 
Patients and caregivers will be provided with emergency contact information by the 
site.  Patients and caregivers should be instructed to recognize the signs and 
symptoms of hypersensitivity reactions and to seek immediate medical attention if 
the patient develops symptoms of acute hypersensitivity reactions.  Patients and 
caregivers should confirm with the investigator whether treatment with study drug 
may be continued. 
• 
If an anaphylactic reaction or other serious hypersensitivity reaction occurs, the 
study drug should be discontinued.  
• 
For other hypersensitivity reactions, a decision to continue or discontinue treatment 
with satralizumab will be made by the investigator in consultation with the Medical 
Monitor, taking into account the benefits and risks. 
  
5.1.1.3 
Liver Enzyme and Bilirubin Elevations  
It has been reported that IL-6 appears to have a hepato-protective effect on various 
forms of liver injury and promotes hepatocyte regeneration.  
During the DB period of the Phase III studies in NMOSD patients, mild and moderate 
elevations of liver transaminases (ALT or AST) were observed with satralizumab 
treatment.  Elevations of ALT or AST > 3 × ULN were not associated with increases in 
bilirubin. 
Patients with AST or ALT > 1.5 × ULN at screening, will be excluded from the study. 
Liver function markers should be closely monitored, especially when satralizumab is 
administered concomitantly with hepatotoxic drugs, or to patients with elevated 
transaminases (in the range of ULN to 1.5 × ULN).  Some of the allowed background 
therapies, mycophenolate mofetil, azathioprine, tacrolimus, and cyclosporine A, are 
hepatotoxic.  Please refer to the local prescribing information of the background 
treatment(s) for details on their individual safety profile(s). 
Recommended dose interruption or discontinuation for elevated liver enzymes is shown 
in Table 8. 


 
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Table 8 
Management of Patients with Elevated Transaminases 
(ALT and/or AST) 
ALT or AST 
Values 
Action to Be Taken 
> 1 to 3 × ULN 
• 
Reduction (interruption if necessary) of concomitant hepatotoxic 
drugs could be considered. 
• 
For persistent increases in this range, the study drug could be 
interrupted until AST and ALT is below ULN. 
> 3 to 5 × ULN 
• 
Don’t dose study drug, and laboratory tests (ALT, AST, ALP and 
TBL) should be repeated within 72 hours to confirm value.  Patients 
who are far away from the trial site may be retested locally if prompt 
return to the trial site is difficult. 
• 
The presence of clinical symptoms should be queried.   
• 
Study drug should be interrupted until AST and ALT is below 
3 × ULN. Follow recommendations outlined above for ALT/AST 
values >1 to 3 × ULN. 
• 
If at least one of following is associated with the ALT/AST increase, 
study drug should be discontinued immediately: 
– 
TBL > 2 × ULN and/or 
– 
INR > 1.5 × ULN and/or 
– 
Appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia 
> 5 × ULN 
• 
Don’t dose study drug.  Laboratory tests (ALT, AST, ALP, and TBL) 
should be repeated within 72 hours.  If value is confirmed, study 
drug should be discontinued immediately and gastroenterologist 
should be contacted. 
• 
The presence of clinical symptoms should be queried.  
• 
If prompt return to the trial site is difficult, the patients may be 
retested locally. 
• 
Repeat LFT weekly until AST or ALT are ≤ 1.5 × ULN. 
LFT=  liver function test; TBL=total bilirubin; ULN=upper limit of normal. 
  
5.1.1.4 
Neutropenia 
In the DB period of the Phase III studies in NMOSD patients, decreases in neutrophil 
counts (including Grade 3 and Grade 4) occurred following treatment with satralizumab.  
The majority of neutrophil decreases were transient or intermittent. 
Participants with a low neutrophil count (< 2 × 103/µL) will be excluded from the study 
(see Section 4.1.2.4). 
Recommended dose interruption or discontinuation for absolute neutrophil counts (ANC) 
decreases are shown in Table 9.  


 
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Table 9 
Management of Neutropenia Low Neutrophil Count 
ANC (/µL) 
Action to Be Taken 
 > 1,000 
• Maintain dose. 
500−1,000 
• If neutropenia persists, the study drug should be interrupted until ANC 
is above 1,000/µL (for restarting study drug administration please refer 
to Section 4.3.2.2). 
• If ANC was under 1,000/µL at the previous laboratory test, ANC must be 
checked before treatment with the study drug (e.g., ANC test at site). 
 < 500 
• Study drug should be discontinued. 
ANC = absolute neutrophil count. 
 
5.1.1.5 
Thrombocytopenia 
In Phase III studies in NMOSD patients, decreases in platelet counts were observed in 
patients treated with satralizumab.  The majority of the decreased platelets were 
transient and not below 75 × 109/L.   
Patients with Platelet count < 10 × 104/µL at screening will be excluded from the study 
(see Section 4.1.2.4). 
Recommended dose interruption on the basis of platelet counts are shown in Table 10. 
Table 10 Management of Low Platelet Count 
Platelet Count (/µL） 
Action 
 > 75,000 
• Maintain dose. 
50,000−75,000 
• If thrombocytopenia persists, the study drug should be 
interrupted until platelet count is above 75,000 cells/µL 
(for restarting study drug administration please refer to 
Section 4.3.2.2). 
 < 50,000 
• The study drug should be discontinued. 
  
5.1.1.6 
Elevations in Lipid Levels 
In DB period of the Phase III studies in NMOSD patients, elevations in total cholesterol 
and triglycerides were observed more often in patients treated with satralizumab 
compared with placebo.   
Elevations in lipid levels in study participants should be managed according to local 
guidelines. 


 
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5.1.1.7 
Laboratory Abnormalities Associated with the 
Pharmacodynamic Effect of Satralizumab 
In addition to the above abnormal laboratory parameters, in the Phase III studies with 
satralizumab in NMOSD patients, decreases in CRP, fibrinogen and complement 
(C3, C4 and CH50) were observed, which are anticipated PD effects of satralizumab. 
5.1.1.8 
CYP450 Enzyme Normalization 
Elevation of serum IL-6 levels is known to be associated with inhibition of CYP450 
enzyme activity.  Blockade of IL-6 signaling by satralizumab may result in normalization 
of CYP450 activity and therefore increases in the metabolism of CYP450 substrates.  
Caution should therefore be exercised when starting or discontinuing study treatment in 
patients also receiving substrates of CYP450 3A4, 1A2, 2C9 or 2C19, including some 
immunosuppressive agents (e.g., tacrolimus, cyclosporine), and particularly those with a 
narrow therapeutic index (such as warfarin, carbamazepine, phenytoin, and 
theophylline), and doses adjusted if needed.   
Please refer to Section 4.4.2.1 for further details.  
Given the prolonged terminal drug-elimination half-life of satralizumab, the effect of 
satralizumab may persist for several months after stopping therapy. 
5.1.2 
Other Risks Associated with Drugs in the Same Class 
5.1.2.1 
Gastrointestinal Perforations (Complications of Diverticulitis)  
GI perforations have been reported rarely in patients with RA treated with other 
anti−IL-6R antibodies.  IL-6R inhibition may suppress the acute symptoms (abdominal 
pain, pyrexia, etc.) associated with diverticulitis, etc., causing delayed diagnosis and 
progression to perforation.  
Patients with a history of diverticulitis or concurrent severe GI disorders (such as 
symptomatic diverticulosis) that, in the investigator’s opinion, may lead to increased risk 
of complications such as GI perforation are excluded from the study. 
Special caution should be exercised in those patients who receive background therapy 
that has been associated with a risk of GI perforation, including tacrolimus, azathioprine, 
mycophenolate mofetil, and OCSs.  Please refer to the local prescribing information of 
the background therapy for additional details on the risk of GI perforation. 
Management of Patients with (Suspected) Gastrointestinal Perforation 
• 
Patients presenting with symptoms potentially indicative of complicated diverticulitis, 
such as abdominal pain, hemorrhaging, and/or unexplained change in bowel habits 
with fever should be evaluated promptly for early identification of diverticulitis which 
can be associated with GI perforation and appropriate measures taken.  The study 
drug should be discontinued for patients who develop GI perforation.  Patients 
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diverticular disease, and they should be instructed to alert their healthcare provider 
as soon as possible if these symptoms arise. 
• 
In patients who receive OCS and/or non-steroidal anti-inflammatory drugs, 
prophylactic treatment with proton pump inhibitors or H2 blocker should be 
considered.  
 
5.1.2.2 
Malignancies 
Although malignancies have been reported in patients given other IL-6R antibodies, 
there have been no reports to date that there is an appreciable increase in the 
occurrence of malignancies.  No increased risk of malignancies has been observed in 
clinical trials with satralizumab. 
Patients with a history of malignancy within the last 5 years prior to study entry, including 
solid tumors, hematologic malignancies and in situ carcinoma (except basal cell and 
squamous cell carcinomas of the skin, or in situ carcinoma of the cervix uteri that have 
been completely excised and cured), will be excluded from the study 
(see Section 4.1.2.3). 
 
Management of Patients with Malignancies 
The study drug should be discontinued in patients with malignancies (with the exception 
of local basal or squamous cell carcinoma of the skin that is completely excised with free 
margins). 
5.1.2.3 
Demyelinating Disorders 
Demyelinating diseases, including multiple sclerosis and chronic inflammatory 
demyelinating polyneuropathy, have been reported in patients with RA administered with 
another anti−IL-6R antibody, but it is not known whether there is a causal relationship.  If 
symptoms suggestive of a demyelinating disorder are reported, a complete neurological 
examination should be performed and additional diagnostic studies performed if 
indicated. 
5.1.3 
Concomitant Immunosuppressive Treatment 
Patients receiving background treatment with allowed ISTs should also be informed of 
the risks associated with taking OCSs, azathioprine, mycophenolate mofetil, tacrolimus, 
and cyclosporine A, as per local prescribing information.  
5.1.4 
Management of Patients Who Experience Adverse Events 
5.1.4.1 
Treatment Interruption or Discontinuation 
Satralizumab treatment may be interrupted or discontinued in patients who experience 
an adverse event or abnormal laboratory value (see Section 5.1.1).  Satralizumab may 
be suspended for reasons other than adverse events (e.g., surgical procedures) at the 
investigator’s discretion following consultation with the Medical Monitor.  The investigator 
may consult the Medical Monitor to determine the acceptable length of treatment 
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5.1.4.2 
Management Guidelines for Adverse Events 
Guidelines for management of specific adverse events are presented in Section 5.1.1.   
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.9 
and 5.3.5.10 for more information) 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Is fatal (i.e., the adverse event actually causes or leads to death) 
• 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.11) 


 
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• 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions) 
• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]; see 
Section 5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.3.5.7) 
• 
Suspected transmission of an infectious agent by the study drug, as defined below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
 


 
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5.2.4 
Selected Adverse Events  
Additional data will be collected and/or analyzed for the following selected adverse 
events: 
• 
Infections 
• 
Injection reactions, adverse events considered injection reactions, which occur 
during or within 24 hours after study drug administration and are judged to be 
related to the study drug injection 
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.4−5.6.  
The investigator is also responsible for reporting medical device complaints (see 
Section 5.4.4). 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  
All adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events will be reported until 12 weeks after the 
final dose of study drug. 
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 


 
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5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 11 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
Table 11 Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration: 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
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• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Injection Reactions  
Adverse events, considered to be injection reactions, that occur during or within 
24 hours after study drug administration and are judged to be related to study drug 
injection should be captured as a diagnosis (e.g., "injection related reaction", 
"injection-site reaction" or "anaphylactic reaction") on the Adverse Event eCRF.  If 
possible, avoid ambiguous terms such as "systemic reaction."  Associated signs and 
symptoms should be recorded on the dedicated Injection Reaction eCRF.  If a patient 
experiences both a local and systemic reaction to the same dose of study drug, each 
reaction should be recorded separately on the Adverse Event eCRF, with signs and 
symptoms also recorded separately on the dedicated Injection Reaction eCRF. 
5.3.5.2 
 Diagnosis versus Signs and Symptoms 
For adverse events other than injection reactions (see Section 5.3.5.1), a diagnosis (if 
known) should be recorded on the Adverse Event eCRF rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases).  However, if a constellation of signs and/or symptoms cannot 
be medically characterized as a single diagnosis or syndrome at the time of reporting, 
each individual event should be recorded on the Adverse Event eCRF.  If a diagnosis is 
subsequently established, all previously reported adverse events based on signs and 
symptoms should be nullified and replaced by one adverse event report based on the 
single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 


 
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• 
If a severe GI hemorrhage leads to renal failure, both events should be reported 
separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Is clinically significant in the investigator's judgment  
 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 


 
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If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range (e.g., 
"elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator's judgment  
 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × ULN) in combination with either an elevated 
total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin 
> 2 × ULN 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with clinical jaundice 
 


 
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The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2). 
5.3.5.8 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of gMG. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
If the death is attributed solely to progression of gMG, "generalized myasthenia gravis 
progression" should be recorded on the Adverse Event eCRF.   
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.9 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.10 
Lack of Efficacy or Worsening of Generalized Myasthenia 
Gravis 
Events that are clearly consistent with the expected pattern of the underlying disease 
should not be recorded as adverse events.  These data will be captured as efficacy 
assessment data only.  If there is any uncertainty as to whether an event is due to 
clinical deterioration (gMG exacerbation), it should be reported as an adverse event. 


 
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5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.   
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol (e.g., for study drug administration)  
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
– 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
– 
The patient has not experienced an adverse event 
• 
Hospitalization due solely to progression of the underlying disease, gMG 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
• 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.12 
Cases of Overdose, Medication Error, Drug Abuse, or Drug 
Misuse 
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as "special situations"), are defined as follows: 
• 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
• 
Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose 
• 
Medication error:  accidental deviation in the administration of a drug  
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
• 
Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm 
• 
Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse 
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient. 


 
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Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, the event should be 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).  For satralizumab or matching placebo, adverse events 
associated with special situations should be recorded as described below for each 
situation: 
• 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 
• 
Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box. 
• 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
• 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
• 
Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box. 
• 
Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes. 
• 
 Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box. 
• 
Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes. 
 
In addition, all special situations associated with satralizumab or matching placebo, 
regardless of whether they result in an adverse event, should be recorded on the 
Adverse Event eCRF as described below: 
• 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
• 
Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box. 
• 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 
• 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details. 


 
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• 
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details. 
• 
Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box. 
• 
Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes. 
• 
Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box. 
• 
Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes. 
• 
Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box. 
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
5.3.5.13 
Patient-Reported or Clinician-Reported Outcome Data 
Adverse event reports will not be derived from PRO or ClinRO data by the Sponsor.  
Sites are not expected to review the PRO or ClinRO data for adverse events. 
5.3.5.14 
Safety Biomarker Data  
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on patient 
management. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements) 


 
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• 
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements) 
• 
Pregnancies (see Section 5.4.3 for details on reporting requirements) 
• 
Medical device complaints (see Section 5.4.4 for details on reporting requirements) 
 
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event's outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Medical Monitors and Emergency Medical Contacts 
Contact Information for All Sites  
 
To ensure the safety of study patients access to Medical Monitor is available 24 hours 
per day, 7 days per week. An Emergency Medical Call Center will also be available 
24 hours per day, 7 days per week.   The Emergency Medical Call Center will connect 
the investigator with an Emergency Medical Contact, provide medical translation service 
if necessary, and track all calls.  Contact information, including toll-free numbers for the 
Emergency Medical Call Center, will be distributed to investigators.  
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Adverse Event/Special Situations Form provided to investigators 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the event), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators. 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 12 weeks after the final dose of study drug.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 


 
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electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Adverse 
Event/Special Situations Form provided to investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the event), either by faxing or by scanning and emailing the form using the 
fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.   
Instructions for reporting serious adverse events that occur > 12 weeks after the final 
dose of study treatment are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study or 
within 3 months after the final dose of study drug.  A paper Clinical Trial Pregnancy 
Reporting Form should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the pregnancy), either by 
faxing or by scanning and emailing the form using the fax number or email address 
provided to investigators.  Pregnancy should not be recorded on the Adverse Event 
eCRF.  The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any serious adverse 
events associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF.  In addition, the investigator will submit a Clinical 
Trial Pregnancy Reporting Form when updated information on the course and outcome 
of the pregnancy becomes available.   
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Nonclinical studies with satralizumab did not indicate harmful effects with respect to 
reproductive toxicity.  The follow up of partner pregnancies is therefore not required in 
this study.  Please refer to the Satralizumab Investigator’s Brochure for additional 
information on reproductive toxicity. 
5.4.3.3 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2). 


 
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If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.  
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2). 
5.4.4 
Reporting Requirements for Medical Device Complaints  
In this study, PFS with NSD/EFF is considered a medical device constituent part of the 
integral medicinal product.  The investigator must report all medical device related 
complaints to the Sponsor.  The investigator should document as much information as 
possible on the IMP Deviation Form, including the product batch number, and forward 
the form to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event) (refer to the pharmacy manual for further details).  If the medical device 
constituent parts result in an adverse event to the study patient, the event must be 
reported on the Adverse Event eCRF and submitted through the EDC system.  If the 
event is serious, the Adverse Event eCRF must be completed immediately (i.e., no more 
than 24 hours after learning of the event), as outlined in Section 5.4.2. 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification. 
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5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
12 weeks after the final dose of study drug), if the event is believed to be related to prior 
study drug treatment.  These events should be reported through use of the Adverse 
Event eCRF.  However, if the EDC system is not available, the investigator should report 
these events directly to the Sponsor or its designee, either by faxing or by scanning and 
emailing the paper Clinical Trial Adverse Event/Special Situations Form using the fax 
number or email address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
The Sponsor has a legal responsibility to notify regulatory authorities about the safety of a study 
treatment under clinical investigation.  The Sponsor will comply with regulatory requirements 
for expedited safety reporting to regulatory authority (which includes the use of applicable 
systems, such as EudraVigilance), IRBs, ECs, and investigators. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the document listed below: 
Drug 
Document 
Satralizumab 
Satralizumab Investigator's Brochure  
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
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6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
Full details of all statistical issues and planned statistical analyses will be specified in a 
separate SAP, which will be finalized prior to the locking and unblinding of the study 
database. 
This study will compare 120 mg or 180 mg satralizumab (for patients with body weight 
≤ 100 kg or > 100 kg respectively) with placebo, administered for 24 weeks, in patients 
with gMG as defined by the study inclusion and exclusion criteria.  Patients will be 
required to be on stable background therapy at baseline and during the DB treatment 
period, as outlined in Section 3.1. 
Statistical analysis will follow the estimand framework and considers three intercurrent 
events: 
• 
Withdrawal from study treatment 
• 
Receiving a rescue therapy 
• 
Treatment interruption due to infection 
 
The primary comparison of interest is the difference between the placebo and 
satralizumab groups in the change from baseline to Week 24 in the total MG-ADL score 
on the AChR + population, irrespective of treatment adherence or use of rescue 
medication.  
Analysis of primary and secondary endpoint will be conducted on the mITT population unless 
otherwise specified.  The mITT population consists of all patients who have a baseline and at least 
one post-baseline DB period MG-ADL assessment.  Adolescent patients enrolled after the last 
adult randomized will not be part of the mITT population.  For additional subgroup analysis, 
subgroups within the mITT population will be considered. 
6.1 
DETERMINATION OF SAMPLE SIZE 
Determination of sample size is based on all globally AChR + enrolled patients.  In this 
study, approximately 160 AChR+  patients and up to 25 AChR − (MuSK + or LRP4 +) patients 
will be enrolled.  Participants enrolled in the DB period will be randomized in a 1:1 ratio to 
each treatment group (satralizumab or placebo).  Randomization will be stratified by 
baseline SOC treatment, region, and autoantibody type as described in Section 3.1.  
Adolescent patients will be enrolled directly in the OLE period and will receive open-label 
satralizumab treatment (see Section 3.1.3).  


 
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The estimated sample size required to demonstrate efficacy with regard to the MG-ADL 
is based on the AChR + population and the following assumptions: 
• 
The primary hypotheses test in the AChR +  population is the difference between the 
placebo and satralizumab groups in the change from baseline to Week 24 in total 
MG-ADL score.  
• 
The assumed change from baseline to Week 24 in the placebo group is 2.3 points. 
• 
The assumed change from baseline to Week 24 in the satralizumab group is 
4.3 points. 
• 
The assumed change from baseline accounts for approximately 10% of patients in 
the satralizumab group and approximately 20% of patients in the placebo group 
receiving rescue therapy. 
• 
The SD of the change from baseline to Week 24 is 3.97 in both the placebo and 
satralizumab groups. 
• 
The assumed study treatment withdrawal rate is 10%. 
 
