Conditions: Neuromyelitis Optica Spectrum Disorder
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 119
Healthy volunteers: no

Brief summary:
This multicenter, single-arm, open-label study will evaluate the long-term safety and efficacy of satralizumab in participants with neuromyelitis optica spectrum disorder (NMOSD) who completed open-label extension (OLE) period of studies BN40898 and BN40900. Participants will receive satralizumab as monotherapy or in combination with one of the following background immunosuppressive treatments: azathioprine (AZA), mycophenolate mofetil (MMF), or oral corticosteroids.

Detailed description:

Arms:
arm 1: Participants will receive satralizumab subcutaneously (SC) every 4 weeks (Q4W)

Interventions: intervention 1: satralizumab intervention 2: azathioprine (AZA) intervention 3: mycophenolate mofetil (MMF) intervention 4: oral corticosteroids
Intervention descriptions: intervention 1: Satralizumab will be administered by SC injection in the abdominal or femoral region at a dose of 120 mg (fixed dose) Q4W for up to 3 years intervention 2: Participants are permitted to use AZA during the study as background immunosuppressive treatment at a maximum dose of 3 milligram per kilogram per day (mg/kg/day) intervention 3: Participants are permitted to use MMF during the study as background immunosuppressive treatment at a maximum dose of 3000 mg/day intervention 4: Participants are permitted to use oral corticosteroids (prednisolone equivalent) during the study as background immunosuppressive treatment at a maximum dose of 15 mg/day

Protocol document:
Prot_SAP_000.pdf: 
 
Official Title: 
 
A Multicenter, Single Arm, Open-Label Study to Evaluate the Long-
Term Safety and Efficacy of Satralizumab in Patients With 
Neuromyelitis Optica Spectrum Disorder (NMOSD) 
NCT Number: NCT04660539 
Document Date: Protocol Version 1: 28-July-2020 
 
 


FINAL PROTOCOL APPROVAL
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contained in this document, especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) 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.
a 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 (SA237)—F. Hoffmann-La Roche Ltd
Protocol WN42349, Version 1
PROTOCOL
TITLE:
A MULTICENTER, SINGLE ARM, OPEN-LABEL 
STUDY TO EVALUATE THE LONG-TERM SAFETY 
AND EFFICACY OF SATRALIZUMAB IN PATIENTS 
WITH NEUROMYELITIS OPTICA SPECTRUM
DISORDER (NMOSD)
PROTOCOL NUMBER:
WN42349
VERSION NUMBER:
1
EUDRACT NUMBER:
2020-003413-35
IND NUMBER:
To be determined
NCT NUMBER:
To be determined
TEST PRODUCT:
Satralizumab (SA237) (RO5333787)
MEDICAL MONITOR:
 M.D.
SPONSORS:
F. Hoffmann-La Roche Ltd
Chugai Pharmaceutical Co. Ltd. a
DATE FINAL:
See electronic date stamp below.
 
27-Jul-2020 20:15:04
Deputy EU QPPV
28-Jul-2020 17:11:11
Tanrikulu, Yusuf (tanrikuy)
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
2/Protocol WN42349, Version 1
TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................... 9
PROTOCOL SYNOPSIS .................................................................................... 10
1.
BACKGROUND .......................................................................................... 17
1.1
Background on Neuromyelitis Optica Spectrum 
Disorder................................................................................. 17
1.1.1
Introduction to Neuromyelitis Optica Spectrum 
Disorder................................................................................. 17
1.1.2
Interleukin-6 as a Target Molecule for the 
Treatment of NMOSD............................................................ 18
1.2
Background on Satralizumab................................................. 18
1.3
Study Rationale and Benefit-Risk Assessment...................... 19
2.
OBJECTIVES AND ENDPOINTS ............................................................... 20
2.1
Safety Objective .................................................................... 20
2.2
Efficacy Objectives ................................................................ 20
2.3
Pharmacodynamic Objective................................................. 20
2.4
Pharmacokinetic Objectives .................................................. 21
2.5
Immunogenicity Objectives.................................................... 21
2.6
Biomarker Objective .............................................................. 21
2.7
Health Status Utility Objective ............................................... 21
3.
STUDY DESIGN......................................................................................... 22
3.1
Description of the Study......................................................... 22
3.1.1
Overview of Study Design ..................................................... 22
3.2
End of Study and Length of Study......................................... 23
3.3
Rationale for Study Design.................................................... 23
3.3.1
Rationale for Satralizumab Dose and Schedule .................... 23
3.3.2
Rationale for Patient Population ............................................ 23
3.3.3
Rationale for Biomarker Assessments................................... 24
4.
MATERIALS AND METHODS .................................................................... 24
4.1
Patients.................................................................................. 24
4.1.1
Inclusion Criteria.................................................................... 24
4.1.2
Exclusion Criteria................................................................... 25