The assumptions are based on data reported in Howard et al. (2017).  
Based on these assumptions and using a two-sided α level of 0.05, the sample size to 
achieve 85% power was estimated at 160 patients (80 per group) in the AChR + 
population. Under the assumption that up to 25 patients meeting the study eligibility 
criteria will be AChR − (MuSK + or LRP4 +), the total study sample size will be 
approximately 185 patients.  This sample size also provides approximately 80% power for 
an analysis of the difference between the placebo and satralizumab groups in the 
proportion of MG-ADL responders in the mITT and AChR + population.  This power 
calculation assumes a 50% response rate in the placebo group and a 75% response 
rate in the satralizumab group. 
Following the PK interim analysis, the iDMC recommended that the initial doses 
(120 mg ≤ 100 kg > 180 mg) should be retained, therefore patients (from both placebo and 
satralizumab groups) dosed prior to the dose confirmation will be included in the primary 
analysis and no patient replacement is required.  
6.2 
SUMMARIES OF CONDUCT OF STUDY 
The number of patients who enroll, discontinue, or complete the study will be 
summarized.  The frequency and timing of intercurrent events will be summarized 
including reasons for premature study and study treatment discontinuation, and patients 
receiving rescue therapy.  Enrollment and major protocol deviations will be listed and 
evaluated for their potential effects on the interpretation of study results. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic and baseline characteristics (including age, sex, race, region, MGFA 
classification, antibody type and background medication use) will be summarized using 


 
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means, standard deviations, medians, and ranges for continuous variables and 
proportions for categorical variables, as appropriate.  Summaries will be presented 
overall and by treatment group. 
6.4 
EFFICACY ANALYSES 
There are two analysis populations for the efficacy analyses:  
• 
All randomized AChR + patients, with patients grouped according to their 
randomized treatment 
• 
All randomized patients (OP), with patients grouped according to their randomized 
treatment  
Each efficacy analysis will be conducted on all randomized patients that have at least 
one postbaseline MG-ADL assessment (mITT population). 
6.4.1 
Primary Efficacy Estimand 
The primary comparison of interest is the difference between the placebo and 
satralizumab groups in the change from baseline to Week 24 in the total MG-ADL score 
in the AChR + population. 
If a patient withdraws from treatment, the reason for withdrawal will be classified as 
either study drug or condition related (SDCR) or not study drug or condition related 
(NSDCR).  More details of this classification will be given in the SAP.  The primary 
comparison will include both patients who withdraw due to SDCR and NSDCR reasons, 
with the assumption that patients who withdrew due to NSDCR reasons would have 
continued receiving their randomized treatment. 
The primary comparison will be made regardless of whether a patient receives rescue 
therapy or has a treatment interruption due to infection. 
The elements of the primary estimand are defined below.  The primary analysis 
approach and determination of sample size is aligned with the primary estimand. 
Population:   
• 
Patients with AChR + gMG as defined by the study inclusion and exclusion criteria 
and who are part of the mITT population. 
 
Primary efficacy variable:  MG-ADL total score 
Treatment:  satralizumab 120 mg (for patients with body weight ≤ 100 kg) or 180 mg (for 
patients with body weight > 100 kg) versus matching placebo, administered for 24 
weeks, in combination with stable background therapy  
Intercurrent events:   
• 
SDCR withdrawal from study treatment:  treatment policy 


 
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• 
NSDCR withdrawal from study treatment:  hypothetical 
• 
Taking rescue therapy:  treatment policy 
• 
Treatment interruption due to infection:  treatment policy  
 
Summary measure:  The difference in the change from baseline to Week 24 in MG-ADL 
total score 
Supplementary estimands will be detailed in the SAP and will include using a 
hypothetical approach for the intercurrent event of taking rescue therapy and 
discrimination between the different types of rescue therapy. 
6.4.2 
Primary Efficacy Estimator 
The primary efficacy analyses will compare satralizumab with placebo at Week 24 in the 
AChR + population.  
The following null and alternative hypotheses will be tested at a two-sided significance 
level: 
H0:  µsatralizumab = µplacebo versus H1:  µsatralizumab ≠ µplacebo 
for which µsatralizumab and µplacebo refer to the mean change from baseline to Week 24 in 
the total MG-ADL score in the satralizumab and placebo groups respectively.  The 
primary efficacy objective is to evaluate the efficacy of satralizumab versus placebo on 
daily function.  Patients will be grouped according to the treatment assigned at 
randomization. 
An estimate of the treatment effect will be computed using a “Mixed Model Repeated 
Measures” analysis adjusting for the randomization stratification factors (background 
therapy, autoantibody type, and region) and baseline MG-ADL score.  
For NSDCR withdrawals, data will be censored at the time of the treatment withdrawal.  
Any data collected after NSDCR withdrawal will be disregarded.  Missing data following 
a withdrawal that is determined to be NSDCR will be imputed using multiple imputation 
with a “Missing at Random” assumption.   
Missing data following a withdrawal that is determined to be SDCR will be imputed using 
reference based multiple imputation with a "Copy Reference" assumption.  This 
approach will only be used if observed data following a treatment withdrawal are not 
available.  Where observed data are available, they will continue to be included in the 
analysis.   
Data following rescue therapy and treatment interruption due to infection will be included 
in the analysis.  Approaches to handle item level missing data will be described in the 
SAP. 


 
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The robustness of the primary estimation method will be explored by a series of 
sensitivity estimators based on varying assumptions underlying the multiple imputation 
strategy and classification of treatment withdrawal intercurrent events as SDCR or 
NSDCR.  Additional details will be provided in the SAP. 
Patients who discontinue from the study treatment for any reason should continue with 
all remaining assessments defined during the DB period of the protocol.  However, 
patients who are unwilling to return to the clinic for all assessments will be asked to 
complete the EOT within 4 weeks and a SFU visit 12 weeks after the final dose of study 
drug.  
6.4.3 
Type I Error Control 
The primary and secondary endpoints will be tested using a hierarchical gatekeeping 
procedure.  Where the hierarchical gatekeeping procedure is used, if any test result is 
not statistically significant, formal testing of subsequent endpoints will not occur.  If the 
primary endpoint is statistically significant, the confirmatory secondary endpoints are 
tested in the following order: 
1. 
Mean change from baseline in QMG score in AChR +  patients at Week 24 
2. 
Mean change from baseline in MG‑QOL 15r total score in AChR +  patients at 
Week 24 
3. 
Mean change from baseline in MGC total score in AChR +  patients at Week 24 
4. 
Mean change from baseline in MG-ADL score in the overall population (OP) at 
Week 24 
5. 
Mean change from baseline in QMG score in the OP at Week 24 
6. 
Proportion of AChR + patients receiving rescue therapy between baseline and 
Week 24 
7. 
Mean change from baseline in MG-ADL score in MuSK and LRP4 patients at Week 24 
8. 
Mean change from baseline in Neuro−QoL Fatigue Subscale total score in 
AChR + patients at Week 24 
 
6.4.4 
Secondary Efficacy Endpoints 
The following secondary efficacy endpoints will be analyzed in the same way as the 
primary efficacy endpoint, using the primary estimand: 
• 
Mean change from baseline in MG-ADL score in the OP at Week 24 
• 
Mean change from baseline in QMG score (in AChR + patients and the OP) at Week 
24 
• 
Mean change from baseline in MG-QOL 15r total score (in AChR + patients and the 
OP) at Week 24 
• 
Mean change from baseline in MGC total score (in AChR + patients and the OP) at 
Week 24 


 
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• 
Mean change from baseline in Neuro−QoL Fatigue Subscale total score (in AChR + 
patients and the OP) at Week 24 
The following secondary efficacy endpoints will be analyzed using the responder 
estimand and estimator (Section 6.4.5): 
• 
Percentage of AChR + patients (and patients in the OP) with a ≥ 2-point reduction 
from baseline in total MG-ADL score at Week 24 
• 
Percentage of AChR + patients (and patients in the OP) with a ≥ 3-point reduction 
from baseline in QMG score at Week 24 
• 
Percentage of AChR + patients (and patients in the OP) with a ≥ 3-point reduction 
from baseline in total MGC score at Week 24 
• 
Proportion of patients who have achieved minimal disease manifestation (total 
MG-ADL score of 0 or 1) at Week 24 
 
The following secondary efficacy endpoints will be analyzed using the count estimand 
and estimator (Section 6.4.6): 
• 
Annualized rate of gMG related exacerbations 
 
The following secondary efficacy endpoints will be analyzed using the duration estimand 
and estimator (Section 6.4.7): 
• 
Duration (average number of consecutive months that patients show a meaningful 
improvement, defined as ≥ 2 point reduction from baseline in total MG-ADL score 
 
In addition, the following secondary endpoints will not be analyzed using the estimand 
framework: 
• 
Proportion of patients with at least one gMG-related exacerbation between baseline 
and Week 24 
• 
Proportion of patients receiving rescue therapy between baseline and Week 24 
  
6.4.5 
Responder Estimand and Estimator 
The elements of the responder estimand are defined below using the following endpoint 
as an example: 
• 
Percentage of AChR + patients with a ≥ 2-point reduction from baseline in total MG-
ADL score at Week 24 
 
The intercurrent event of starting a rescue therapy is handled using a composite strategy 
and is consequently included in the variable definition below. 
Population:  Patients with AChR + gMG as defined by the study inclusion and exclusion 
criteria. 
Secondary efficacy variable:  a ≥ 2-point reduction from baseline in total MG-ADL score 
at Week 24 without rescue therapy 


 
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Treatment:  satralizumab 120 mg (for patients with body weight ≤ 100 kg) or 180 mg (for 
patients with body weight > 100 kg) versus matching placebo, administered for 24 
weeks, in combination with stable background therapy  
Intercurrent events:   
• 
SDCR withdrawal from study treatment:  treatment policy 
• 
NSDCR withdrawal from study treatment:  hypothetical 
• 
Taking rescue therapy: composite (included in variable definition) 
• 
Treatment interruption due to infection:  treatment policy  
 
Summary measure:  The difference in the proportion of responders at Week 24 
An estimate of the treatment effect will be computed using a Cochran-Mantel-Haenszel 
test adjusting for the randomization stratification factors (background therapy, 
autoantibody type, and region).  Data following a NSDCR withdrawal from study 
treatment and any missing data will be imputed using multiple imputation as in the 
primary estimand.  
Two endpoints require different considerations: 
• 
The proportion of patients with at least one gMG related exacerbation 
• 
The proportion of patients receiving rescue therapy between baseline and Week 24 
  
In the first case, it is not possible to start a rescue therapy before observing a gMG 
related exacerbation.  In the second, the event of interest is starting a rescue therapy.  
Therefore, starting a rescue therapy is not considered an intercurrent event for these 
endpoints and consequently is not included in the estimand definition. 
Supplementary estimands will be detailed in the SAP and will include using a composite 
approach for the intercurrent event of SDCR withdrawal from study treatment. 
6.4.6 
Count Estimand and Estimator 
The elements of the count estimand are defined below using the AChR + population as 
an example: 
• 
Population:  Patients with AChR + gMG as defined by the study inclusion and 
exclusion criteria 
• 
Secondary efficacy variable:  Annualized rate of gMG-related exacerbations defined 
as the total number of gMG-related exacerbations divided by the patient years at 
risk 
• 
Treatment:  satralizumab 120 mg (for patients with body weight ≤ 100kg) or 180 mg 
(for patients with body weight > 100kg) versus matching placebo, administered for 
24 weeks, in combination with stable background therapy  
 


 
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Intercurrent events:   
• 
SDCR withdrawal from study treatment:  treatment policy 
• 
NSDCR withdrawal from study treatment:  hypothetical 
• 
Taking rescue therapy:  treatment policy  
• 
Treatment interruption due to infection:  treatment policy  
Summary measure:  The ratio of the annualized rates of gMG-related exacerbations at 
Week 24 
An estimate of the treatment effect will be computed using a negative binomial 
regression model adjusting for the randomization stratification factors (background 
therapy, autoantibody type, and region).  
6.4.7 
Duration Estimand and Estimator 
The elements of the duration estimand are defined below using the AChR + population 
as an example: 
• 
Population:  Patients with AChR + gMG as defined by the study inclusion and 
exclusion criteria  
• 
Secondary efficacy variable:  Number of consecutive visits when a patient achieved 
a ≥ 2-point reduction from baseline in MG-ADL, without receiving rescue therapy 
• 
Treatment:  satralizumab 120 mg (for patients with body weight ≤ 100 kg) or 180 mg 
(for patients with body weight > 100 kg) versus matching placebo, administered for 
24 weeks, in combination with stable background therapy  
 
Intercurrent events:   
• 
SDCR withdrawal from study treatment:  treatment policy 
• 
NSDCR withdrawal from study treatment:  hypothetical 
• 
Taking rescue therapy:  composite (included in variable definition) 
• 
Treatment interruption due to infection:  treatment policy  
 
Summary measure:  The difference in the mean duration of meaningful improvement at 
Week 24 
An estimate of the treatment effect will be computed using an ANCOVA adjusting for the 
randomization stratification factors (background therapy, autoantibody type, and region).  
6.4.8 
Exploratory Efficacy Endpoints 
More details on the definition and analysis of exploratory efficacy endpoints will be given 
in the SAP.   


 
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In addition to the exploratory efficacy endpoint specified in Table 1, subgroup analyses 
will also be performed in the following sub-groups: 
• 
Patients receiving AChEI monotherapy and/or an OCS as background SOC 
treatment 
• 
Patients receiving a steroid-sparing IST monotherapy or a combination of a 
steroid-sparing IST with other treatments (an AChEI and/or an OCS) as background 
SOC treatment  
• 
MuSK + patients  
• 
LRP4 + patients 
• 
AChR antibody-seronegative patients 
• 
MGFA Class II patients 
• 
MGFA Class III patients 
• 
MGFA Class IV patients 
• 
Efficacy endpoints of adolescent patients (aged ≥ 12 − < 18 years old at the time of consent) 
exposed to satralizumab in the DB or OLE period will be summarized descriptively, without 
statistical testing and without the estimand framework. 
  
6.5 
SAFETY ANALYSES 
The safety analysis population will consist of all enrolled patients who received at least 
one dose of study drug, with patients grouped according to treatment received.  
Safety will be assessed through summaries of exposure to study treatment, adverse 
events, changes in targeted laboratory test results, and changes in vital signs and 
ECGs. 
Study treatment exposure (such as treatment duration, total dose received, and number 
of cycles and dose modifications) will be summarized with descriptive statistics. 
In addition, safety analyses will also be performed in the sub-groups detailed in 
Section 6.4.8.  
6.6 
PHARMACOKINETIC ANALYSES  
The PK analysis population consists of all patients in the safety analysis set with at least 
one valid post-dose concentration result with a dosing record and sampling time.  The 
trial will evaluate the PK characteristics of satralizumab treatment over 24 weeks by 
summary statistics and non-linear mixed effects analysis (population PK).  PK samples 
will also be taken during the OLE study period, to further characterize the PK of 
satralizumab in gMG over longer term treatment. 
The serum concentration at each sampling timepoint will be described with means and 
standard deviation of Ctrough irrespective of whether patients receive rescue therapy, 


 
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change in baseline therapy for MG, miss a dose, or if study drug administration is 
delayed, or if they withdraw from treatment before data collection at Week 24.  Individual 
and mean serum-concentration-versus-time curves will be plotted. 
Non-linear mixed effects analysis will be performed to analyze the satralizumab 
concentration−time data collected in the trial.  The model to be used was previously 
developed on the basis of PK data from adult HV and adult and adolescent patients with 
NMOSD.  Further model development may be undertaken if needed in order to achieve 
a satisfactory description of the data, and the data from this study may be pooled with 
data from other studies with satralizumab.  Population and individual PK and exposure 
parameters will be generated based on the model.  Covariate analysis, including 
demographic factors and ADA status, will also be performed.  Both the satralizumab 
concentration data and the results of the pop PK analysis will be reported separately 
from the CSR. 
Further details are described in a separate Data Analysis Plan. 
6.7 
IMMUNOGENICITY ANALYSES  
The immunogenicity analysis population will consist of all patients with at least one ADA 
assessment.  Patients will be grouped according to treatment received or, if no treatment 
is received prior to study discontinuation, according to treatment assigned. 
The numbers and proportions of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after drug administration (post-baseline incidence) 
will be summarized by treatment group.  When determining post-baseline incidence, 
patients are considered to be ADA positive if they show treatment-induced ADA 
response or treatment-enhanced ADA response.  Patients who are ADA-negative or 
have missing data at baseline, but develop an ADA response following study drug 
exposure have a treatment-induced ADA response.  Patients who are ADA positive at 
baseline and the titer of one or more post-baseline samples is at least at least 4-fold 
(0.60 titer unit) greater than the titer of the baseline sample have a treatment-enhanced 
ADA response.  Patients are considered to be ADA-negative if they are ADA-negative or 
have missing data at baseline and all post-baseline samples are negative, or if they are 
ADA positive at baseline but do not have any post-baseline samples with a titer that is at 
least 4-fold (0.60 titer unit) greater than the titer of the baseline sample (treatment 
unaffected). 
The percentage of patients who have positive or negative ADA results for satralizumab 
will be tabulated.  PK, PD, efficacy parameters, and safety will be summarized by 
anti-satralizumab antibody (i.e., satralizumab ADA) status. 
In addition, immunogenicity analyses will also be performed in the sub-groups detailed in 
Section 6.4.8. 


 
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6.8 
PHARMACODYNAMIC ANALYSES 
Serum IL-6 and sIL-6R levels will be summarized by treatment group and timepoint 
graphically and descriptively, as appropriate.  
6.9 
EXPLORATORY BIOMARKER ANALYSES 
Exploratory biomarkers will be summarized graphically and descriptively, as appropriate, 
by treatment group.  They may include, but are not limited to:  
• 
Absolute and relative changes from baseline in biomarkers at each sampling 
timepoint  
• 
Relationships between change in biomarkers from baseline and efficacy measures 
and other biomarkers 
• 
The relationship between biomarkers at baseline and clinical response 
  
6.10 
HEALTH STATUS UTILITY ANALYSES  
The change from baseline in EQ-5D-5L health utility index-based and VAS scores will be 
calculated at specified timepoints. 
6.11 
INTERIM ANALYSIS 
Periodic reviews of the safety data will be conducted by an iDCC with the results 
reviewed by the iDMC.  A planned independent unblinded early review of the PK data 
from approximately 15 patients receiving satralizumab will be performed to confirm the 
adequacy of the chosen doses (see Section 6.11.2).  The iDMC will then make a dose 
recommendation. 
Details of these analyses will be described in the iDMC Charter. 
6.11.1 
Optional Interim Analysis 
To adapt to information that may emerge during the course of this study, the Sponsor 
may choose to conduct one interim analysis for futility.  Below are the specifications in 
place to ensure the study continues to meet the highest standards of integrity when an 
optional interim analysis is executed.  
If an interim analysis is conducted, the Sponsor will remain blinded.  The interim analysis 
will be conducted by an external statistical group and reviewed by the iDMC.  
Interactions between the iDMC and Sponsor will be carried out as specified in the iDMC 
Charter.  
The decision to conduct the optional interim analysis, along with the rationale, timing, 
and statistical details for the analysis will be documented in the SAP.  The iDMC Charter 
will be updated to document potential recommendations the iDMC can make to the 
Sponsor as a result of the analysis (e.g., continue the trial without modification, stop the 
study for futility).  


 
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The study will not be stopped for positive efficacy as a result of the interim analysis. 
6.11.2 
Interim Pharmacokinetic Analysis 
An interim analysis of PK data was performed when approximately 30 patients, (including 
approximately 15 patients from the satralizumab group), completed a minimum of 
8 weeks of DB treatment.  The purpose of the interim analysis was to confirm that the 
achieved exposure to satralizumab (and predicted RO) was within the predicted range.    
Patients with gMG with body weights representative of the overall gMG population, both 
in terms of range and approximate proportion, were included in the PK interim analysis 
dataset.  
A dose decision framework (including a pre-specified alternative higher dose, in case 
exposures are lower than predicted) was defined in an analysis plan prior to study start.  
This plan set out the criteria for predicted exposure and RO (derived using the existing 
pop PK model updated following incorporation of the new data in gMG) under which the 
decision for an adapted dose will be made.   
This interim PK analysis was performed by an external contract research organization 
(CRO) while the Sponsor, patients, and investigators remained blinded.  The review by 
the external CRO was restricted to PK and ADA data only, not safety or efficacy data, 
and no information that would reveal individual treatment assignments was shared with 
the Sponsor.  The external CRO performed blinded simulations for exposure and RO, 
which were made available to the iDMC, and collaborated with the iDMC, such that the 
iDMC made a dose recommendation on the basis of these simulations.  Following this 
review, the iDMC recommended that the initially proposed doses (120 mg ≤ 100 kg > 180 mg) 
should be retained and that the Sponsor should continue the study without dose modification.  
Study recruitment will continue during the review period.  Should a dose change be 
warranted, any patients treated at the original dose level will continue in the study on 
randomized treatment at the revised dose level, but will not contribute to the primary 
analysis.  Additional patients will be recruited to ensure that the number of patients 
eligible for inclusion in the primary analysis reaches the target sample size.  No type I 
error multiplicity correction will be performed as only PK data, unrelated to efficacy 
outcome, will be used for interim decision-making. 
6.12 
CHINA SUBPOPULATION ANALYSES 
The China subpopulation will include all patients enrolled at China’s sites: current resident 
of mainland China, Hong Kong, or Taiwan, and of Chinese ancestry.  Results from these 
analyses will be summarized in a separate Clinical Study Report.  
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 


 
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eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and other 
electronic data will be sent directly to the Sponsor, using the Sponsor's standard 
procedures to handle and process the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures. 
PRO and ClinRO data will be collected on paper questionnaires.  The data from the 
questionnaires will be entered into the EDC system by site staff. 
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial. 


 
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Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PRO, ClinRO data, Informed Consent Forms, 
laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for 15 years after completion or discontinuation of the study or for 
the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
The Sponsor will retain study data for 25 years after the final study results have been 
reported or for the length of time required by relevant national or local health authorities, 
whichever is longer. 


 
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8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directives (2001/20/EC) 
or Clinical Trials Regulation (536/2014) and applicable local, regional, and national laws. 
8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/EC−approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
If the Consent Forms are revised (through an amendment or an addendum) while a 
patient is participating in the study, the patient or a legally authorized representative 


 
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must re-consent by signing the most current version of the Consent Forms or the 
addendum, in accordance with applicable laws and IRB/EC policy.  For any updated or 
revised Consent Forms, the case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
using the updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file.  
8.4 
CONFIDENTIALITY 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or access.  


 
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In the event of a data security breach, appropriate mitigation measures will be 
implemented. 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.6). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
Study data, which may include data on genomic variants, may be submitted to 
government or other health research databases or shared with researchers, government 
agencies, companies, or other groups that are not participating in this study.  These data 
may be combined with or linked to other data and used for research purposes, to 
advance science and public health, or for analysis, development, and commercialization 
of products to treat and diagnose disease.  In addition, redacted Clinical Study Reports 
and other summary reports will be provided upon request (see Section 9.6). 
8.5 
FINANCIAL DISCLOSURE 
Investigators 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 health 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 (see definition of end of 
study in Section 3.2). 


 
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9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.3 
MANAGEMENT OF STUDY QUALITY 
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  Prior 
to study initiation, the Sponsor will identify potential risks associated with critical trial 
processes and data and will implement plans for evaluating and controlling these risks.  
Risk evaluation and control will include the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters prior to study initiation.  Detection of deviations 
from quality tolerance limits will trigger an evaluation to determine if action is needed.  
Details on the establishment and monitoring of quality tolerance limits will be provided in 
a Quality Tolerance Limit Management Plan. 
9.4 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.5 
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to HCPs and to the public, at scientific congresses, in clinical trial 


 
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registries, and in peer-reviewed journals.  The Sponsor will comply with all requirements 
for publication of study results.  Study data may be shared with others who are not 
participating in this study (see Section 8.4 for details), and redacted Clinical Study 
Reports and/or other summaries of clinical study results may be available in health 
authority databases for public access, as required by local regulation, and will be made 
available upon request.  For more information, refer to the Roche Global Policy on 
Sharing of Clinical Study Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/ 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by F. Hoffmann−La Roche Ltd; Chugai 
Pharmaceutical Co., Ltd. is co-sponsor in Taiwan and Japan.  The Sponsor will provide 
clinical operations management, data management, and medical monitoring. 
Approximately 120 sites globally will participate to enroll approximately 160 AChR + 
patients and up to 25 MuSK + or LRP4 +  patients.  Enrollment will occur through an IxRS.   


 
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Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker, PK, and PD analyses), as specified in 
Section 4.5.   
An iDMC will be employed to monitor and evaluate patient safety throughout the study.   
9.7 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only. 
 
 


 
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Satralizumab—F. Hoffmann-La Roche Ltd 
144/Protocol WN42636, Version 5 
Appendix 1  
Schedule of Activities:  Screening and Double-Blind Periods 
 
 
Screening a 
DB Tx Period 
US 
Visit b 
DD 
Visit c 
RLD 
 Visit 
1,2,3 d 
SFU 
Visit e 
EOT 
Visit f 
Weeks 
–4 to –1 
0 
2 
4 
8 
12 
16 
20 
24 
 
 
 
 
 
Days 
–28 to –1 
1 
15 
29 
57 
85 
113 
141 
169 
 
 
 
 
 
Window in days 
NA 
NA 
± 3 
± 3 
± 7 
± 7 
± 7 
± 7 
± 7 
 
 
 
± 7 
± 7 
Informed consent g 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of inclusion/exclusion 
criteria 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and baseline 
conditions 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
x 
x h 
 
 
x h 
 
xh 
 
x h 
x h 
x h 
x h 
x h 
x h 
Body weight 
x 
x 
 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
Study drug administration 
 
x 
x 
x 
x 
x 
x 
x 
 
 
x 
x 
 
 
Complete Physical 
examination i 
x 
x 
 
 
 
x 
 
 
x 
 
 
x j 
x 
x 
Limited Physical examination i  
 
 
x 
x 
x 
 
x 
x 
 
x 
x 
x k 
 
 
Vital signs l 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
12-Lead ECG m 
x 
x 
 
 
 
x 
 
 
x 
x 
 
x j 
 
x 
Hematology n,o 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x p 
x 
x 
x 
Chemistry o,q 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x p 
x 
x 
x 
Fibrinogen, INR o 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x p 
x 
x 
x 
 
 
 








Appendix 1:Schedule of Activities:  Screening and Double-Blind Periods (cont.) 
  
Satralizumab—F. Hoffmann-La Roche Ltd 
148/Protocol WN42636, Version 5 
a Visit not specified by the protocol. 
b Unscheduled visit:  Assessments performed at unscheduled (non-dosing) visits will depend on the clinical needs of the patient.  In case of 
suspected gMG exacerbation the patient should undergo the following evaluations before or immediately after any administration of the rescue 
therapy: MG-ADL, QMG, MGC, and MG-QOL 15r.  Additional assessments, such as hematology, chemistry, and urinalysis, will be performed if 
infection or metabolic disturbance is suspected to be contributing to the clinical presentation necessitating the unscheduled visit. 
c In the event that the study drug is not administered within the scheduled visit window and is subsequently administered outside the visit window.  
Minimum dosing interval should be 8 days for loading doses and 14 days for maintenance doses. 
d Re-loading doses 1 and 2 are needed for drug interruption for a duration between 8 to 12 weeks.  Re-loading doses 1, 2, and 3 are needed for a 
drug interruption longer than 12 weeks, inclusive (see Section 4.3.2.2, Table 7). 
e All patients who permanently discontinue study treatment during the DB period for any reason should continue with all remaining assessments 
defined in the protocol.  However, at a minimum, patients who are unwilling to return to the clinic for all assessments will be asked to complete 
SFU visits. For adults, a SFU visit is required 12 weeks after the final dose.  For adolescents, SFU visits are required 12 weeks and 24 weeks 
after the final dose. For all patients, a telephone interview will be conducted by site personnel every 4 weeks after the final dose until the final 
SFU visit to identify any new or worsening neurological symptoms.  
f An EOT visit will be performed for patients who permanently discontinue from satralizumab treatment in this study.  The EOT visit should be 
conducted at time of discontinuation, within 4 weeks after the final dose.  At this visit a complete set of assessments will be conducted.  If the 
EOT coincides with a scheduled visit, the EOT visit should be completed instead of the scheduled visit.  
g Must be obtained and documented in written form before any study-specific screening procedure and initiation of study treatment. 
h Height should be measured for adolescent patients (aged ≥ 12 years to < 18 years).  
i Perform a complete physical examination at screening and other specified visits that should include an evaluation of the head, eyes, ears, nose, 
and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems (see 
Section 4.5.4).  Any abnormality identified at baseline should be recorded on the General Medical History and Baseline Conditions eCRF.  
During the study conduct, perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record changes 
from baseline in patient notes.  Record new or worsened clinically significant abnormalities as adverse events on the Adverse Event eCRF. 
j These assessments only apply to RLD Visit 1. 
k These assessments only apply to RLD Visits 2 and 3. 
l Includes body temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position.  Vital 
signs are measured just before dosing and 15 ( ±  5) minutes and 60 ( ±  5) minutes after dosing for the first 5 doses in case of study drug injection 
visit.  Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the participant in a quiet setting without 
distractions. 
m ECG should be performed prior to blood draws. 


Appendix 1:Schedule of Activities:  Screening and Double-Blind Periods (cont.) 
  
Satralizumab—F. Hoffmann-La Roche Ltd 
149/Protocol WN42636, Version 5 
n Hematology includes hemoglobin, hematocrit, RBC, WBC (absolute and differential: neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, other cells), quantitative platelet count. 
o All clinical laboratory, PK, PD, biomarker, and ADA samples should be obtained pre-dose at indicated visits.  Samples should be taken in the 
morning if possible, and approximately at the same time across visits. 
p If study drug was not administered on schedule because of a safety issue with laboratory abnormality, then the relevant laboratory parameter 
should be tested at the DD Visit. 
q Chemistry includes albumin, total protein, total bilirubin, ALP, AST, ALT, GGT, LDH, total cholesterol, LDL cholesterol, HDL cholesterol, 
triglycerides, ferritin, BUN, creatinine, sodium, Cl, K, Ca, P, complements (CH50, C3, C4), lipase, CRP, serum CK, and uric acid. 
r All female patients of childbearing potential will have a serum pregnancy test at screening.  Urine pregnancy tests will be performed pre-dose at 
specified subsequent visits.  If a urine pregnancy test is positive, the patient will not receive the scheduled dose, and a confirmatory serum 
pregnancy test will be performed.  Urine β−hCG (sensitivity of at least 25 mU/mL) will be performed locally. 
s For adolescent patients testing/sampling procedures will be adjusted in conformance with guidelines for pediatric blood volume limits from health 
authorities.  Please refer to the laboratory manual for detailed instructions. 
t Samples for clinical laboratory tests should be collected pre-dose on dosing days.  If any abnormalities are detected on urine dipstick tests 
(including urinary glucose, urinary protein, urinary occult blood, urobilinogen), a complete urinalysis (including microscopic of examination of 
urine) and/or urine culture is to be performed as deemed necessary. 
u A TB test (e.g., tuberculin test and/or Quantiferon® test) should be conducted according to local guidance.  If the patient is positive for latent TB, 
then the patient must be treated with appropriate anti-mycobacterial therapy for at least 4 weeks prior to initiating study treatment administration. 
Additional tests for the diagnosis of latent and active TB should be done as per the local guidance, including a chest X-ray or chest CT, in 
addition to the TB tests in individuals with a positive TB test or in individuals who have a potential risk for TB infection/TB reactivation (e.g., on 
immunosuppressive therapies, recently in contact with a person who has infectious TB disease, live in or recently traveled to a high-prevalence 
region/countries). 
v HBsAg, HBcAb, HBsAb, HCVAb:  All patients must have negative HBsAg test result at screening prior to enrollment.  
Hepatitis B screening:  Patients who are HBsAg positive will be excluded from the study. If HBcAb status is positive, hepatitis B viral DNA will be 
measured.  If HBV DNA is detectable, the individual must be excluded. If HBV DNA is undetectable, the individual may be enrolled. In these 
participants, HBV DNA measurement must be performed regularly at 12 weekly intervals during the study.  
Hepatitis C screening:  If HCVAb is positive, HCV RNA will be measured.  If HCV RNA is undetectable ≥ 12 weeks after HCV treatment 
completion, the patient can be enrolled. 
w Quantitative immunoglobulins may include IgA, IgE, IgG, and IgM. 
x IgG subtypes include IgG1, IgG2, IgG3 and IgG4. 
y Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment. 


Appendix 1:Schedule of Activities:  Screening and Double-Blind Periods (cont.) 
  
Satralizumab—F. Hoffmann-La Roche Ltd 
150/Protocol WN42636, Version 5 
z All adverse events will be reported for as long as the patient remains in the study.  Serious adverse event reporting starts with signing of the 
Informed Consent Form.  The investigator should follow each adverse event until the event has resolved to baseline grade or better, the event is 
assessed as stable by the investigator, the patient is lost to follow up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or to trial-related procedures until a final outcome can be reported. 
aa Efficacy assessments must be performed prior to dosing and prior to any other assessments, preferably at the same time in the morning across 
all visits. 
bb These assessments only apply to RLD Visits 1 and 3. 
cc PD biomarkers will include, but are not limited to, IL-6 and sIL-6R. 
dd RNA may be assessed for exploratory biomarkers including, but not limited to, plasmablast signature.   
ee For adolescent patients at the time of informed consent, this sample is not to be collected. 
ff Blood samples will be processed for flow cytometry (e.g., B-cell subsets).   
gg Autoantibodies will include AChR, MuSK and LRP4.  Note that for sites in the Netherlands and Germany, the central laboratory autoantibody tests at 
screening to confirm gMG diagnosis are not required. 
hh Exploratory serum biomarkers may include, but will not be limited to autoantibodies (AChR, MuSK, and LRP4) and IL-17. 
ii Plasma generated from the blood sample obtained for PBMC processing will be stored for biomarker research.  No additional blood draw is 
needed. 
jj A single mandatory DNA sample will be collected for patient genotyping at the baseline visit.  If the DNA sample is not collected at the baseline 
visit, it may be collected at any subsequent visit.  Collection and submission of this sample is contingent upon the review and approval of the 
exploratory research by each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not been granted approval for WGS 
sampling, collection of this sample will not be applicable at that site. 
kk These sample types to be collected for research purposes if a patient signs the Optional RBR Informed Consent Form.  
 


 
Satralizumab—F. Hoffmann-La Roche Ltd 
151/Protocol WN42636, Version 5 
Appendix 2  
Schedule of Activities:  Open-Label Extension Period  
 
Screening a 
From Week 0 to Week 24 
After Week 24 
US 
Visit 
DD 
Visitb 
RLD 
Visit 
1,2,3 c 
EOT 
Visitd 
SFU/ 
EOS 
Visit e 
Week 
−4 to −1 
0f,g 
2 
4 
8 
12 
16 
20 
24 
Q4Wh 
Q12W 
Q24W 
Q48W 
 
 
 
 
 
Window in 
days 
NA 
NA 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
 
 
 
±7 
±7 
Informed 
Consent i 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of 
inclusion/ 
exclusion 
criteria 
x 
x a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic 
Data 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
and baseline 
conditions  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug 
administration 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
 
Height 
x 
 
 
 
 
x j 
 
 
x j 
 
x j 
x j 
x j 
 
 
 
 
 
Body weight 
x 
x 
 
 
 
x 
 
 
x 
 
x 
x 
x 
 
x 
x 
x 
x 
Complete 
physical 
examinationk 
x 
x 
 
 
 
x 
 
 
x 
 
 
x 
x 
 
 
x l 
x 
x 
Limited 
physical 
examinationk 
 
 
x 
x 
x 
 
x 
x 
 
 
x m 
 
 
x 
x 
xn 
 
 


Appendix 2:Schedule of Activities:  Schedule of Activities:  Open-Label Extension Period (cont.) 
  
Satralizumab—F. Hoffmann-La Roche Ltd 
152/Protocol WN42636, Version 5 
 
Screening a 
From Week 0 to Week 24 
After Week 24 
US 
Visit 
DD 
Visitb 
RLD 
Visit 
1,2,3 c 
EOT 
Visitd 
SFU/ 
EOS 
Visit e 
Week 
−4 to −1 
0f,g 
2 
4 
8 
12 
16 
20 
24 
Q4Wh 
Q12W 
Q24W 
Q48W 
 
 
 
 
 
Window in 
days 
NA 
NA 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
 
 
 
±7 
±7 
Vital signs o 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
12-Lead 
ECG p 
x 
x 
 
 
 
x 
 
 
x 
 
 
x 
x 
x 
 
xl 
x 
x 
Hematology q,r 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x s 
x 
x 
x 
Chemistry t, r 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x s 
x 
x 
x 
Fibrinogen, 
INR r 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
 
x 
x 
x 
Cortisol u 
 
 
 
 
 
x 
 
 
x 
 
x 
x 
x 
 
x 
 
x 
x 
Low-dose 
ACTH 
stimulation 
test u 
 
 
 
 
 
x 
 
 
x 
 
x 
x 
x 
 
x 
 
x 
x 
Pregnancy 
test v 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
Urinalysis w 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
 
x 
x 
x 
TBNK r 
x 
x 
 
 
 
x 
 
 
x 
 
 
 
x 
x 
 
x  
x 
x 
TB screeningx,y 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quantitative 
Igs r, y, z 
x 
x 
 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x l 
x 
x 
C−SSRS 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
 
x 
x 
x 
 








Appendix 2:Schedule of Activities:  Schedule of Activities:  Open-Label Extension Period (cont.) 
  
Satralizumab—F. Hoffmann-La Roche Ltd 
156/Protocol WN42636, Version 5 
a Applicable only to adolescent patients who first enter the study in the OLE period because screening would not have been completed previously.  Visit is not 
specified by the protocol. 
b In the event that the study drug is not administered within the scheduled visit window and is subsequently administered outside the visit window.  
The minimum dosing interval should be 14 days. 
c RLDs 1 and 2 are needed for drug interruption for a duration between 8 to 12 weeks.  RLDs 1, 2, and 3 are needed for a drug interruption longer 
than 12 weeks, inclusive. 
d An EOT visit will be performed for all patients who permanently discontinue treatment during the OLE period and who continue treatment with 
satralizumab outside of this study.  At this visit a complete set of assessments will be conducted.  If the EOT visit coincides with a scheduled 
visit, the EOT visit should be completed instead of the scheduled visit. 
e Adult patients will be asked to complete a SFU visit 12 weeks after the final dose of satralizumab.  Adolescent patients will be asked to complete 
SFU visits 12 weeks and 24 weeks after the final dose of satralizumab.  Patients who decide to continue treatment with satralizumab outside of 
this study will have to complete the EOT visit, but they will not have to complete the SFU nor the EOS visit.  
f For adult and adolescent patients who complete the DB period, Week 0 visit of the OLE period coincides with the final visit of the DB period.  
The assessments performed at Week 24 (final week) of the DB period will be used as the active treatment baseline for the patients who receive 
placebo during the DB period and as the OLE baseline for patients who receive satralizumab during the DB period.  Duplicate assessments 
should be avoided.  
g For adolescent patients who do not complete the DB period and transition to the OLE period, the assessments performed at the visit at which they receive the 
first active treatment will be used as the active treatment baseline. 
h In accordance with local regulations, administration of satralizumab outside of the study site (home treatment) is allowed.  Patients should be 
followed up by study site personnel through phone calls around the scheduled study drug administration dates to monitor compliance, 
concomitant medications, and adverse events. 
i Must be obtained and documented in written form before any study-specific screening procedure and initiation of study treatment. 
j Height should be measured for adolescent patients (aged ≥ 12 years to < 18 years). 
k Perform a complete physical examination at screening and other specified visits that should include an evaluation of the head, eyes, ears, nose, and throat, and 
the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems (see Section 4.5.4).  Any abnormality 
identified at baseline should be recorded on the General Medical History and Baseline Conditions eCRF.  During the study conduct, perform a limited, 
symptom-directed examination at specified timepoints or as clinically indicated.  Record changes from baseline in patient notes.  Record new or worsened 
clinically significant abnormalities as adverse events on the Adverse Event eCRF. 
l These assessments only apply to RLD D Visit 1. 
m Limited physical examination will be performed Q12W and during the re-loading dose visits except on visits when a complete physical 
examination will be performed. 


Appendix 2:Schedule of Activities:  Schedule of Activities:  Open-Label Extension Period (cont.) 
  