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4.2
Treatment Assignment........................................................... 25
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 26
4.3.1
Study Treatment Formulation and Packaging........................ 26
4.3.1.1
Satralizumab.......................................................................... 26
4.3.2
Dosage, Administration, and Compliance.............................. 26
4.3.3
Investigational Medicinal Product Accountability ................... 27
4.3.4
Continued Access to Satralizumab........................................ 28
4.4
Concomitant Therapy ............................................................ 28
4.4.1
Permitted Therapy................................................................. 29
4.4.2
Prohibited Therapy ................................................................ 29
4.5
Study Assessments ............................................................... 29
4.5.1
Description of Study Assessments ........................................ 29
4.5.2
Informed Consent Forms and Screening Log........................ 30
4.5.3
Medical History, Baseline Conditions, 
Concomitant Medication, and Demographic Data ................. 30
4.5.4
Physical Examinations........................................................... 31
4.5.5
Vital Signs.............................................................................. 31
4.5.6
Relapse Assessment............................................................. 31
4.5.6.1
Procedure for Detection of Potential Relapse........................ 31
4.5.6.2
Protocol-Defined Relapse...................................................... 32
4.5.7
Expanded Disability Status Scale.......................................... 32
4.5.8
Visual Acuity/Function Testing............................................... 33
4.5.9
EQ-5D-3L .............................................................................. 33
4.5.10
Columbia-Suicide Severity Rating Scale ............................... 33
4.5.11
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 33
4.5.12
Electrocardiograms................................................................ 35
4.5.13
Optional Samples for Research Biosample 
Repository ............................................................................. 35
4.5.13.1
Overview of the Research Biosample Repository.................. 35
4.5.13.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 36
4.5.13.3
Sample Collection.................................................................. 36


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4.5.13.4
Confidentiality........................................................................ 37
4.5.13.5
Consent to Participate in the Research 
Biosample Repository............................................................ 37
4.5.13.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 38
4.5.13.7
Monitoring and Oversight....................................................... 38
4.5.14
Assessments at the Treatment Discontinuation 
and End of Study Visit ........................................................... 38
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 39
4.6.1
Study Treatment Discontinuation........................................... 39
4.6.2
Patient Discontinuation from the Study.................................. 39
4.6.3
Study Discontinuation............................................................ 40
4.6.4
Site Discontinuation............................................................... 40
5.
ASSESSMENT OF SAFETY....................................................................... 40
5.1
Safety Plan ............................................................................ 40
5.1.1
Risks or Laboratory Abnormalities Associated 
with Satralizumab .................................................................. 41
5.1.1.1
Infections ............................................................................... 41
5.1.1.2
Serious Hypersensitivity Reactions ....................................... 41
5.1.1.3
Liver Enzyme Elevations and Potential Risk of 
Hepatotoxicity........................................................................ 42
5.1.1.4
Neutropenia........................................................................... 43
5.1.1.5
Thrombocytopenia................................................................. 44
5.1.1.6
Elevations in Lipid Parameters .............................................. 44
5.1.1.7
Laboratory Findings Associated with 
Pharmacodynamic Effects..................................................... 44
5.1.1.8
CYP450 Enzyme Normalization ............................................ 44
5.1.2
Other Risks Associated with IL-6R Inhibitors......................... 45
5.1.2.1
Gastrointestinal Perforations (Complications of 
Diverticulitis) .......................................................................... 45
5.1.2.2
Malignancies.......................................................................... 45
5.1.2.3
Other Demyelinating Disorders.............................................. 45
5.1.3
Concomitant Immunosuppressive Treatment ........................ 45


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5/Protocol WN42349, Version 1
5.1.4
Management of Patients Who Experience 
Adverse Events ..................................................................... 46
5.1.4.1
Treatment Interruption ........................................................... 46
5.2
Safety Parameters and Definitions ........................................ 46
5.2.1
Adverse Events ..................................................................... 46
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 47
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 47
5.2.4
Selected Adverse Events....................................................... 48
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 48
5.3.1
Adverse Event Reporting Period ........................................... 48
5.3.2
Eliciting Adverse Event Information....................................... 49
5.3.3
Assessment of Severity of Adverse Events ........................... 49
5.3.4
Assessment of Causality of Adverse Events ......................... 49
5.3.5
Procedures for Recording Adverse Events............................ 49
5.3.5.1
Injection Related Reactions................................................... 50
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 50
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 50
5.3.5.4
Persistent or Recurrent Adverse Events................................ 51
5.3.5.5
Abnormal Laboratory Values ................................................. 51
5.3.5.6
Abnormal Vital Sign Values ................................................... 52
5.3.5.7
Abnormal Liver Function Tests.............................................. 52
5.3.5.8
Deaths ................................................................................... 53
5.3.5.9
Preexisting Medical Conditions.............................................. 53
5.3.5.10
Lack of Efficacy or Worsening of NMOSD............................. 53
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 53
5.3.5.12
Cases of Overdose, Medication Error, Drug 
Abuse, or Drug Misuse .......................................................... 54
5.3.5.13
Patient-Reported Outcome Data ........................................... 56
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 56


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5.4.1
Medical Monitors and Emergency Medical 
Contacts ................................................................................ 57
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 57
5.4.3
Reporting Requirements for Pregnancies.............................. 58
5.4.3.1
Pregnancies in Female Patients............................................ 58
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 58
5.4.3.3
Abortions ............................................................................... 58
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 59
5.4.4
Reporting Requirements for Medical Device 
Complaints............................................................................. 59
5.5
Follow-Up of Patients after Adverse Events .......................... 59
5.5.1
Investigator Follow-Up........................................................... 59
5.5.2
Sponsor Follow-Up ................................................................ 60
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 60
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees.......................................................... 60
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 60
6.1
Analysis Populations ............................................................. 61
6.1.1
Efficacy Analysis Populations................................................ 61
6.1.2
All-Patients-Treated Population............................................. 61
6.1.3
Safety Analysis Populations .................................................. 61
6.1.4
Pharmacokinetics Per-Protocol Set and 
Pharmacodynamics Analysis Population............................... 61
6.2
Determination of Sample Size ............................................... 61
6.3
Summaries of Conduct of Study............................................ 62
6.4
Summaries of Demographic and Baseline 
Characteristics....................................................................... 62
6.5
Efficacy Analyses .................................................................. 62
6.5.1
Further Analyses ................................................................... 66
6.5.1.1
Subgroup Analysis................................................................. 66
6.6
Safety Analyses..................................................................... 66
6.7
Pharmacokinetic/Pharmacodynamic Analyses...................... 67


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
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6.8
Immunogenicity Analyses...................................................... 67
6.9
Biomarker Analyses............................................................... 68
6.10
Health Status Utility Analyses................................................ 68
6.11
Interim Analyses .................................................................... 69
6.12
Handling OF Missing Data..................................................... 69
7.
DATA COLLECTION AND MANAGEMENT ............................................... 69
7.1
Data Quality Assurance......................................................... 69
7.2
Electronic Case Report Forms............................................... 69
7.3
Source Data Documentation.................................................. 70
7.4
Use of Computerized Systems .............................................. 70
7.5
Retention of Records............................................................. 70
8.
ETHICAL CONSIDERATIONS.................................................................... 71
8.1
Compliance with Laws and Regulations ................................ 71
8.2
Informed Consent.................................................................. 71
8.3
Institutional Review Board or Ethics Committee.................... 72
8.4
Confidentiality........................................................................ 73
8.5
Financial Disclosure .............................................................. 73
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 74
9.1
Study Documentation ............................................................ 74
9.2
Protocol Deviations................................................................ 74
9.3
Management of Study Quality ............................................... 74
9.4
Site Inspections ..................................................................... 74
9.5
Administrative Structure......................................................... 74
9.6
Dissemination of Data and Protection of Trade 
Secrets .................................................................................. 75
9.7
Protocol Amendments ........................................................... 76
10. REFERENCES ........................................................................................... 76
LIST OF TABLES
Table 1:
Hepatic Enzyme Risk Mitigation.................................................. 43
Table 2:
Neutropenia Risk Mitigation ........................................................ 43


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
8/Protocol WN42349, Version 1
Table 3:
Thrombocytopenia Risk Mitigation.............................................. 44
Table 4
Adverse Event Severity Grading Scale ....................................... 49
LIST OF FIGURES
Figure 1
Study Design............................................................................... 23
LIST OF APPENDICES
Appendix 1
Schedule of Activities.................................................................. 78
Appendix 2
EDSS/FSS Assessment Form .................................................... 81
Appendix 3
EuroQol-5D (EQ-5D)................................................................... 83
Appendix 4
C-SSRS since Last Visit ............................................................. 87