Satralizumab—F. Hoffmann-La Roche Ltd 
157/Protocol WN42636, Version 5 
n Applicable only for RLD Visits 2 and 3. 
o Includes body temperature, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position.  Vital signs are 
measured just before dosing and 15 ( ± 5) minutes and 60 ( ± 5) minutes after dosing for the first 5 OLE doses in case of study drug injection 
visit.  Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the participant in a quiet setting without 
distractions.  
p ECG should be performed prior to blood draws. 
q Hematology includes hemoglobin, hematocrit, RBC, WBC (absolute and differential: neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, and other cells), quantitative platelet count. 
r All clinical laboratory, PK, PD, ADA, and biomarker samples should be obtained pre-dose at indicated visits.  Samples should be taken in the 
morning if possible, and approximately at the same time across visits. 
s If study drug was not administered on schedule because of a safety issue with laboratory abnormality, then the relevant laboratory parameter 
should be tested at the DD Visit. 
t Chemistry includes albumin, total protein, total bilirubin, ALP, AST, ALT, GGT, LDH, total cholesterol, LDL cholesterol, HDL cholesterol, 
triglycerides, ferritin, BUN, creatinine, sodium, Cl, K, Ca, P, complements (CH50, C3, C4), lipase, CRP, serum CK, and uric acid. 
u For patients on the corticosteroid taper with symptoms of AS early morning cortisol has to be measured.  If morning cortisol is normal, but patient 
has symptoms of AS, perform low-dose ACTH stimulation test to confirm AS diagnosis.  
v Urine pregnancy tests will be performed at specified visits.  If a urine pregnancy test is positive, the patient will not receive the scheduled dose, 
and a confirmatory serum pregnancy test will be performed.  Urine β−hCG (sensitivity of at least 25 mU/mL) will be performed locally.  All female 
adolescent patients of childbearing potential who enter directly in the OLE will have a serum pregnancy test at screening. 
w Samples for clinical laboratory tests should be collected pre-dose on dosing days.  If any abnormalities are detected on urine dipstick tests 
(including urinary glucose, urinary protein, urinary occult blood, urobilinogen), a complete urinalysis (including microscopic of examination of 
urine) and/or urine culture is to be performed as deemed necessary. 
x  A TB test (e.g., tuberculin test and/or Quantiferon test) should be conducted according to local guidance.  If the patient is positive for latent TB, then the 
patient must be treated with appropriate anti-mycobacterial therapy for at least 4 weeks prior to initiating study treatment administration. Additional tests for 
the diagnosis of latent and active TB should be done as per the local guidance, including a chest X-ray or chest CT, in addition to the TB tests in individuals 
with a positive TB test or in individuals who have a potential risk for TB infection/TB reactivation (e.g., on immunosuppressive therapies, recently in contact 
with a person who has infectious TB disease, live in or recently traveled to a high-prevalence region/countries). 
y For adolescent patients testing/sampling procedures will be adjusted in conformance with guidelines for pediatric blood volume limits from health 
authorities.  Please refer to the laboratory manual for detailed instructions. 
z Quantitative immunoglobulins may include IgA, IgE, IgG and IgM. 
aa  IgG subtypes include IgG1, IgG2, IgG3 and IgG4. 


Appendix 2:Schedule of Activities:  Schedule of Activities:  Open-Label Extension Period (cont.) 
  
Satralizumab—F. Hoffmann-La Roche Ltd 
158/Protocol WN42636, Version 5 
bb  HBsAg, HBcAb, HBsAb, HCVAb:  All patients must have negative HBsAg test result at screening prior to enrollment.  
Hepatitis B screening:  Patients who are HBsAg positive will be excluded from the study. If HBcAb status is positive, hepatitis B viral DNA will be measured.  
If HBV DNA is detectable, the individual must be excluded. If HBV DNA is undetectable, the individual may be enrolled. In these participants, HBV DNA 
measurement must be performed regularly at 12 weekly intervals during the study.  
Hepatitis C screening:  If HCVAb is positive, HCV RNA will be measured.  If HCV RNA is undetectable ³ 12 weeks after HCV treatment completion, the 
patient can be enrolled. 
cc  Hepatitis B viral DNA must be monitored every 12 weeks in patients whose HBcAb is positive and HBV DNA was negative at screening. 
dd  Change in background therapy is allowed after Week 12 in the OLE period to ensure patients treated with placebo in the DB period have 
reached steady-state levels of satralizumab prior to steroid or IST taper. 
ee These assessments only apply to RLD Visits 1 and 3. 
ff PD measurements will include, but not be limited to IL-6 and sIL-6R. 
gg RNA may be assessed for exploratory biomarkers including, but not limited to, plasmablast signature. 
hh  For adolescent patients (at the time of informed consent) this sample is not to be collected. 
ii  A single mandatory DNA sample will be collected for patient genotyping at the baseline visit.  If the DNA sample is not collected at the baseline visit, it may be 
collected at any subsequent visit.  Collection and submission of this sample is contingent upon the review and approval of the exploratory research by each 
site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not been granted approval for WGS sampling, collection of this sample will not be 
applicable at that site. 
jj Blood samples will be processed for flow cytometry (e.g., B-cell subsets). 
kk Autoantibodies will include AChR, MuSK and LRP4. Note that for sites in the Netherlands and Germany, the central laboratory autoantibody tests at 
screening to confirm gMG diagnosis are not required. 
ll Exploratory serum biomarkers may include but not be limited to autoantibodies (AChR, MuSK and LRP4) and IL-17. 
mm Plasma sample will also be collected at all visits following PBMC sample processing and will be stored for biomarker research. 
nn Sample types to be collected for research purposes if a patient signs the Optional RBR Informed Consent Form. 
 


 
Satralizumab—F. Hoffmann-La Roche Ltd 
159/Protocol WN42636, Version 5 
Appendix 3  
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples 
 
Visit  
Timepoint 
Instructions 
Sample Type 
Screening  
Weeks − 4 to − 1 
 
• Biomarker (PD serum) 
• Biomarker (serum) 
• Biomarker (flow cytometry) 
• Biomarker (PBMCs) 
• Autoantibodies (serum) a 
DB 
Weeks 0 to 24 
Only at Week 0 
• Biomarker (DNA)  
Prior to each 
administration of 
satralizumab 
• PK sample (serum)  
• Biomarker (PD serum)  
• Anti-satralizumab antibodies (serum)  
• Biomarker (serum)  
Prior to 
administration of 
satralizumab, Q12W 
• Biomarker (flow cytometry) 
• Biomarker (PBMCs)  
• Biomarker (optional RBR serum)  
• Biomarker (optional RBR plasma)  
• Biomarker (RNA)  
OLE 
Weeks 0 to 24 
Prior to 
administration of 
satralizumab for 
Week 0, 2 and 4, 
then prior to each 
administration of 
satralizumab, Q4W 
• PK sample (serum)  
• Biomarker (PD serum)  
• Anti-satralizumab antibodies (serum) 
Prior to each 
administration of 
satralizumab, Q4W 
• Biomarker (serum)  
Prior to each 
administration of 
satralizumab, Q12W 
• Biomarker (flow cytometry)  
• Biomarker (PBMCs)  
• Biomarker (optional RBR serum) 
• Biomarker (optional RBR plasma) 
• Biomarker (RNA) 


Appendix 3: Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples (cont.) 
  
Satralizumab—F. Hoffmann-La Roche Ltd 
160/Protocol WN42636, Version 5 
Visit 
Timepoint 
Instructions 
Sample Type 
OLE (cont.) 
After Week 24 
Prior to 
administration of 
satralizumab, Q12W 
• PK sample (serum)  
• Biomarker (PD serum)  
• Anti-satralizumab antibodies (serum) 
Prior to 
administration of 
satralizumab, Q48W 
• Biomarker (flow cytometry)  
• Biomarker (PBMCs)  
• Biomarker (RNA)  
• Biomarker (serum) 
• Biomarker (optional RBR serum)  
• Biomarker (optional RBR plasma)  
Unscheduled 
visit 
 
 
• PK sample (serum)  
• Biomarker (PD serum)  
• Anti-satralizumab antibodies (serum) 
• Biomarker (flow cytometry)  
• Biomarker (RNA)  
• Biomarker (serum) 
DD 
 
 
• PK sample (serum)  
• Biomarker (PD serum)  
• Anti-satralizumab antibodies (serum) 
RLD (visit 1) 
 
 
• PK sample (serum)  
• Biomarker (PD serum)  
• Anti-satralizumab antibodies (serum) 
• Biomarker (RNA)  
• Biomarker (flow cytometry) 
• Biomarker (serum) 
• Biomarker (PBMCs) 
RLD (visit 2 
and 3) 
 
 
• PK sample (serum)  
• Biomarker (PD serum)  
• Anti-satralizumab antibodies (serum)  
• Biomarker (flow cytometry) 
• Biomarker (serum) 


Appendix 3: Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples (cont.) 
  
Satralizumab—F. Hoffmann-La Roche Ltd 
161/Protocol WN42636, Version 5 
Visit 
Timepoint 
Instructions 
Sample Type 
EOT and 
SFU 
 
 
• PK sample (serum)  
• Biomarker (PD serum)  
• Anti-satralizumab antibodies (serum) 
• Biomarker (RNA)  
• Biomarker (flow cytometry) 
• Biomarker (serum) 
• Biomarker (PBMCs) 
• Biomarker (optional RBR serum)  
• Biomarker (optional RBR plasma)  
DB = double-blind; DD = delayed dosing; EOT = end of treatment; FU = follow-up; 
OLE = open-label extension; PBMC = peripheral blood mononuclear cell; 
PD = pharmacodynamic; PK = pharmacokinetic; Q4W = every 4 weeks; Q12W = every 12 weeks; 
Q24W = every 24 weeks; Q48W = every 48 weeks; RBR = Research Biosample Repository; 
RLD = re-loading dose SFU = safety follow-up. 
a  For sites in the Netherlands and Germany, the central laboratory autoantibody tests at screening to 
confirm gMG diagnosis are not required. 
 
 
 
 


 
Satralizumab—F. Hoffmann-La Roche Ltd 
162/Protocol WN42636, Version 5 
Appendix 4  
Anaphylaxis Precautions 
These guidelines are intended as a reference and should not supersede pertinent local 
or institutional standard operating procedures. 
REQUIRED EQUIPMENT AND MEDICATION 
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment infusion: 
• 
Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer 
• 
Oxygen 
• 
Epinephrine for SC, intramuscular, intravenous, and/or endotracheal administration 
in accordance with institutional guidelines 
• 
Antihistamines 
• 
Corticosteroids 
• 
Intravenous infusion solutions, tubing, catheters, and tape 
 
PROCEDURES 
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed: 
1. 
Stop the study treatment infusion. 
2. 
Call for additional medical assistance. 
3. 
Maintain an adequate airway. 
4. 
Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring if possible. 
5. 
Administer antihistamines, epinephrine, or other medications and IV fluids as 
required by patient status and as directed by the physician in charge. 
6. 
Continue to observe the patient and document observations. 
7. 
Collect serum samples for immunogenicity testing. 
8. 
Ask the patient to return for immunogenicity sample collection at the time of 
washout, if appropriate. 


 
Satralizumab—F. Hoffmann-La Roche Ltd 
163/Protocol WN42636, Version 5 
Appendix 5  
Instructions for Tuberculosis Screening and Treatment  
INTERPRETATION OF TUBERCULOSIS SCREENING RESULTS 
Immunosuppressant biologic treatments have been shown to increase the risk of 
tuberculosis (TB) infection or to cause conversion from latent to active TB in some 
circumstances.  Because of this, patients must be screened for active or latent TB prior 
to entry to this study. 
DEFINITIONS 
Active TB is a disease caused by Mycobacterium tuberculosis in any part of the body 
and that is in an active state as determined by either a smear or culture taken from any 
source which tests positive for TB or if there is radiographic evidence of TB.  Individuals 
with active TB are symptomatic, depending upon the location of the disease (most 
commonly in the lungs but also possibly in the brain, kidneys, spine or elsewhere) and 
can spread the infection to others.  
Diagnosis of latent TB is established when an individual is infected with M. tuberculosis, 
as evidenced by a positive tuberculin skin test (TST) or interferon gamma release assay 
(IGRA; e.g., QuantiFERON-TB Gold In-Tube assay) but is asymptomatic and has no 
evidence of active infection on screening pathology or radiographic tests.  Such 
individuals do not pass the disease to others.  Appropriate anti-mycobacterial therapy 
must start for such individuals at least 4 weeks before initiating study drug administration 
in this study, because the effect of anti-mycobacterial therapy may not appear 
immediately after initiating. 
Tuberculosis Screening  
TB screening must be performed prior to initiation of study drug treatment.  TB screening 
should be conducted per local guidance. For reference, the U.S. Centers for Disease 
Control’s (CDC) notes on TB testing may be found at 
http://www.cdc.gov/TB/TOPIC/testing/default.htm. 
• 
As part of recording the patient's medical history, the patient will be asked if he or 
she has had either active or latent TB and whether the patient has received a Bacille 
Calmette−Guérin (BCG) vaccination.  The patient will also be asked if he or she has 
been in contact with any individuals known to have active TB. 
• 
TB test (e.g., TST [using purified protein derivative] and/or IGRA 
[e.g., Quantiferon-TB Gold]) is required at screening.  
A chest X-ray or chest CT should be performed in individuals with a positive TB test or in 
individuals who have a potential risk for TB infection /TB reactivation (e.g., on 
immunosuppressive therapies, recently in contact with a person who has infectious TB 
disease, live in or recently traveled to a high-prevalence region/countries). 


Appendix 5: Instructions for Tuberculosis Screening and Treatment (cont.) 
  
Satralizumab—F. Hoffmann-La Roche Ltd 
164/Protocol WN42636, Version 5 
Additional diagnostic tests should be done, as recommended per the local guidance, 
in individuals with a positive TB test or in individuals who have a potential risk 
for TB infection /TB reactivation (e.g., on immunosuppressive therapies, recently 
in contact with a person who has infectious TB disease, live in or recently traveled 
to a high-prevalence region/countries). 
Notes: 
1. 
The TST may be positive if the patient has had a BCG vaccination or has been 
infected with TB in the past; IGRA results may also be positive in some cases of 
past infection. 
2. 
Positive results of the TST and IGRA test may be reduced by immune suppression. 
3. 
Local guidance may vary depending upon the sensitivity of strains of Mycobacterium 
tuberculosis present locally. 
 
In case of any doubt as to the diagnosis of latent TB, it is advised that a local physician 
with expertise in the treatment of TB or the Medical Monitor is consulted. 
A combination of the medical history, the results of the TST test and/or IGRA test, other 
diagnostic tests recommended as per local guidance, and any other investigations deemed 
appropriate by the Investigator on the basis of clinical signs and symptoms indicative of 
TB infection elsewhere in the body will be used by the investigator to determine study 
eligibility at screening for this study. 
 
TB Treatment  
If the patient is positive for latent TB, then appropriate anti-mycobacterial therapy must 
start for the patient at least 4 weeks before initiating study drug administration in this 
study, because the effect of anti-mycobacterial therapy may not appear immediately 
after initiating.  Treatment regimens should be followed by the local guidance.  If no local 
guidance exists for treatment of immunocompromised individuals, then the U.S. CDC’s 
guidance must be followed (http://www.cdc.gov/TB/publications/LTBI/default.htm). 
In case of any doubt as to the appropriate course of anti-mycobacterial therapy of latent 
TB, it is advised that a local physician with expertise in the treatment of TB or the 
Medical Monitor is consulted. 
Management of signs/symptoms of TB during the study 
If new signs/symptoms of TB infection develop during the study, perform diagnostic tests 
as above.  If TB infection is diagnosed, interrupt study drug and consult the Medical 
Monitor.  Report TB infection as a "Selected Adverse Event" (see Section 5.2.4).  
 






 
Satralizumab—F. Hoffmann-La Roche Ltd 
167/Protocol WN42636, Version 5 
Appendix 8  
Myasthenia Gravis Composite Scale 
 
Ptosis, upward gaze (physician 
examination) 
 > 45 seconds = 0 
11−45 seconds = 1 
1−10 seconds = 2 
Immediate = 3 
Double vision on lateral gaze, left 
or right (physician examination) 
 > 45 seconds = 0 
11−45 seconds = 1 
1−10 seconds = 3 
Immediate = 4 
Eye closure (physician 
examination) 
Normal = 0 
Mild weakness (can be forced 
open with effort)  = 0 
Moderate weakness (can be 
forced open easily)  = 1 
Severe weakness (unable 
to keep eyes closed)  = 2 
Talking (patient history) 
Normal = 0 
Intermittent slurring or nasal 
speech  = 2 
Constant slurring or nasal but 
can be understood  = 4 
Difficult to understand 
speech  = 6 
Chewing (patient history) 
Normal = 0 
Fatigue with solid food = 2 
Fatigue with soft food = 4 
Gastric tube = 6 
Swallowing (patient history) 
Normal = 0 
Rare episode of choking or 
trouble swallowing = 2 
Frequent trouble swallowing, 
e.g., necessitating changes in 
diet  = 5 
Gastric tube = 6 
Breathing (thought to be caused 
by MG) 
Normal = 0 
Shortness of breath with 
exertion  = 2 
Shortness of breath at rest  = 4 
Ventilator dependence = 9 
Neck flexion or extension 
(weakest) (physician 
examination) 
Normal = 0 
Mild weakness = 1 
Moderate weakness (i.e., 
~50% weak,  ± 15% = 3
a 
Severe weakness = 4 
 
 
 


Appendix 8:   Myasthenia Gravis Composite Scale (cont.) 
 
 
Satralizumab—F. Hoffmann-La Roche Ltd 
168/Protocol WN42636, Version 5 
 
Shoulder abduction (physician 
examination) 
Normal = 0 
Mild weakness = 2 
Moderate weakness (i.e., 
~50% weak,  ± 15% = 4
a 
Severe weakness = 5 
Hip flexion (physician 
examination) 
Normal = 0 
Mild weakness = 2 
Moderate weakness (i.e., 
~50% weak,  ± 15% = 4
a 
Severe weakness = 5 
a Moderate weakness for neck and limb items should be construed as weakness that equals roughly 50% ± 15% of expected normal strength. Any weakness milder than 
that would be mild and any weakness more severe than that would be classified as severe 
                                                                                                                                                                               Total MGC Score 
 
The actual forms will be provided to the sites and should be used for assessment. 
 
REFERENCE 
Burns T, Conaway M, Sanders, D. The MG Composite:  A valid and reliable outcome measure for myasthenia gravis. Neurology 
2010;74:1434−40. 
 


























 
Satralizumab—F. Hoffmann-La Roche Ltd 
181/Protocol WN42636, Version 5 
Appendix 15  
Investigational Medicinal Product and Auxiliary Medicinal 
Products Designations (for Use in European Economic Area) 
Table 1 
Investigational, Authorized Auxiliary, and Unauthorized Auxiliary 
Medicinal Product Designations for European Economic Area 
Product Name 
IMP/AxMP 
Designation 
Marketing Authorization 
Status in EEA  
Used within Marketing 
Authorization 
Satralizumab 
(RO5333787) 
IMP (test product) 
Authorized 
No a 
Placebo (satralizumab 
RO5333787) 
IMP (placebo) 
Unauthorized 
Not applicable 
Azathioprine 
AxMP (background 
therapy) 
Authorized 
Yes b 
Mycophenolate mofetil 
AxMP c (background 
therapy) 
Authorized 
No  
Cyclosporin A 
AxMP c (background 
therapy) 
Authorized 
No  
Tacrolimus 
AxMP c (background 
therapy) 
Authorized 
No  
Oral glucocorticoids 
AxMP (background 
therapy) 
Authorized 
Yes b 
 
Pyridostigmine 
AxMP (background 
therapy) 
Authorized 
Yes b 
Neostigmine  
AxMP (background 
therapy) 
Authorized 
Yes b 
Ambenonium 
AxMP (background 
therapy) 
Authorized 
Yes b 
Intravenous 
immunoglobulin  
AxMP c (rescue 
medication)  
Authorized 
No  
Methylprednisolone 
(IV) 
AxMP (rescue 
medication) 
Authorized 
Yes b 
AxMP  =   auxiliary medicinal product; EEA  =   European Economic Area; IMP  =   investigational medicinal 
product;  
a 
Satralizumab is approved as a monotherapy or in combination with immunosuppressive therapy 
(IST) for the treatment of neuromyelitis optica spectrum disorders (NMOSD) in adult and adolescent 
patients from 12 years of age who are anti-aquaporin-4 IgG (AQP4-IgG) seropositive 
b 
Azathioprine, oral glucocorticoids, pyridostigmine, neostigmine, ambenonium and 
Methylprednisolone (IV) are approved for the treatment of myasthenia gravis in the EEA, and thereforeare 
considered authorized AxMPs 
c 
Mycophenolate mofetil, cyclosporin A, tacrolimus and itravenous immunoglobulin are classified as 
authorized AxMPs based on the International Consensus Guideline for management of Myasthenia Gravis 
(Neurology 2016) even though not authorized in EEA for this indication 


Signature Page for Protocol - WN42636 - ENSPRYNG - v5 - Global/Core - Published
System identifier: RIM-CLIN-496147
Approval Task
Company Signatory
21-Jul-2023 10:58:13 GMT+0000

SAP_001.pdf: 
 
Official Title: 
A Phase III, Randomized, Double-Blind, Placebo-Controlled, 
Multicenter Study to Evaluate Efficacy, Safety, Pharmacokinetics, and 
Pharmacodynamics of Satralizumab in Patients with Generalized 
Myasthenia Gravis 
NCT Number: NCT04963270 
Document Date: Statistical Analysis Plan Version 3: 16-Jan-2024 
 
 
 


 
 
STATISTICAL ANALYSIS PLAN APPROVAL 
 
 
 
 
 
 
SPONSOR: 
LEGAL REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd 
Grenzacherstrasse 124 
4070 Basel, Switzerland 
DATE FINAL: 
See electronic date stamp on the last page of this 
document 
 
CONFIDENTIAL 
 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
 
Satralizumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WN42636 
 
STATISTICAL ANALYSIS PLAN 
STUDY TITLE: 
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, MULTICENTER STUDY 
TO EVALUATE EFFICACY, SAFETY, 
PHARMACOKINETICS, AND 
PHARMACODYNAMICS OF SATRALIZUMAB IN 
PATIENTS WITH GENERALIZED MYASTHENIA 
GRAVIS 
STUDY NUMBER: 
WN42636 
STUDY NAME:  
Luminesce 
VERSION NUMBER: 
3 
ROCHE COMPOUND(S): 
Satralizumab (RO5333787) 
EUDRACT NUMBER: 
2020-004436-21 
IND NUMBER: 
151937 
NCT NUMBER: 
NCT04963270 
PLAN PREPARED BY: 
, Ph.D 


 
Satralizumab —F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WN42636 
        2 
STATISTICAL ANALYSIS PLAN VERSION HISTORY 
This Statistical Analysis Plan (SAP) was developed based on Roche SAP model 
document 28 February 2022. 
SAP Version 
Approval Date 
Based on Protocol  
(Version, Approval Date) 
2 
See electronic date stamp 
below 
Protocol version 5, dated 
19 July 2023 
1 
30 May 2023 
Protocol version 3, dated 
10 Nov 2021 
 


 
Satralizumab —F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WN42636 
        3 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE VERSION 3 
Key changes to the SAP, along with the rationale for each change, are summarized 
below. 
Section 
Description of Change 
Rationale for Change 
4.2 Primary Endpoint 
Analysis 
Pooling of North America and 
Europe for stratification by 
Region 
Low number of participants from North 
America 
4.2.3.1 Missingness of 
covariate data 
Removed section 
Does not apply to the collected data set 
4.2.4 Sensitivity 
Analyses for Primary 
Endpoints 
Removal of Sections: Impact 
of Imputations on Item Level, 
Impact of Imputation 
Modeling Approach, Impact of 
Outliers 
Sections are not needed and have been 
replaced by FDA Requested Tipping 
Point Analysis 
4.2.5 Supplementary 
Analyses for Primary 
Endpoint 
Rephrased subgroup 
analyses and removed 
subgrouping by type of 
rescue therapy 
Low number of rescue therapy 
administration 
Table 6/Table 3 
MuSK as a separate 
population to assess mean 
change in MG-ADL from 
baseline to Week 24  
Low number of LRP4 participants, 
MuSK has distinct pathophysiology 
and clinical picture (Gilhus et al. 2019) 
4.3.4 Secondary 
Endpoints Under the 
count Estimand 
Removed paragraph 
No definition for repeated exacerbations 
is applicable 
4.4.1 Additional 
Evidence of Efficacy in 
MuSK and LRP4 
Removed pooling analysis 
and replaced by MMRM 
combining DB  OLE, the 
section is now named 
sustained efficacy. 
Aligning analysis to external analyses in 
gMG 
4.4.2 Additional 
evidence of efficacy 
Time-to-event analyses 
defined in the original protocol 
objectives are now detailed in 
this section 
To align with protocol objectives 
DB  double-blind; gMG  generalized myasthenia gravis; LRP4  low-density lipoprotein 
receptor-related protein 4 positive; MG-ADL  Myasthenia Gravis Activities of Daily Living; 
MMRM  mixed model repeated measures; MuSK  muscle-specific kinase positive; 
OLE  open-label extension.  
  
Additional minor changes have been made throughout to improve clarity and 
consistency. 
 
 


 
Satralizumab —F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WN42636 
        4 
 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE VERSION 3 ......... 3 
1. 
INTRODUCTION ............................................................................. 9 
1.1 
Objectives and Endpoints .......................................................... 9 
1.2 
Study Design ........................................................................... 13 
1.2.1 
Treatment Assignment ............................................................. 15 
1.2.2 
Data Monitoring ....................................................................... 16 
1.2.3 
Global Protocol Version 5 ........................................................ 16 
2. 
STATISTICAL HYPOTHESES AND SAMPLE SIZE 
DETERMINATION ........................................................................ 16 
2.1 
Statistical Hypotheses ............................................................. 16 
2.2 
Sample Size Determination ..................................................... 17 
3. 
ANALYSIS SETS .......................................................................... 17 
4. 
STATISTICAL ANALYSES ........................................................... 18 
4.1 
General Consideration ............................................................. 19 
4.2 
Primary Endpoint Analysis ....................................................... 19 
4.2.1 
Definition of Primary Endpoint ................................................. 20 
4.2.1.1 
Definition of Primary Estimand ................................................. 20 
4.2.1.2 
Intercurrent Events for the Primary Estimand .......................... 21 
4.2.2 
Main Analytical Approach for Primary Endpoint ....................... 25 
4.2.2.1 
Derivation of ICE’s ................................................................... 25 
4.2.3 
Missing Data and Imputation ................................................... 25 
4.2.3.1 
Lateral Item Missingness ......................................................... 25 
4.2.3.2 
Item Missingness ..................................................................... 25 
4.2.3.3 
Longitudinal Missingness ......................................................... 26 
4.2.3.4 
Imputation Due to Intercurrent Events ..................................... 26 
4.2.3.5 
Analysis and Inference of the Primary Endpoint ...................... 27 
4.2.4 
Sensitivity Analyses for Primary Endpoints .............................. 27 
4.2.4.1 
Impact of Rescue Therapy ....................................................... 27 
4.2.4.2 
Impact of Major Protocol Deviations ........................................ 28 
4.2.4.3 
Tipping Point Analysis ............................................................. 28 
4.2.5 
Supplementary Analyses for Primary Endpoint(s) ................... 28 


 
Satralizumab —F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WN42636 
        5 
4.3 
Secondary Endpoints Analyses ............................................... 29 
4.3.1 
Estimands for Secondary Endpoint Analyses .......................... 30 
4.3.1.1 
ICE Strategies for Estimands for Secondary Endpoints ........... 30 
4.3.2 
Secondary Endpoints Under the Primary (Continuous) 
Estimand Framework ............................................................... 34 
4.3.3 
Secondary Endpoints Under the Responder Estimand ............ 34 
4.3.4 
Secondary Endpoints Under the Duration Estimand ................ 34 
4.3.5 
Secondary Endpoint of Rescue Therapy ................................. 35 
4.3.6 
Population of Imputation Models .............................................. 35 
4.3.7 
Hierarchy of Secondary Endpoints .......................................... 35 
4.3.8 
Software for Computation of Primary and Secondary 
Endpoints Analysis .................................................................. 35 
4.4 
Exploratory Endpoints Analyses .............................................. 36 
4.4.1 
Sustained Efficacy ................................................................... 36 
4.4.2 
Additional Evidence of Efficacy ................................................ 36 
4.4.2.1 
Time to Disease Improvement and Disease Worsening .......... 36 
4.4.2.2 
Quality of Life Analyses ........................................................... 37 
4.4.3 
Dose Reduction of Oral Corticosteroids and 
Immunosuppressants .............................................................. 37 
4.5 
Safety Analyses ....................................................................... 37 
4.5.1 
Extent of Exposure .................................................................. 38 
4.5.2 
Adverse Events ........................................................................ 38 
4.5.3 
Laboratory Data ....................................................................... 39 
4.5.4 
Vital Signs ................................................................................ 39 
4.5.5 
ECGs ....................................................................................... 40 
4.5.6 
Columbia Suicide Severity Rating Scale (C-SSRS) ................. 40 
4.6 
Other Analyses ........................................................................ 40 
4.6.1 
Summaries of Screened Population ........................................ 40 
4.6.2 
Summaries of Study Conduct .................................................. 40 
4.6.3 
Summaries of Treatment Group 
Comparability/Demographics and Baseline Characteristics .... 41 
4.6.4 
Overview of Intercurrent Events ............................................... 41 
4.6.4.1 
Analysis of the Adolescents Population ................................... 41 
4.6.5 
Pharmacokinetic Analyses ....................................................... 41 


 
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4.6.6 
Immunogenicity Analyses ........................................................ 42 
4.6.6.1 
Further Analyses of ADA Classification ................................... 43 
4.6.6.1.1 
Pharmacodynamic Analyses .................................................... 43 
4.6.7 
Analyses of China Subpopulation ............................................ 43 
4.7 
Interim Analyses ...................................................................... 43 
4.7.1 
Safety Review .......................................................................... 43 
4.7.2 
Optional Interim for Futility ....................................................... 43 
4.7.3 
Pharmacokinetic Interim Analysis ............................................ 44 
5. 
SUPPORTING DOCUMENTATION .............................................. 45 
6. 
REFERENCES.............................................................................. 46 
 
 
LIST OF TABLES 
Table 1 
Objectives and Corresponding Endpoints ..................................... 9 
Table 2 
Objectives and Corresponding Endpoints ................................... 12 
Table 3 
Analysis Sets .............................................................................. 18 
Table 4 
Attributes for the Estimand of the Primary Endpoint ................... 21 
Table 5 
Handling of ICEs for the Primary Endpoint.................................. 23 
Table 6 
Secondary Endpoints and Corresponding Estimand and 
Relevance ................................................................................... 31 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 15 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Term 
Description 
AChEI 
acetylcholinesterase 
AChR 
acetylcholine receptor 
AChR  
AChR-antibody seropositive (participants/population) 
ADA 
anti-drug antibody 
AE 
adverse event 
ANCOVA 
analysis of covariance 
CCOD 
clinical cut‑off date 
CRO 
contract research organization 
C‑SSRS 
Columbia Suicide Severity Rating Scale 
Ctrough 
trough concentration 
DB 
double-blind 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
gMG 
generalized Myasthenia Gravis 
ICE 
intercurrent event 
ICH 
International Council on Harmonization 
iDMC 
independent Data Monitoring Committee 
IL‑6 
interleukin‑6 
IST 
immunosuppressant 
ITT 
intent to treat 
IxRS 
interactive voice/web-based response system 
LRP4 
low-density lipoprotein receptor‑related protein 4 
MG 
Myasthenia gravis 
MG‑ADL 
Myasthenia Gravis Activities of Daily Living 
MGC 
Myasthenia Gravis Composite 
MG‑QoL 
Myasthenia Gravis Quality of Life 
mITT 
modified intent to treat population 
MMRM 
mixed model repeated measures 
MuSK 
muscle-specific kinase 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
Neuro‑QoL 
Quality of Life in Neurological Disorders 
NSDCR 
not study drug or condition related 
OCS 
oral corticosteroids 
OLE 
open-label extension 


 
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OP 
overall population (ITT) 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
Q4W 
every four weeks 
QMG 
Quantitative Myasthenia Gravis score 
RO 
receptor occupancy 
ROtr,ss 
trough receptor occupancy at steady-state 
SAE 
serious adverse events 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SDCR 
study drug or condition related 
sIL‑6R 
soluble interleukin‑6 receptor 
SOC 
standard of care 
 
 


 
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1. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) details the planned analyses and considerations of 
statistical methodology for Study WN42636.  Study WN42636 is a Phase III, 
randomized, placebo-controlled, double-blind, multicenter clinical study to evaluate the 
efficacy, safety, pharmacokinetic (PK), and biomarker effects of satralizumab in 
participants with generalized Myasthenia Gravis (gMG).  For background information 
about the study, please refer to the Study Protocol WN42636.  The analyses described 
in this SAP will supersede any analysis described in the Protocol for regulatory filings. 
1.1 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety, PK, and pharmacodynamics (PD) of 
satralizumab compared with placebo in participants with gMG on stable background 
therapy.  In addition, the study will assess the long-term safety and efficacy of 
satralizumab during the open‑label extension (OLE) period.  
The study has the following objectives and corresponding endpoints (Table 1). 
Table 1 
Objectives and Corresponding Endpoints 
Primary Efficacy Objective 
Corresponding Endpoint 
 
To evaluate the efficacy of 
satralizumab versus placebo on 
function in daily life in the AChR 
population  
 
Mean change from baseline in total MG‑ADL 
score at Week 24 
Secondary Efficacy Objectives 
Corresponding Endpoints 
 
To evaluate the efficacy of 
satralizumab versus placebo on 
function in daily life in the OP  
 
Mean change from baseline in total MG‑ADL 
score at Week 24 
 
To evaluate the efficacy of 
satralizumab versus placebo in the 
AChR and OP on: 
 
– 
Function in daily life 
 
Percentage of participants with a 2-point 
reduction from baseline in total MG-ADL score 
at Week 24 a 
– 
QMG, QoL, and Fatigue 
 
Mean change from baseline in QMG score, 
MG‑QOL 15r total score and Neuro‑QoL 
Fatigue Subscale total score at Week 24  
 
Percentage of participants with a 3-point 
reduction from baseline in QMG score at 
Week 24 a 


 
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Table 1 
Objectives and Corresponding Endpoints 
– 
Clinical status 
 
Mean change from baseline in total MGC score 
at Week 24 
 
Percentage of participants with a 3-point 
reduction from baseline in total MGC score at 
Week 24 a 
– 
Disease severity 
 
Proportion of participants: 
 
Who have achieved minimal symptom 
expression (total MG‑ADL score of 0 or 1) at 
Week 24 a 
 
With at least one gMG‑related exacerbation 
between baseline and Week 24 
 
Receiving rescue therapy between baseline 
and Week 24 
 
To evaluate the durability of the 
efficacy of satralizumab versus 
placebo in the AChR population and 
the OP 
 
Duration (average number of consecutive 
months) of meaningful improvement, defined 
as 2‑point reduction from baseline in total 
MG‑ADL score a 
Exploratory Efficacy Objectives 
Corresponding Endpoints 
 
To evaluate the efficacy of 
satralizumab versus placebo in the 
AChR and OP on  
 
– 
Time-to-event 
 
Time to disease improvement as measured by: 
– 
2‑point reduction in total MG‑ADL score 
or 
– 
3-point reduction in QMG score or 
– 
3-point reduction in total MGC score or 
– 
MG‑ADL score of 0 or 1 (minimal symptom 
expression) 
 
Time to disease worsening as measured by the 
time from baseline to: 
– 
Start of rescue therapy 
– 
MG-related exacerbation 
 
QoL 
 
Mean change from baseline to Week 24 in 
EuroQoL EQ‑5D‑5L Health Utility Index 
score b 


 
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Table 1 
Objectives and Corresponding Endpoints 
Safety Objective 
Corresponding Endpoints 
 
To evaluate the safety of 
satralizumab versus placebo 
 
Incidence and severity of adverse events, with 
severity determined according to 
NCI CTCAE v5.0 grading 
 
Change from baseline in targeted vital signs, 
ECG results, targeted clinical laboratory test 
results, and suicidality 
Pharmacodynamic Objective 
Corresponding Endpoint 
 
To confirm target engagement and 
pathway inhibition in response to 
satralizumab 
 
Absolute values and change from baseline in 
serum levels of biomarkers IL‑6 and sIL‑6R 
Pharmacokinetic Objective 
Corresponding Endpoints 
 
To investigate the PK of satralizumab 
by evaluating plasma exposure over 
24 weeks 
 
 
Serum concentrations of satralizumab (mean 
and SD of Ctrough) at specified timepoints b 
 
Estimates of primary PK parameters (e.g., CL/F 
and V/F) and secondary PK parameters (e.g., 
AUC) derived using population‑PK modeling b 
 
 


 
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Table 2 
Objectives and Corresponding Endpoints 
Exploratory Pharmacokinetic Objective 
Corresponding Endpoints 
 
To evaluate potential relationships 
between drug exposure and the 
efficacy and safety of satralizumab 
 
Relationship between selected covariates and 
exposure to satralizumab b 
 
Relationship between serum concentration or 
PK parameters for satralizumab and efficacy 
endpoints, PD biomarkers, and safety 
endpoints b 
Immunogenicity Objective 
Corresponding Endpoint 
 
To evaluate the immune response to 
satralizumab 
 
Prevalence of ADAs at baseline and incidence 
of ADAs during the study 
Exploratory Immunogenicity Objective 
Corresponding Endpoint 
 
To evaluate potential effects of ADAs 
on efficacy, biomarker, safety, and 
PK endpoints 
 
Relationship between ADA status, biomarker, 
safety, or PK endpoints 
Exploratory Biomarker Objective 
Corresponding Endpoint 
 
To identify and/or evaluate 
biomarkers that are predictive of 
response to satralizumab, can 
provide evidence of satralizumab 
activity, or can increase the 
knowledge and understanding of 
disease biology 
 
Relationship between biomarkers in blood and 
efficacy endpoints b 
AChR  acetylcholine receptor; AChR  AChR-antibody seropositive (participants/population); 
ADA  anti-drug antibody; AUC  area under the concentrationtime curve; CL/F  apparent 
clearance; Ctrough  trough concentration; gMG  generalized myasthenia gravis; 
IL-6  interleukin-6; MG-ADL  Myasthenia Gravis Activities of Daily Living; MGC  Myasthenia 
Gravis Composite; MG-QOL 15r  Myasthenia Gravis Quality of Life 15 Scale (revised); 
NCI CTCAE v5.0  National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 5.0; NeuroQoL  Quality of Life in Neurological Disorders; OP  overall population; 
PD  pharmacodynamic; PK  pharmacokinetic; QMG  Quantitative Myasthenia Gravis; 
QoL  quality of life; sIL-6R  soluble interleukin-6 receptor; V/F  apparent volume of distribution. 
a  
Participants who receive rescue therapy will be considered non-responders. 
b 
Endpoints are mentioned in above table for alignment with the Study Protocol.  They will not 
be analyzed as part of this SAP and will be presented separately.  
Note:  Efficacy, safety, pharmacokinetic, pharmacodynamics, and immunogenicity-related 
endpoints for adolescents enrolled in the study will be analyzed descriptively. 
 
 
 


 
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1.2 
STUDY DESIGN 
Study WN42636 has the following characteristics: 
1. 
Type/Design: Phase 3, randomized, double-blind (DB), placebo‑controlled, 
multicenter study.  The randomization ratio is 1:1.  Randomization will be 
stratified based on the following factors: 
– 
Baseline standard of care (SOC) treatment:   
 
Acetylcholinesterase (AChEI) monotherapy and/or an oral corticosteroid 
(OCS)  
 
A steroid-sparing immunosuppressant (IST) monotherapy or a combination 
of a steroid-sparing IST with other treatments (an AChEI and/or an OCS) 
– 
Auto-antibody type: 
 
Acetylcholine receptor (AChR) antibody‑positive  
 
AChR-antibody-negative, which are either muscle-specific kinase (MuSK) 
antibody- or low-density lipoprotein receptor‑related protein 4 (LRP4) 
antibody-positive. 
– 
Region:   
 
North America 
 
Europe 
 
Rest of world 
 
2. 
Population: Participants must fulfill the following selected inclusion criteria to be 
eligible for recruitment into the study: 
– 
Age 12 
– 
Confirmed diagnosis of gMG: 
 
Documented history of myasthenic weakness 
 
Myasthenia gravis (MG) severity of Myasthenia Gravis Foundation of 
America Class II, III, or IV at screening 
 
The confirmation of the diagnosis has to be documented and supported by 
positive serologic test for one of the three antibody types: anti‑AChR, 
anti‑MuSK or anti-LRP4 at screening 
– 
A total Myasthenia Gravis Activities of Daily Living (MG‑ADL) score of 5 at 
screening with more than 50% of this score attributed to non‑ocular items 
– 
Ongoing gMG treatment at a stable dose (for precise listing refer to the Study 
Protocol) 
– 
Female participants with childbearing potential agree to remain abstinent 
 
3. 
Duration: The study will include a 28‑day screening period, a 24‑week DB 
treatment period, and approximately 2 years OLE period after the last participant 
initiates open-label treatment.  


 
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4. 
Dosing of blinded study drug:  Blinded study drug will be administered 
subcutaneously to participants at Weeks 0, 2, 4, and every four weeks (Q4W) 
thereafter until the end of the DB period in addition to background treatments at a 
stable dose (see the Study Protocol, Section 4.3).  The dosing regimen proposed 
for this study is 120 mg Q4W for participants 100 kg, and 180 mg Q4W for 
participants 100 kg. 
5. 
Reviews and Interim analyses:  An independent Data Monitoring Committee 
(iDMC) will conduct safety reviews approximately every 3 months.  The dosing 
regimen was confirmed in a PK interim analysis performed after 40 participants 
(including approximately 20 receiving satralizumab) had been enrolled for at least 
8 weeks in the trial.  The purpose was to confirm whether the initial doses were 
sufficient, or whether higher (pre-defined) doses were necessary, to achieve 
target exposure and receptor occupancy (RO).  This PK interim was conducted 
analytically by a PK contract research organization (CRO) and the dose 
recommendation was by the iDMC.  All other interim analyses will be conducted 
by an independent Data Coordinating Center (iDCC) and the Sponsor will remain 
fully blinded.  Interim analyses to stop for efficacy will not be performed.  Futility 
analyses will be pre-specified in a separate Statistical Analysis Plan.   
6. 
Primary analysis: The primary efficacy (final) analysis will be conducted once all 
participants which are part of the modified intent to treat (mITT) population 
(specified later in this document) have either reached Week 24 or withdrawn 
early from the study and data have been cleaned and verified, and the database 
has been locked. 
7. 
As of the Global Protocol version 5, adolescents will be enrolled directly into the 
OLE period after completion of the screening period.  This document specifies 
how these participants will be analyzed.  They are not part of the primary 
analysis. 
The study schema is shown in Figure 1. 


 
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Figure 1 Study Schema 
 
LA  last assessment; LO  last observation; PK  pharmacokinetic; R  randomization; 
SOC  standard of care  
a 
Week 0 baseline assessments will be collected pre-dose. 
b 
Week 0 of OLE period coincides with Week 24 of DB period. 
c 
Participants treated with active drug in DB period will be administered a placebo dose at 
Week 2 of the OLE period to maintain blinding of treatment assignment in the DB period. 
d 
The length of OLE period is approximately 2 years after the last participant enters OLE or 
approximately 4 years after the first participant enters the OLE.  
e 
Following global protocol amendment to version 5 adolescent participants will be enrolled 
directly into the OLE period (after completion of screening; see the Study Protocol, Section 3.1.3) 
and will receive open-label satralizumab SC loading doses at Weeks 0, 2, and 4 in the OLE, 
followed by maintenance doses Q4W thereafter during the OLE period.   
  
1.2.1 
Treatment Assignment  
The study uses an interactive voice/web-based response system (IxRS) to randomize 
participants to two treatment arms and ensure blinding of both treating physician and the 
participant and the Sponsor.  The IxRS implements a block randomization scheme with 
a block size specified in the Biostatistics Randomization Specification Document.  
Treatment assignments are stratified and hence balanced across the following baseline 
factors: 
 
Region:  North America versus Europe versus Rest of World 
 
Baseline SOC treatment:  AChEI monotherapy and/or an OCS versus a 
steroid-sparing IST monotherapy or a combination of steroid-sparing IST with other 
treatments (an AChEI and/or an OCS) 
 
Auto-antibody type:  AChR-antibody positive versus AChR-antibody negative 
(includes MuSK or LRP4 antibody-positive) 
 
If a stratification factor level has a very low sample size compared to other levels, 
the Sponsor may group the levels together for the statistical analysis.  Such a 
grouping would be determined before the data are unblinded. 
 


 
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1.2.2 
Data Monitoring 
An iDMC will be used during the DB period and until the database lock for the primary 
analysis.  The iDMC will perform periodic (approximately every 3 months scheduled in 
agreement with the iDMC) unblinded safety reviews and make recommendations on trial 
continuation or modification.  The iDMC will be involved in the interim PK analysis as 
detailed in the iDMC charter.  All summaries and analyses will be prepared by the iDCC 
and presented by treatment group for the iDMC’s review.  Members of the iDMC and 
iDCC will be external to the Sponsor and the study team and will follow the iDMC charter 
that outlines their roles and responsibilities.  The Sponsor will remain blinded.  
Interactions between the iDMC and Sponsor will be carried out as specified in the iDMC 
Charter. 
1.2.3 
Global Protocol Version 5 
In July 2023, the Global Protocol was amended to Version 5 resulting in a sample size 
reduction.  Given the number of participants already recruited, screening of new 
participants was stopped for adult participants.  Due to recruitment difficulties for 
adolescents related to placebo use in the double-blind period, adolescents will continue 
to be recruited and will enroll directly into the OLE period, once the protocol amendment 
is approved in their countries.  Adolescents who are enrolled in the study after the last 
adult was randomized will not contribute to the primary analysis. 
2. 
STATISTICAL HYPOTHESES AND SAMPLE SIZE 
DETERMINATION 
2.1 
STATISTICAL HYPOTHESES 
The primary study objective is to demonstrate superiority of the experimental treatment 
(satralizumab) over the comparator treatment (placebo) on the primary endpoint defined 
as the change from baseline to Week 24 in the total MG-ADL score (Section 4.2.1) in the 
AChR-antibody seropositive (participants/population) (AChR ) population. 
The primary efficacy analysis will compare the mean for the primary endpoint between 
the treatment arms using a two-sided Wald test at the  level of 0.05 following the 
estimand framework as described in Section 4.2.2.1. 
The following null and alternative hypotheses will be tested:  
H0: satralizumab placebo versus H1: satralizumab  placebo 
For which satralizumab and placebo refer to the mean change from baseline to Week 24 in the 
total MG-ADL score in the satralizumab and placebo groups respectively. 
The primary comparison of interest is the mean change difference for the primary 
endpoint (i.e., the estimated difference between the two treatment groups as detailed in 
Section 4.2.3.5). 


 
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2.2 
SAMPLE SIZE DETERMINATION 
Determination of sample size is based on all globally enrolled participants.  In this study, 
approximately 185 participants will be enrolled and randomized in a 1:1 ratio to each 
treatment group (satralizumab or placebo).  Randomization will be stratified by baseline 
SOC treatment, region, and auto-antibody type as described in the Study Protocol, 
Section 3.1. 
The estimated sample size required to demonstrate efficacy with regard to the MG‑ADL 
is based on the AChR population and the following assumptions: 
 
The primary hypotheses test in the AChR population is the difference between the 
placebo and satralizumab groups in the change from baseline to Week 24 in total 
MG‑ADL score  
 
The assumed change from baseline to Week 24 in the placebo group is 2.3 points 
 
The assumed change from baseline to Week 24 in the satralizumab group is 
4.3 points 
 
The assumed change from baseline accounts for approximately 10% of participants 
in the satralizumab group and approximately 20% of participants in the placebo 
group receiving rescue therapy 
 
The standard deviation (SD) of the change from baseline to Week 24 is 3.97 in both 
the placebo and satralizumab groups 
 
The assumed study treatment withdrawal rate is 10% 
 
The assumptions are based on data reported in Howard et al. (2017).  Due to changes in 
the treatment landscape the assumed mean change from baseline to Week 24 in the 
satralizumab arm is now assumed to be 4.3 (instead of 4).  
Based on these assumptions and using a two-sided  level of 0.05, the sample size to 
achieve 85% power was estimated at 160 participants (80 per group) in the AChR 
population.  Under the assumption that up to 25 participants meeting the study eligibility 
criteria will be AChR (MuSK or LRP4), the total study sample size will be 
approximately 185 participants.  This sample size also provides approximately 80% 
power for an analysis of the difference between the placebo and satralizumab groups in 
the proportion of MG-ADL responders in the mITT and AChR population.  This power 
calculation assumes a 50% response rate in the placebo group and a 75% response 
rate in the satralizumab group.  
3. 
ANALYSIS SETS 
The following populations are defined (Table 3): 


 
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Table 3 
Analysis Sets 
Population 
Definition 
Intent to treat (ITT) 
All randomized participants. This excludes adolescents joining the 
study after the last adult participant is randomized. 
modified intent to treat 
(mITT) 
All participants that are part of the ITT and have a baseline and at 
least one post-baseline MG-ADL assessment during the double-
blind period.  This excludes adolescents joining the study after the 
last adult participant is randomized. 
Overall Population (OP)  
 
All randomized participants who are either AChR or AChR. 
AChR (AChR positive) 
All participants in the study who are acetylcholine receptor antibody 
seropositive (AChR).  
AChR (AChR negative) 
 
All participants in the study who are not AChR, i.e., participants 
who are either low‑density lipoprotein receptor‑related protein 4 
(LRP4) or muscle-specific kinase (MuSK) antibody seropositive.  At 
least one of the two has to be positive. 
MuSK (MuSK positive) 
All participants in the study who are MuSK, but are not AChR and 
are not LRP4. 
Adolescent Population 
All adolescent participants who entered the study. 
Safety‑evaluable 
All participants randomly assigned to study treatment who received 
at least one dose of study treatment.  This includes adolescents 
enrolled after the last adult participant is randomized. 
Pharmacokinetic (PK) 
evaluable 
All participants randomly assigned to study treatment who received 
at least one dose, and had sufficient sampling to permit PK 
evaluation. This includes adolescents enrolled after the last adult 
participant is randomized. 
Immunogenicity 
All participants randomly assigned to study treatment who received 
any study treatment with at least one post‑dose anti‑drug antibody 
assessment.  This includes adolescents enrolled after the last adult 
participant is randomized. 
  
4. 
STATISTICAL ANALYSES 
The primary study objective is to demonstrate superiority of the experimental arm 
(satralizumab, 120 mg or 180 mg for participants with body weight 100 kg or 100 kg, 
respectively) over the control arm (placebo), administered for 24 weeks in participants 
with generalized myasthenia gravis on daily function. 
The statistical analysis will follow the estimand framework aligned with the ICH E9 
Addendum: 
 
The primary comparison of interest is the difference between the placebo and 
satralizumab groups (120 mg or 180 mg satralizumab for participants with body 
weight 100 kg or 100 kg, respectively) in the change from baseline to Week 24 in 


 
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the total MG‑ADL score in the mITT population restricted to the AChR population, 
irrespective of treatment adherence or use of rescue medication (Section 4.2). 
 
The estimands for the secondary endpoints to be included in the hierarchical 
statistical testing process (Section 4.3.7) are defined in Section 4.3. 
 
4.1 
GENERAL CONSIDERATION 
In addition to specific analyses and presentations that are detailed in the following 
sections, study results will be presented by treatment arm (with total when appropriate) 
and summarized according to the nature of the variables. 
For continuous variables, using descriptive statistics, including the number of 
participants contributing to summary statistics, mean, standard deviation, median, and 
range as appropriate. 
For categorical variables, using the frequency and proportion of participants falling into 
each category, grouped by treatment arm (and total).  The percentages given in these 
tables will be rounded and therefore may not always sum to 100%.  If a missing category 
is not presented in the data display, only participants with non-missing values for the 
parameter being assessed will be included in the percentage calculation. 
All efficacy analyses will be performed on the mITT (or subpopulations of the mITT) 
unless otherwise specified.  If additional subpopulations are specified (i.e. AChR or 
AChR), then the mITT restricted to those subpopulations will be analyzed.  The mITT 
ensures that each participant is able to contribute a minimal meaningful amount of 
information to evaluate the treatment effect of satralizumab.  The ITT and mITT exclude 
adolescents joining the study after the last adult participant is randomized.  Adolescent 
participants not part of the mITT will be analyzed separately. 
The primary efficacy analysis will be performed on the AChR participants.  Participants 
will be analyzed according to the treatment assigned at randomization by the IxRS. 
All safety analyses will be performed in the safety‑evaluable population, unless 
otherwise specified.  Participants will be analyzed according to the first treatment they 
received after randomization. 
The baseline value will be defined as the last available value recorded prior to the 
initiation of study treatment, unless otherwise specified. 
4.2 
PRIMARY ENDPOINT ANALYSIS 
The primary endpoint analysis will be performed on the mITT population restricted to 
AChR participants.  Participants will be analyzed according to the treatment assigned 
at randomization by the IxRS.  Given the low number of participants from North America, 
the Region stratification factor will be pooled for participants from Europe and North 
America for the primary analyses. 


 
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The primary endpoint will be summarized by treatment group using tables, listings, and 
graphs, as appropriate. 
This section first introduces the primary estimand, the sensitivity and subgroup analyses, 
the section that follows will describe the secondary endpoints and related estimands. 
4.2.1 
Definition of Primary Endpoint 
The primary endpoint is the difference between the placebo and satralizumab groups in 
combination with stable background therapy in the change from baseline to Week 24 in 
the total MG‑ADL score in AChR participants.  
The MG‑ADL was developed by Wolfe et al. (1999) to assess the degree of gMG 
symptoms (six items: diplopia, ptosis, difficulties with chewing, swallowing, talking, and 
respiratory problems) and functional limitations in carrying out activities of daily living 
(two items: ability to brush teeth or comb hair and impairment in the ability to arise from 
a chair) that have been shown to be present and clinically relevant in gMG patients.  
Each of the eight items is ranked on a 0‑3 scale yielding a total score that ranges from 
0 to 24, with higher scores indicating greater disease severity (see the Study Protocol, 
Appendix 6).  The items of the MG‑ADL were all derived from the original 13‑item 
symptom list that comprises the clinician‑rated Quantitative Myasthenia Gravis score 
(QMG) scale.  
4.2.1.1 
Definition of Primary Estimand 
In accordance to the Addendum to International Council on Harmonization (ICH) E9 and 
to ensure alignment between trial objective, trial design, data collection, analysis, and 
interpretation, the estimand which describes the target of estimation and its five 
attributes including population, treatment condition of interest, variable (endpoint), 
intercurrent events (IECs; defined as events that can occur post-randomization and 
preclude or affect the interpretation of the variable) and summary of measure are 
described in Table 4. 
 
 


 
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Table 4 
Attributes for the Estimand of the Primary Endpoint 
Attribute 
Description 
Estimand 
The primary endpoint will be evaluated irrespective of taking rescue therapy, 
treatment discontinuation due to SDCR, as though participants with treatment 
discontinuation due to NSDCR continued treatment and as though participants 
with missing data after SDCR, rescue therapy, treatment interruption due to 
infection continued with placebo.  
Population 
The population targeted are all participants recruited to the study (satisfying all 
inclusion criteria) and are part of the mITT restricted to AChR. 
Variable 
MG-ADL total score 
Treatments 
Experimental Treatment: Satralizumab 120 mg (for participants with body 
weight 100 kg) or 180 mg (for participants with body weight 100 kg) and 
background therapy.  Control Treatment: Placebo, administered for 24 weeks 
and background therapy. 
Intercurrent 
Events 
See next Section 4.2.1.2. 
Summary of 
Measure 
The difference in the change from baseline to Week 24 in MG-ADL total score.  
An estimate of the treatment effect will be computed using an analysis of 
covariance regression approach using the “Variable” as a response and 
adjusting for randomization stratification factors (background therapy, 
auto-antibody type, region) and the baseline “Variable” value.  The computation 
will be performed on a completed data set which is obtained by a mixed model 
repeated measures imputation model. 
AChR  AChR-antibody seropositive (participants/population); MG-ADL  Myasthenia Gravis 
Activities of Daily Living; mITT  modified intent to treat; NSDCR  not study drug or condition 
related; SDCR  study drug or condition related. 
  
4.2.1.2 
Intercurrent Events for the Primary Estimand 
In this section, we will discuss specifically how ICEs are categorized and approaches for 
handling missing data due to ICEs. 
In this study, three different ICEs are considered:  
 
Withdrawal from study treatment  
 
Receiving a rescue therapy 
 
Treatment interruption due to infection. 
 
As described in Table 5, the ICEs are classified into two main categories: 
 
Study Drug or Condition Related ICE (SDCR ICE) 
 
Not Study Drug or Condition Related ICE (NSDCR ICE). 
 


 
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For the generic ICE “Withdrawal from study treatment” information on the cause and 
categorization into whether the interruption is SDCR or NSDCR is collected in the 
electronic Case Report Form (eCRF): 
 
NSDCR: Pregnancy, study terminated by Sponsor 
 
SDCR: Adverse Event (AE), death, lack of efficacy 
 
NSDCR or SDCR: Lost to follow-up, protocol deviation, withdrawal by subject, 
physician decision, other. 
 
The last bullet collects cause that the investigator will be asked for categorization into 
NSDCR or SDCR in the eCRF. 
Depending on to the classification of ICEs, we propose estimand strategies and statistical 
imputation methodology in handling SDCR- and NSDCR-ICEs in Table 5. 
 


 
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Table 5 
Handling of ICEs for the Primary Endpoint 
Intercurrent Event 
Classification 
Study Drug or Condition Related (SDCR) 
Not Study Drug or Condition Related (NSDCR) 
Intercurrent event  
Withdrawal from study treatment (AE, death, lack of 
efficacy).1 
Lost to follow-up, protocol deviation, withdrawal by 
subject, physician decision and other, that are specified 
for the individual participant as SDCR. 
Receiving a rescue therapy.2 
Treatment interruption due to infection.3 
Withdrawal from study treatment (Pregnancy, study terminated by 
Sponsor). 1 
Lost to follow-up, protocol deviation, withdrawal by subject, 
physician decision, other., that are specified as NSDCR for the 
individual participant. 
 
Estimand Strategy 
Treatment Policy 
In the treatment policy strategy, the occurrence of 
SDCR ICE is ignored and measurements of the variable 
of interest are used as such. 
In other words, the analysis does not make any 
statistical adjustment for SDCR ICE. 
Hypothetical Approach 
The hypothetical approach envisages a scenario wherein it is 
presumed that NSDCR ICE would not have occurred. 
Thus, assumes that NSDCR ICE did not happen in the 
participants who consented to participate. 
 
Data Collection 
Regardless of ICE occurrence, the participant will be asked to remain in the study to be evaluated for the primary efficacy 
endpoint and data collection will continue as long as possible. 
Data Strategy 
Data are used as available to estimate a treatment 
effect irrespective of the occurrence of SDCR ICE. 
This assumption will estimate the treatment effect by 
analyzing outcomes as they were observed, assuming 
rescue therapy is part of the standard treatment regimen 
and hence data are considered as recorded. 
All data after an ICE is ignored. 


 
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Table 5 
Handling of ICEs for the Primary Endpoint 
Intercurrent Event 
Classification 
Study Drug or Condition Related (SDCR) 
Not Study Drug or Condition Related (NSDCR) 
Imputation Strategy 
If data are unavailable, or only partial data are available 
subsequent to a SDCR ICE, then data are used as 
available and the remainder is imputed using copy 
reference. 
Data are imputed using copy reference methodology 
(i.e., data are imputed from the placebo arm).  The 
underlying assumption being that participants who 
discontinue the active arm did not get a benefit from the 
proposed treatment after the SDCR ICE.  In other 
words, the participant profile following SDCR ICE tracks 
that of the reference arm but starting from the benefit 
already obtained. 
Data are imputed using a missing at random assumption that is 
data will be imputed conditional on observed data. 
The imputation under a missing at random assumption estimates 
a treatment effect as if the ICE had not happened. 
 
1 For the generic ICE “Withdrawal from study treatment” information on the cause and categorization into whether the interruption is study drug or 
condition related (SDCR) or not SDCR (NSDCR) is collected in the electronic Case Report Form. 
2 Receiving rescue therapy might not result in a treatment interruption but is a relevant ICE in this study that always falls under the SDCR 
category. 
3 Treatment interruption due to infection will always be categorized as SDCR. 
If a participant has recorded multiple ICEs, then the category of the first ICE will determine the handling strategy of all subsequent missing data. 
 


 
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The precise statistical imputation methodology is detailed in section on missingness and 
imputation. 
For the efficacy analysis data entries will be mapped to the closest visit available.  No 
visit will be mapped across their respective period for DB or OLE.  If two data entries are 
mapped to the same visit, then the one closer to it and later will be used. 
4.2.2 
Main Analytical Approach for Primary Endpoint 
4.2.2.1 
Derivation of ICE’s 
To facilitate the analysis of the primary endpoint a data set containing all ICEs will be 
derived.  For each participant it will contain a row for each ICE, the date and time of the 
ICE, the cause/description of the ICE and the categorization into SDCR/NSDCR.  
4.2.3 
Missing Data and Imputation 
Obviously, the optimal strategy for dealing with missing data is to make every effort to 
obtain complete data during the conduct of the study.  The Sponsor will work diligently 
and use a variety of methods to minimize the percentage of missing data in this trial.  
Nevertheless, there is likely to be a small percentage of missing data.  In this context, 
approaches to handle missing data for the primary and secondary analysis are 
described in this section.  
If a participant discontinues treatment the Sponsor will ensure all planned assessments 
are continued whenever possible to avoid unnecessary missingness. 
The following missing data and imputation procedure applies to relevant baseline 
covariates (Stratification factors [auto-antibody type, background therapy and region]) 
and all longitudinal efficacy scores (MG-ADL, QMG, Myasthenia Gravis Composite 
[MGC], Myasthenia Gravis Quality of Life [MG-QoL] and Quality of Life in Neurological 
Disorders [Neuro‑QoL]) including baseline.   
In the following the resolution of different missingness types are described and will be 
addressed in the order listed. 
4.2.3.1 
Lateral Item Missingness 
For specific lateral items such as right/Left-hand grip, right/left arm outstretched and 
right/left leg outstretched one side might be missing when the other is present.  In such a 
case the mean lateral difference across all past visits for the participant will be 
computed, and the missing item will be imputed based on the contralateral side and the 
mean lateral difference. 
4.2.3.2 
Item Missingness 
For the efficacy scores (MG-ADL, QMG, MG-QoL, MGC, NeuroQoL) items might be 
missing.  This is the case if at any measurement visit date at least one item has been 


 
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recorded.  In this case, missing items will be estimated using the proportional method of 
imputation based on participants' responses to the other items on the questionnaire. 
The following rule is applied: 
1.) If less than 50% of items (number of items available MG‑ADL   4, QMG 7, 
MG‑QoL 8, NeuroQoL: 4) are missing, the final score is computed as the sum 
of the non-missing items times the total number of items divided by the number 
of non-missing items.  As an example, the sum of available items is 6, the 
number of available items is 9 and the total number of items is 13 then the result 
is 6*(13/9). 
2.) In case more items than in the previous instruction are missing then data are 
considered fully missing and one of the next steps is applied. 
 
The Sponsor will always trust the entered result of the Investigator but might query a site 
if a result seems incomplete or inconsistent.  If a result contains a total score but some 
items remain incomplete the total score will be used in the statistical analysis.  
Imputation will only take place if items and total score are missing. 
4.2.3.3 
Longitudinal Missingness 
In case data are missing for intermediate visits and missingness is not caused by an ICE 
then data will be imputed based on a missing at random assumption.  This imputation 
will be performed at the same time imputation due to missingness of ICE is performed.  
4.2.3.4 
Imputation Due to Intercurrent Events 
In the following we describe missingness and data imputation due to IECs.  A detailed 
statistical justification for this imputation strategy can be found in Wolbers M et al. 
(2021).  
1. 
For each participant the time of the first ICE is determined using the ICE data set.  
For each efficacy score a data set is created where all subsequent data to the 
first ICE is removed.  If a participant has multiple ICEs between which normal 
dosing of study drug is attained all the data are nevertheless removed in a first 
step, i.e., data that would be dealt under treatment policy is still removed in this 
step.  This ensures that the imputation model is fitted on data that is completely 
unaffected by ICEs. 
2. 
A mixed model repeated measures (MMRM) model is fitted as an imputation 
model to address all the missingness due to ICEs.  The MMRM is modeling 
change from baseline of the efficacy score (separate MMRMs will be fitted for 
each score) and has the following covariates: treatment group, visit, treatment 
group x visit, baseline stratification factors (background therapy, auto-antibody 
type [where this applies], region), baseline efficacy score and baseline efficacy 
score x visit. (“x” refers to complete interactions).  The MMRM will use an 
unstructured covariance overall, in case of convergence issues the covariance 
structure will be simplified to compound symmetry.  The resulting model will serve 
as a model for all imputations of longitudinal data in the next step. 


 
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3. 
The MMRM model implies a multivariate normal imputation distribution 
conditional on baseline covariates and conditional on observed longitudinal data 
that is not affected by an ICE.  The implied conditional mean of this normal 
distribution is used to impute missing data.  Participants with an ICE but 
subsequent data available which falls under treatment policy will use the 
observed data and will not be imputed.  Participants on the satralizumab arm with 
missing data due to an ICE in category SDCR will be imputed using the 
imputation model and their treatment group covariate will be artificially set to 
placebo (copy reference imputation), this way their data are imputed as if they 
had not had a benefit from the treatment after the ICE.  This imputation 
procedure will result in a complete data set for each efficacy score.  All the 
efficacy analyses will be conducted on the completed data sets. 
 
4.2.3.5 
Analysis and Inference of the Primary Endpoint 
The treatment effect on the primary endpoint is estimated using an analysis of 
covariance (ANCOVA) with response variable change in MG-ADL from baseline to 
Week 24 adjusting for treatment group and the same covariates as for the imputation 
model.  
The primary treatment effect estimate is the regression coefficient of the treatment 
group. 
The estimate of variance coming from the ANCOVA will underestimate the true variance 
as it ignores the variance due to the imputation.  To correct the underestimation of the 
variance the jackknife is applied to all previous steps (2-3) of the imputation modeling, 
that is an imputation model is fit on each data set with one participant removed.  The 
p‑value of the treatment effect is derived through the Wald test.  
4.2.4 
Sensitivity Analyses for Primary Endpoints 
The robustness of the primary method of estimation will be explored using a series of 
sensitivity and supplementary estimators based on varying different aspects of the 
primary endpoint, including sensitivity analyses exploring robustness of departures from 
statistical assumptions and supplementary analyses investigating the trial data as listed 
in this section.  The p‑values from sensitivity and supplementary analyses of the primary 
endpoint are for descriptive purpose only, and there will be no multiplicity adjustment for 
these analyses. 
We propose a series of sensitivity analyses to further assess the potential dependence 
of the results of the primary analysis on missing values.  However, additional sensitivity 
analyses may be considered if appropriate. 
4.2.4.1 
Impact of Rescue Therapy 
To assess the impact of rescue therapy in AChR participants all values after the 
administration of rescue therapy are replaced by the worst possible MG-ADL 
assessment that a particular participant has had prior to receiving rescue therapy.  This 


 
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imputation overwrites the estimand specified imputation strategy.  The impact will be 
estimated using an MMRM. 
4.2.4.2 
Impact of Major Protocol Deviations 
To assess the impact of major protocol deviations, the primary analysis will be run 
excluding participants with a major protocol deviation of which an impact on the efficacy 
outcome is expected.  A separate analysis for each type of major protocol deviation is 
conducted: 
1. Violation of the inclusion criteria of the MG-ADL score at screening 
2. MG-ADL not performed in the order specified per protocol at DB Week 0 and/or 
Week 24 
3. MG-ADL assessment performed by non-qualified site personnel at DB Week 0 
and/or Week 24 
4. Failure to maintain dual assessor approach. 
 
4.2.4.3 
Tipping Point Analysis 
A  tipping point analysis will be conducted on all participants who discontinue 
satralizumab treatment.  The MG-ADL value after stopping treatment will be replaced by 
the last available assessment prior to stopping plus an additive constant delta.  The 
treatment effect will be re estimated for varying values of delta (0,∞) until the first delta at 
which the primary analysis treatment effect p-value will exceed 5%.  The minimal value 
of delta at which this happens is referred to as the tipping point.  This imputation will 
overwrite the estimand specified imputation strategy. 
4.2.5 
Supplementary Analyses for Primary Endpoint(s) 
In addition to the primary analysis for each efficacy score at Week 24, the same analysis 
will be performed for each other clinical visit date: Week 2, Week 4, Week 8, Week 12, 
Week 16 and Week 20. 
Subgroup analyses for the primary endpoint will be performed to explore whether the 
treatment effect on the primary endpoint is consistent across subgroups.  The influence 
of baseline and demographic characteristics on the treatment effect among participants 
will be explored via exploratory subset analyses for the following factors: 
 
Sex  
 
Age at diagnosis  
 
Race 
 
Region 
 
Background therapy 
 
Baseline disease severity and characteristics 
 
Dose level. 
 


 
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Treatment effects within each subgroup will be examined separately using the imputed 
data of the primary estimand and the model specified previously for the primary 
endpoint. 
Forest plots will be generated displaying the estimated difference (the effect size of the 
primary treatment effect), 95% confidence intervals, and the corresponding p-value for 
each subgroup, with the overall result also included at the bottom.  These subsidiary 
analyses are intended to provide reassurance that the observed treatment effect is 
consistent across all participant subgroups. 
The study is not powered to detect differences between subgroups and any observed 
patterns should be interpreted extremely cautiously, owing to the smaller numbers and 
increased chance of type I error. 
All listed subgroup analyses will be presented in a forest plot showing the effect size of 
the primary treatment effect in that subgroup.  
4.3 
SECONDARY ENDPOINTS ANALYSES 
Secondary endpoints are based on the following scores (see the Study Protocol for 
details): 
 
 
QMG: The QMG is a 13-item direct physician assessment scoring system that 
quantifies disease severity based on impairments of body functions and structures.  
Each item is quantitatively assessed and scored from 0 to 3 (where 3 represents the 
most severe), providing a total QMG score ranging from 0 to 39 (Clinical Review 
Report) 
 
MG-QoL: The MG-QOL-15 is a disease-specific health-related quality of life 
measure that consists of 15 items: mobility (9 items), symptoms (3 items), and 
contentment and emotional well-being (3 items).  Items are scored on a Likert scale 
from 0 to 4 with the total score ranging from 0 to 60 (Burns et al. [2008])  
 
MGC: The MGC is a composite measure consisting of items drawn from the 
MG‑ADL (chewing, swallowing, speech, and breathing), QMG (diplopia and ptosis), 
and Manual Muscle Test (hip, neck, facial, and deltoid strength) in an effort to 
include both clinician- and participant-reported elements in a single measure (Burns 
et al. [2008]).  Each of the ten items contribute to a total score ranging from 0 to 50, 
with higher values indicating increasing symptom severity (Burns et al. [2010]) 
 
Neuro-QoL: The NeuroQoL Fatigue scale is a short form that is part of a collection 
of instruments and item banks, developed through a National Institute of 
Neurological Disorders and Stroke–sponsored initiative to evaluate the 
health‑related quality of life of adults and children diagnosed with neurological 
disorders.  It consists of eight items, each using a 5‑level Likert scale ranging 
between 1  never to 5  always, with a 7‑day recall period (Cella et al. [2012]). 
 


 
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4.3.1 
Estimands for Secondary Endpoint Analyses 
In addition to the primary estimand, the analysis of the secondary endpoints will rely on 
the responder estimand and the Duration Estimand.  Except for the difference in 
estimands with regards to composite strategies, the analysis of secondary endpoints is 
the same as for the primary endpoint and will make use of the same imputation scheme. 
4.3.1.1 
ICE Strategies for Estimands for Secondary Endpoints 
Endpoints depending on different estimands than the primary will still be computed on 
the imputed data set of the primary estimand and their ICE strategies will be 
implemented on top of the imputed data set: 
 
Responder Estimand: Same imputation as for primary estimand, if a participant 
requires rescue therapy the participant is categorized as non-responder (composite 
strategy).  For example, for the secondary endpoint percentage of participants with 
a 2‑point reduction from baseline in total MG-ADL score at Week 24, the dataset 
with MG‑ADL score imputed as in Section 4.2.3.4.  Completed MG‑ADL will be used 
to identify the participants with a 2 point reduction from baseline.  On top of that, if 
participants require rescue therapy the participant is categorized as non-responder 
 
Duration Estimand:  Same imputation as for primary estimand, if a participant 
requires rescue therapy the participant will be imputed as not having an endured 
treatment effect after administration of rescue therapy (composite strategy).


 
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The following table lists all secondary endpoints, the corresponding estimand, and relevance as secondary endpoint (Table 6).  All 
populations are to be understood as the mITT restricted to the mentioned population.  LRP4 & MuSK refers to the AChR- population. 
Table 6 
Secondary Endpoints and Corresponding Estimand and Relevance 
Secondary Endpoint 
Population 
Relevance 
Estimand Type (Generic) 
Mean change from baseline in 
MG-ADL score at Week 24 
OP, LRP4 & 
MuSK 
confirmatory Primary (continuous) estimand: Difference in mean change of “Score” from 
baseline in “Population”, treated with satralizumab vs placebo, in combination with 
stable background therapy, irrespective of taking rescue therapy, treatment 
discontinuation due to SDCR, as though participants with treatment 
discontinuation due to NSDCR continued treatment and as though participants 
with missing data after SDCR, rescue therapy, treatment interruption due to 
infection continued with placebo. 
Mean change from baseline in 
MG-ADL score at Week 24 
MuSK 
exploratory 
Mean change from baseline in 
QMG score at Week 24 
AChR, OP confirmatory 
LRP4 & 
MuSK 
exploratory 
Mean change from baseline in 
MG-QOL 15r total score at 
Week 24  
AChR 
confirmatory 
OP 
supportive 
LRP4 & 
MuSK 
exploratory 
Mean change from baseline in 
MGC total score at Week 24 
AChR 
confirmatory 
OP 
supportive 
LRP4 & 
MuSK 
exploratory 
Mean change from baseline in 
Neuro‑QoL Fatigue Subscale 
total score at Week 24 
AChR 
confirmatory 
OP 
supportive 
LRP4 & 
MuSK 
exploratory 
AChR, OP 
supportive 


 
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Table 6 
Secondary Endpoints and Corresponding Estimand and Relevance 
Secondary Endpoint 
Population 
Relevance 
Estimand Type (Generic) 
Percentage of participants with a 
2-point (and more) reduction 
from baseline in total MG-ADL 
score at Week 24 
LRP4 & 
MuSK 
exploratory Responder Estimand: The difference in proportion in population with a x-point 
reduction from baseline in Score at Week 24 between participants treated with 
satralizumab vs placebo, in combination with stable background therapy, as 
though participants with treatment discontinuation due to NSDCR continued 
treatment and as though participants with missing data after SDCR, treatment 
interruption due to infection continued with placebo as though participants 
receiving rescue therapy were not showing a reduction from baseline. 
Percentage of participants with a 
3-point (and more) reduction 
from baseline in QMG score at 
Week 24 
AChR, OP 
supportive 
LRP4 & 
MuSK 
exploratory 
Percentage of participants with a 
3-point (and more) reduction 
from baseline in total MGC score 
at Week 24 
AChR, OP 
supportive 
LRP4 & 
MuSK 
exploratory 
Proportion of participants who 
have achieved minimal symptom 
expression (total MG-ADL score 
of 0 or 1) at Week 24 
AChR, OP 
supportive 
LRP4 & 
MuSK 
exploratory 
Proportion of participants with at 
least one gMG related 
exacerbation between baseline 
and Week 24 
AChR, OP 
supportive 
LRP4 & 
MuSK 
exploratory 
 
 


 
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Duration (# consecutive 
visits) that participants 
show at least 2 point 
reduction from baseline 
MG-ADL 
AChR, OP 
supportive 
Duration Estimand: The difference in the mean duration of meaningful improvement at 
Week 24 in population between participants treated with satralizumab vs placebo, in 
combination with stable background therapy, as though participants with treatment 
discontinuation due to NSDCR continued treatment and as though participants with missing 
data after SDCR, treatment interruption due to infection continued with placebo as though 
participants receiving rescue therapy were not showing a further reduction from baseline. 
LRP4 & MuSK 
exploratory 
AChR  acetylcholine receptor; AChR  AChR-antibody seropositive (participants/population); gMG  generalized Myasthenia Gravis;  LRP4  low-density 
lipoprotein receptor‑related protein 4; MG-ADL  Myasthenia Gravis Activities of Daily Living; ; MGC  Myasthenia Gravis Composite; MG-QoL   Myasthenia 
Gravis Quality of Life; MuSK  muscle-specific kinase; NSDCR  not study drug or condition related; OP  overall population; QMG  Quantitative Myasthenia 
Gravis score; QoL  quality of life; SDCR  study drug or condition related; Exacerbation  increase of non-ocular MG-ADL item by at least two points from 
baseline or achieving non-ocular item value of 3 when baseline was below 3. 


 
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4.3.2 
Secondary Endpoints Under the Primary (Continuous) 
Estimand Framework 
Secondary endpoints falling under the primary estimand framework (Table 6) will be 
analyzed the same way as the primary endpoint.  The ANCOVA model will be analyzed 
by adjusting for the baseline value of the corresponding score, i.e., QMG change from 
baseline to 24 weeks will be adjusted for baseline QMG (instead of baseline MG-ADL). 
The estimands for the secondary endpoints will be derived on the imputed data set of 
the primary estimand if the corresponding endpoint is solely based on the raw score. 
4.3.3 
Secondary Endpoints Under the Responder Estimand  
To analyze secondary endpoints under the responder estimand framework (Table 6)  
each participant will have to be labelled as a responder or non-responder.  This is done 
using the complete data set from the Imputation procedure and by applying the definition 
of the secondary endpoints.  For a rationale on those responder definitions refer to the 
Study Protocol sections on MG-ADL, QMG and MGC responder definitions, which 
employ minimum clinically important difference derived in the relevant clinical literature.  
According to ICE specification of the responder estimand, participants that received 
rescue therapy will be imputed as non-responders (composite strategy) irrespective of 
the actual score in the completed data set.  
A Cochran-Mantel-Haenszel test over the treatment groups stratifying for baseline 
stratification factors is the treatment effect estimator for the responder estimand.  The 
estimate is the difference in proportion at Week 24.  
4.3.4 
Secondary Endpoints Under the Duration Estimand 
The duration estimand is only relevant for the analysis of the number of consecutive 
visits a participant shows an MG‑ADL reduction of at least 2 points from baseline.  
Based on the completed data set, the first time a participant shows a 2-point or more 
reduction from baseline, the duration is measured until Week 24 or until the visit when 
MG-ADL  is no longer reduced by 2 points from baseline MG-ADL.  The duration is the 
difference in weeks between the two visits defining the start and end (or Week 24) of 
reduction from baseline. If the participant shows a reduction for only one visit, the count 
is set to 1 week.  If the participant required rescue therapy, the count is stopped prior to 
the visit at which the participant received rescue therapy (composite). 
The count variable (the number in weeks by consecutive visits) will be modeled using an 
ANCOVA adjusting for the same covariates as the imputation model and baseline 
MG‑ADL.  The treatment effect estimator is the regression coefficient of the treatment 
group.  The estimate is the difference in the mean duration of meaningful improvement 
at Week 24. 


 
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4.3.5 
Secondary Endpoint of Rescue Therapy 
The endpoint of proportions of participants receiving rescue therapy during the 
doubleblind period will analyze the variable that encodes whether a participant received 
rescue therapy during the double-blind period or not.  Treatment policy is used, that is if 
a participant stops study drug but receives rescue therapy during the safety follow-up 
and this occurs within 24 weeks of baseline then this is counted as having received 
rescue therapy.  Stop of study drug and no further information available will be imputed 
as not having received rescue therapy. 
A Cochran-Mantel-Haenszel test over the treatment groups stratifying for baseline 
stratification factors is the treatment effect estimator for the proportions of participants 
receiving rescue therapy.  The estimate is the difference in proportion at Week 24.  
4.3.6 
Population of Imputation Models 
All analyses on the AChR population will use an imputation model fitted on AChR 
only.  Analyses on OP, MuSK, or LRP4 will use the OP to fit the imputation model. 
4.3.7 
Hierarchy of Secondary Endpoints 
The primary and secondary endpoints will be tested using a hierarchical gatekeeping 
procedure.  Where the hierarchical gatekeeping procedure is used, if any test result is 
not statistically significant, formal testing of subsequent endpoints will not occur.  If the 
primary endpoint is statistically significant, the confirmatory secondary endpoints are 
tested in the following order: 
1. 
Mean change from baseline in QMG score in AChR participants at Week 24 
2. 
Mean change from baseline in MG‑QOL 15r total score in AChR at Week 24 
3. 
Mean change from baseline in MGC total score in AChR participants at Week 24 
4. 
Mean change from baseline in MG-ADL score in the OP at Week 24 
5. 
Mean change from baseline in QMG score in the OP at Week 24 
6. 
Proportion of AChR participants receiving rescue therapy between baseline and 
Week 24 
7. 
Mean change from baseline in MG-ADL score in MuSK and LRP4 at Week 24 
8. 
Mean change from baseline in Neuro‑QoL Fatigue Subscale total score in 
AChR participants at Week 24. 
 
4.3.8 
Software for Computation of Primary and Secondary Endpoints 
Analysis 
The implementation of the previous described analyses will be conducted using the 
programing language R.  The estimand framework will be implemented using the 
rbmi package.  The statistical analysis will be conducted using the programing 
languages SAS and R. 


 
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4.4 
EXPLORATORY ENDPOINTS ANALYSES 
Exploratory endpoints analyses are listed in Table 6.  
4.4.1 
Sustained Efficacy 
To demonstrate evidence of sustained efficacy of satralizumab, the mean change from 
baseline to OLE Week 48 will be fitted using an MMRM for both the MG-ADL and the 
QMG in OP, AChR and AChR participants.  This analysis will include participants who 
at the time of the clinical cutoff (CCOD) have been enrolled for at least 40 weeks, i.e. 
with at least an OLE Week 16 visit for those still part of the study. 
4.4.2 
Additional Evidence of Efficacy 
4.4.2.1 
Time to Disease Improvement and Disease Worsening 
Time-to-event analyses of the following endpoints will be conducted on mITT 
participants during the double-blind period. 
Time to disease improvement (composite endpoint): 
 
2 point reduction in total MG-ADL score 
 
3 point reduction in QMG score 
 
3 point reduction in MGC score 
 
MG-ADL score of 0 or 1 (minimal symptom expression status) 
 
Combination (whichever happens first) of reduction by 2 points in total MG-ADL 
or 3 points in total QMG score 
Time to disease worsening: 
 
Time to first use of rescue therapy 
 
Time to MG-related exacerbation. 
 
Participants with no event during the double-blind period will be censored on the day of 
their last double-blind period visit.  The time of each event will be derived from the actual 
time point the event first occurs compared to the timepoint of baseline.  The first four 
endpoints will use a composite strategy for rescue therapy, i.e., participants will be 
coded as not having had an event if they receive rescue therapy during the double-blind 
period and they will be censored at the time they receive rescue therapy.  The treatment 
effect will be estimated using a log-rank test.  Kaplan-Meier curves will be used to plot 
the data and listings will contain survival estimates at regular time points. 


 
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4.4.2.2 
Quality of Life Analyses 
The mean change in EuroQoL EQ-5D-5L Health Utility Index score from baseline to 
Week 24 will be computed by arm and compared. 
4.4.3 
Dose Reduction of Oral Corticosteroids and 
Immunosuppressants 
A descriptive overview of background therapy dose reduction from OLE Week 12 
onward will summarize the proportion of participants with an ongoing tapering or 
substantial dose reduction and/or discontinuation. 
We consider the following ratios: 
 
Ongoing corticosteroid tapering: Number of participants who reduce their dose 
after OLE Week 12 and do not increase their dose subsequently, divided by 
number of participants who reduce their dose after OLE Week 12 
 
Successful corticosteroid tapering and discontinuation: Number of participants 
who either reduce their dose after OLE Week 12 to physiologic dose level of 
7.5 mg prednisone daily dose equivalent or discontinue corticosteroid, divided 
by number of participants who reduce their dose after OLE Week 12 
 
Ongoing immunosuppressant (IST) tapering: Number of participants who reduce 
their dose after OLE Week 12 and do not increase their dose subsequently, 
divided by number of participants who reduce their dose after OLE Week 12 
 
Successful IST tapering and discontinuation: Number of participants who 
substantially reduce their dose after OLE Week 12 (at least 25% dose reduction) 
or withdraw from IST, divided by number of participants who reduce their dose 
after OLE Week 12 
Of note: This analysis will be conducted on CCOD data set used for the primary 
analysis and will include only participants who have at least 24 weeks of OLE period 
data collected.  The analysis will be repeated at the end of the study to provide a 
more complete picture. 
 
4.5 
SAFETY ANALYSES 
The safety analysis population will consist of all randomized participants who received at 
least one dose of study drug, with participants grouped according to treatment and first 
dose received after randomization.  
The main analyses will be done with a while on treatment strategy for two analyses sets: 
double-blind and overall satralizumab treatment period, which refers to the time in which 
participants are either randomized to satralizumab or switch to satralizumab at the 
beginning of the OLE period.  The two analysis sets are defined as follows: 


 
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Analysis Set for the Double-Blind:  All data up to the first dose in OLE, or up to 4 weeks 
after the last dose of the study drug (for participants who permanently discontinued the 
double-blind treatment), or last contact with the participant, or CCOD, whatever occurs 
first. 
Analysis Set for the 'Overall Satralizumab Treatment’:  All data from the first dose of 
satralizumab (in the DB for the participants receiving satralizumab and in the OLE for 
participants receiving placebo during the DB period) until up to 4 weeks after the 
last dose of the satralizumab (for participants who permanently discontinued 
satralizumab), or last contact with the participant, or CCOD, whatever occurs first. 
In addition, the data collected in the remaining period of the safety follow-up will be 
described separately and will use the analyses set for safety follow-up: all data later than 
4 weeks after the last dose of study drug, for participants who permanently discontinued 
from the study drug. 
Safety will be assessed through summaries of exposure to study treatment, AEs, 
changes in targeted laboratory test results, and changes in vital signs and 
electrocardiograms (ECGs).  
Study treatment exposure (such as treatment duration, total dose received, and number 
of doses and dose modifications) will be summarized with descriptive statistics.  
AE analyses will be performed on key subgroups including, but not limited to, age, race 
and region. 
4.5.1 
Extent of Exposure  
Exposure to study drug information will be descriptively summarized by treatment as 
follows:  
 
Treatment duration (in days) 
 
Total number of administrations 
 
Total cumulative dose (mg) 
 
Frequencies of participants in each dose level 
 
Percentage of patients with a dose change due to weight changes. 
 
Exposure to concomitant medications will be shown in a list overall and by treatment 
group showing the total number of uses of concomitant medications. 
4.5.2 
Adverse Events 
All verbatim AE terms will be coded using the Medical Dictionary for Regulatory Activities 
version that is current at the time of the analysis (AE intensity will be graded according to 
the National Cancer Institute Common Terminology Criteria for Adverse Events, version 
5.0 (NCI CTCAE, v5.0) grading scale or according to Table 11 in Section 5.3.3 of the 


 
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Study Protocol (mild/moderate/severe/life-threatening/death), if the event is not 
specifically listed in the NCI CTCAE.  For each treatment group, the frequency of each 
AE preferred term will be defined as the number of participants experiencing at least one 
occurrence of the AE.  Each table will present the overall number of events and 
percentage of participants experiencing at least one AE. 
Additional analyses for the ‘overall satralizumab treatment’ analysis set, summary of AE 
per 100 participant years will be provided.  In this analysis multiple events will be 
counted each time they occur. 
Percentages will be based on the number of participants in the safety-evaluable analysis 
population.  In summary tables, AEs will be sorted by body system (in decreasing order 
of overall incidence), then by preferred term (in decreasing order of overall incidence).  
The following safety information will be summarized by treatment group for the 
double‑blind treatment period:  
 
AEs, AEs by intensity, AEs related to study drug  
 
Deaths  
 
Serious adverse events (SAEs), SAEs related to study drug  
 
AEs leading to discontinuation of study treatment  
 
AEs leading to dose modifications (dose interruption)  
 
Protocol-specified adverse events of special interest  
 
Infections 
 
Injection reactions. 
 
The following data handling rules will be applied for all AE summary tables:  
 
Events that are missing both at onset and at end dates will be considered to have 
started after the first dose of study drug and the duration will be set to missing.  
 
If the onset date is missing, and the end date is on or after the first dosing date or 
unresolved or missing, then the event will be considered to have started after the 
first dose of study drug.  
 
4.5.3 
Laboratory Data 
Laboratory data will be summarized by treatment group using descriptive statistics of 
absolute values and change from baseline values.  In addition, the frequency of 
participants with abnormal laboratory values will be summarized by treatment group, 
visit, and baseline status.  
4.5.4 
Vital Signs 
Vital signs assessments include systolic blood pressure, diastolic blood pressure, and 
pulse rate measured throughout the study.  Vital sign measurements will be summarized 
by treatment group using descriptive statistics of absolute values and change from 


 
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baseline values.  In addition, the frequency of participants with abnormal results will be 
summarized by treatment group, visit, and baseline status.  
4.5.5 
ECGs 
ECG data will be summarized by treatment group for each assessment visit using 
descriptive statistics of absolute values and change from baseline values for the 
following parameters:  
 
Heart rate  
 
QRS duration  
 
RR interval  
 
PR interval  
 
QT interval 
 
In addition, ECG overall interpretations will be summarized by treatment group and visit.  
4.5.6 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The Columbia Suicide Severity Scale (C-SSRS) is an assessment tool used to assess 
the lifetime suicidality of a participant (C-SSRS at baseline) as well as any new 
instances of suicidality (C-SSRS since last visit).  The structured interview prompts 
recollection of suicidal ideation, including the intensity of the ideation, behavior, and 
attempts with actual or potential lethality.  
 
Suicidal ideation, suicidal behavior, and self-injurious behavior without suicidal intent 
will be summarized by treatment group at each assessment visit.  In addition, 
change from baseline to worst post-baseline assessment in suicidality. 
 
Categories will be summarized by treatment group. 
 
4.6 
OTHER ANALYSES 
4.6.1 
Summaries of Screened Population 
A summary of screened participants and reasons for screen failures will be summarized 
by the IxRS report.   
4.6.2 
Summaries of Study Conduct 
The numbers of participants who enroll in the study, discontinue from the study, and 
complete the study will be summarized overall and by treatment arm for each period (DB 
and OLE extension).  Reasons for premature study withdrawal will be listed and 
summarized.  Enrollment and major protocol deviations will be listed and evaluated for 
their potential effects on the interpretation of study results.  
Number of participants with IECs, their category, and timing will be summarized. 
Missingness for each efficacy measure irrespective of ICE will be summarized. 


 
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The impact of COVID-19 infections on missed visits, missed laboratories, AE 
underreporting, and study drug discontinuation due to COVID-19 infections will be 
summarized. 
4.6.3 
Summaries of Treatment Group Comparability/Demographics 
and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by treatment group using 
means, standard deviations, medians and ranges for continuous variables and 
proportions for categorical variables, as appropriate.  Summaries will be presented 
overall and by treatment. 
4.6.4 
Overview of Intercurrent Events 
Number of participants with ICEs and timing will be analyzed and their cause. 
The following summaries will be provided: 
 
Number of ICEs split by type and NSDCR/SDCR and treatment 
 
Listing of ICEs 
 
4.6.4.1 
Analysis of the Adolescents Population 
The adolescents population will be analyzed separately from the mITT.  Due to the low 
number anticipated in this group it will be analyzed descriptively.  
4.6.5 
Pharmacokinetic Analyses 
The PK analysis population consists of all participants in the safety analysis set with at 
least one valid post-dose concentration result with a dosing record and sampling time.  
The trial will evaluate the PK characteristics of satralizumab treatment over 24 weeks by 
summary statistics and non-linear mixed effects analysis (population PK) based on PK 
samples from both the DB and OLE periods. 
The serum concentration at each sampling timepoint will be described by dose with 
means, medians, range and standard deviation and coefficient of variation of trough 
concentration (Ctrough) irrespective of whether participants receive rescue therapy, 
change in baseline therapy for MG, miss a dose, or if study drug administration is 
delayed, or if they withdraw from treatment before data collection at Week 24.  Mean 
serum-concentration-versus-time curves will be plotted.  
Non-linear mixed effects analysis will be performed to analyze the satralizumab 
concentrationtime data collected in the trial.  The model to be used was previously 
developed on the basis of PK data from adult healthy volunteer and adult and 
adolescent participants with neuromyelitis optica spectrum disorder.  Further model 
development may be undertaken if needed to achieve a satisfactory description of the 
data, and the data from this study may be pooled with data from other studies with 
satralizumab.  Population and individual PK and exposure parameters will be generated 
based on the model.  Covariate analysis, including demographic factors and anti-drug 


 
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antibody (ADA) status, will also be performed.  The results of the pop PK analysis will be 
reported separately from the Clinical Study Report.  
Additional exploratory PK analyses may be conducted as appropriate.  The relationship 
between PK and efficacy, safety or pharmacodynamic (PD) endpoints may also be 
explored.  These analyses will be reported separately. 
An early PK data release will be conducted to ensure expedient sample analysis and 
model building by PK experts.  This early release has a CCOD approximately 7 weeks 
prior to the CCOD for the primary analysis.  The data will be released to the PK analysis 
group only after the primary analysis CCOD and the PK team receiving the data will be 
strictly separate from the team working on the analysis of efficacy data and will not 
communicate with them until data has been unblinded.  In this early release the PK team 
will only receive PK-, anti-drug antibody (ADA) data and post-baseline IL6 and sIL-6R 
data, data of which association to clinical response is unknown.  The details of this early 
release are described in a clinical pharmacology access charter. 
4.6.6 
Immunogenicity Analyses 
The immunogenicity analysis population will consist of all participants with at least one 
post-dose ADA assessment.  Participants will be grouped according to treatment 
received or, if no treatment is received prior to study discontinuation, according to 
treatment assigned.  
The numbers and proportions of ADA-positive participants and ADA-negative 
participants at baseline (baseline prevalence) and after drug administration (post-
baseline incidence) will be summarized by treatment group (and dose, if the iDMC 
concludes that dose levels should be increased).  When determining post-baseline 
incidence, participants are considered to be ADA-positive (also called 
treatment-emergent ADA) if they show treatment-induced ADA response or 
treatment-enhanced ADA response.  Participants who are ADA-negative or have 
missing data at baseline but develop an ADA response following study drug exposure 
have a treatment-induced ADA response.  Participants who are ADA-positive at baseline 
and the titer of one or more post-baseline samples is at least 4-fold (0.60 titer unit) 
greater than the titer of the baseline sample have a treatment-enhanced ADA response.  
Participants are considered to be ADA-negative if they are ADA-negative at baseline or 
have missing data at baseline and all post-baseline samples are negative, OR if they are 
ADA-positive at baseline but (a) do not have any post-baseline samples with a titer that 
is at least 4-fold (0.60 titer unit) greater than the titer of the baseline sample, or (b) where 
all post-baseline samples are negative or missing (i.e., treatment unaffected).  
The percentage of participants who have positive or negative ADA results for 
satralizumab will be tabulated.  PD and safety will be summarized by anti‑satralizumab 
antibody (i.e., satralizumab ADA) status.  The impact of ADA on PK will be reported in 
the Pop PK report. 


 
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In addition, immunogenicity analyses may also be performed in the subgroups detailed 
in the Study Protocol, Section 6.4.8.  
4.6.6.1 
Further Analyses of ADA Classification 
ADA responses are further classified as transient ADA response or persistent ADA 
response as follows and summarized using descriptive statistics: 
 
Transient ADA response:  ADA-positive result detected 
a) At only one post-baseline sampling timepoint (excluding last timepoint), OR 
b) At 2 or more time points during treatment where the first and last ADA-positive 
samples are separated by a period 16 weeks, irrespective of any negative 
samples in between 
 
Persistent ADA response:  ADA-positive result detected 
a) At the last post-baseline sampling timepoint, OR  
b)  At 2 or more time points during treatment where the first and last ADA-positive 
samples are separated by a period 16 weeks, irrespective of any negative 
samples in between. 
 
4.6.6.1.1 
Pharmacodynamic Analyses 
Serum interleukin‑6 (IL‑6) and soluble interleukin‑6 receptor (sIL‑6R) levels will be 
summarized by treatment group (and by dose, if the iDMC concludes that dose levels 
should be increased) and timepoint graphically and descriptively, as appropriate.  
4.6.7 
Analyses of China Subpopulation 
The China subpopulation will include all participants enrolled at National Medical 
Products Administration-recognized sites.  Results from these analyses will be 
summarized in a separate Clinical Study Report.  
4.7 
INTERIM ANALYSES  
4.7.1 
Safety Review 
Periodic reviews of the safety data will be conducted by an iDCC with the results 
reviewed by the iDMC on an approximately 3-monthly basis until the last participant has 
completed the DB period. 
4.7.2 
Optional Interim for Futility 
To adapt to information that may emerge during the course of this study, the Sponsor 
may choose to conduct one interim analysis for futility.  Below are the specifications in 
place to ensure the study continues to meet the highest standards of integrity when an 
optional interim analysis is executed.  
The study will not be stopped for positive efficacy as a result of the interim analysis.  


 
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An interim for futility using a threshold at a confidential cutoff value specified in a 
separate interim SAP was conducted on the 24 July 2023 and the iDMC confirmed no 
modification to the study. 
4.7.3 
Pharmacokinetic Interim Analysis 
An interim analysis of PK data will be performed when approximately 30 participants (to 
include approximately 15 participants from the satralizumab group), have completed a 
minimum of 8 weeks of DB treatment.  The purpose of the interim analysis is to confirm 
that the achieved exposure to satralizumab (and predicted trough receptor occupancy at 
steady-state [ROtr,ss]) is within the predicted range.  Participants with gMG with body 
weights representative of the overall gMG population, both in terms of range and 
approximate proportion, are expected to be included in the PK interim analysis dataset.  
The Sponsor may decide to postpone the conduct of the PK interim analysis to allow for 
inclusion of adolescent participants in the PK interim analysis. 
A dose decision framework (including a pre-specified alternative higher dose, in case 
exposures are lower than predicted) will be defined in an analysis plan prior to study 
start (PK interim analysis plan).  This plan will set out the criteria for predicted exposure 
and RO under which the decision for an adapted dose will be made.  Predictions for 
exposure and RO in gMG using both the initial and pre-defined higher doses will be 
made using the existing popPK model, and the regimen that more closely achieves the 
target exposure and RO will be recommended by the iDMC. 
This interim PK analysis will be performed by an external CRO while the Sponsor, 
participants, and investigators will remain blinded.  The review by the external CRO will 
be restricted to PK and ADA data only, not safety or efficacy data, and no information 
that would reveal individual treatment assignments will be shared with the Sponsor.  The 
external CRO will perform blinded simulations for exposure and RO, which will be made 
available to the iDMC, and will collaborate with the iDMC, such that the iDMC can make 
a dose recommendation on the basis of these simulations.  Following this review, the 
iDMC will communicate its recommendation to the Sponsor.  
Study recruitment will continue during the review period.  Should a dose change be 
warranted, any participants treated at the original dose level will continue in the study on 
randomized treatment at the revised dose level, but will not contribute to the primary 
analysis.  Additional participants will be recruited to ensure that the number of 
participants eligible for inclusion in the primary analysis reaches the target sample size.  
No type I error multiplicity correction will be performed as only PK data, unrelated to 
efficacy outcome, will be used for interim decision‑making. 
The PK interim took place on the 2 September 2022 and the iDMC recommended to 
continue the study without dose modification. 


 
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5. 
SUPPORTING DOCUMENTATION 
This section is not applicable since there are no additional supporting documents. 
APPENDIX 1: CHANGES TO PROTOCOL-PLANNED ANALYSES 
This SAP clarifies the main analysis mentioned in the protocol with regards to the 
imputation strategy.  The protocol applies an MMRM directly for the final analysis.  In this 
SAP the final analysis is split into two transparent steps:  Imputation and estimation of 
the treatment effect.  The imputation uses an MMRM and the treatment effect is 
estimated through an ANCOVA. 
 
 


 
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6. 
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Burns TM, Conaway M, Cutter G, et al. Less is more, or almost as much: A 15-item 
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Cella D, Lai JS, Nowinski CJ, et al. Neuro-QOL: brief measures of health-related quality 
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Clinical Review Report: Eculizumab (Soliris): Alexion Pharma Canada Corporation: 
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Harmonization, I. C. (n.d.). ICH E9 (R1) addendum on estimands and Sensitivity 
Analysis in Clinical Trials to the guideline on statistical principles for clinical trials. 
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Howard J, Utsugisawa K, Benatar M, et al. Safety and efficacy of eculizumab in 
antiacetylcholine receptor antibody-positive refractory generalised myasthenia 
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ICH E9, I. C. (n.d.). ICH E9 (R1) addendum on estimands and Sensitivity Analysis in 
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Generalized Myasthenia Gravis. May 2023. 
Rbmi package. Available at: https://github.com/insightsengineering/rbmi (Assessed on 6 
April 2022). 
Wolbers M, Noci A, Delmar P, et al. Reference-based imputation methods based on 
conditional mean imputation. arXiv preprint arXiv. 2021, 2109.11162. 
Wolfe GI, Herbelin L, Nations SP, et al. Myasthenia gravis activities of daily living profile. 
Neurology 1999;52:1487-9.  


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