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
9/Protocol WN42349, Version 1
PROTOCOL ACCEPTANCE FORM
TITLE:
A MULTICENTER, SINGLE ARM, OPEN-LABEL 
STUDY TO EVALUATE THE LONG-TERM SAFETY 
AND EFFICACY OF SATRALIZUMAB IN PATIENTS
WITH NEUROMYELITIS OPTICA SPECTRUM 
DISORDER (NMOSD)
PROTOCOL NUMBER:
WN42349
VERSION NUMBER:
1
EUDRACT NUMBER:
2020-003413-35
IND NUMBER:
To be determined
NCT NUMBER:
To be determined
TEST PRODUCT:
Satralizumab (SA237) (RO5333787)
MEDICAL MONITOR:
 M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
Chugai Pharmaceutical Co. Ltd. a
a 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.
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 (SA237)—F. Hoffmann-La Roche Ltd
10/Protocol WN42349, Version 1
PROTOCOL SYNOPSIS
TITLE:
A MULTICENTER, SINGLE ARM, OPEN-LABEL STUDY TO 
EVALUATE THE LONG-TERM SAFETY AND EFFICACY OF 
SATRALIZUMAB (SA237) IN PATIENTS WITH NEUROMYELITIS 
OPTICA SPECTRUM DISORDER (NMOSD)
PROTOCOL NUMBER:
WN42349
VERSION NUMBER:
1
EUDRACT NUMBER:
2020-003413-35
IND NUMBER:
To be determined
NCT NUMBER:
To be determined
TEST PRODUCT:
Satralizumab (SA237) (RO5333787)
PHASE:
Phase IIIb
INDICATION:
Neuromyelitis Optic Spectrum Disorder (NMOSD)
SPONSOR:
F. Hoffmann-La Roche Ltd
Chugai Pharmaceutical Co. Ltd. a
a 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.
Objectives and Endpoints
This study will evaluate the long-term safety, efficacy, and pharmacokinetics/
pharmacodynamics of satralizumab and will provide continued treatment with satralizumab to 
patients with Neuromyelitis Optic Spectrum Disorder (NMOSD) who completed the open-label 
extension (OLE) periods of the Phase III Studies BN40898 and BN40900.  Specific objectives 
and corresponding endpoints for the study are outlined below.
Safety Objective
The primary safety objective for this study is:

To evaluate the long-term safety of satralizumab in patients with NMOSD
The secondary safety objective for this study is:

To further evaluate the risks of serious infections and hepatotoxicity in patients with 
NMOSD who are treated with satralizumab
Safety outcome measures:

Incidence and severity of adverse events (AE), adverse events of special interest (AESI), 
serious AEs (SAE), and selected AEs

Vital signs (temperature, blood pressure, and pulse rate), clinical laboratory tests 
(hematology, chemistry, and urinalysis), 12-lead electrocardiograms (ECG), and suicidality 
(Columbia-Suicide Severity Rating Scale [C-SSRS])


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
11/Protocol WN42349, Version 1
Efficacy Objectives
The efficacy objective for this study is to evaluate long-term efficacy of satralizumab on the 
basis of the following endpoints:

Time to first relapse (TFR) and proportion of relapse-free patients

Annualized relapse rate (ARR)

Change in Expanded Disability Status Scale (EDSS) score

Time to EDSS worsening and proportion of patients without EDSS worsening

Change in visual acuity
Pharmacodynamic Objective
The pharmacodynamics (PD) objective for this study is to further characterize the target 
engagement in response to satralizumab treatment on the basis of the assessment of IL-6, 
soluble IL-6R (sIL-6R) and C-reactive protein (CRP).
Pharmacokinetic Objectives
The pharmacokinetic (PK) objective for this study is to further characterize the satralizumab PK 
profile on the basis of the following endpoint:

Serum concentration of satralizumab at specified timepoints
The exploratory PK objectives for this study are as follows:

To evaluate potential relationships between drug exposure and the efficacy and safety of 
satralizumab on the basis of the following endpoints:

Relationship between serum concentration or PK parameters for satralizumab and 
efficacy endpoints

Relationship between serum concentration or PK parameters for satralizumab and 
safety endpoints

To evaluate potential relationships between selected covariates and exposure to 
satralizumab on the basis of the following endpoint:

Relationship between selected covariates and serum concentration or PK parameters 
for satralizumab
Immunogenicity Objectives
The immunogenicity objective for this study is to evaluate the immune response to satralizumab 
on the basis of the following endpoint:

Incidence of anti-drug antibodies (ADAs) from the first dose of satralizumab in 
Studies BN40898 or BN40900 (parent studies)
The exploratory immunogenicity objective for this study is to evaluate potential effects of ADAs 
on the basis of the following endpoint:

Relationship between ADA status and efficacy, safety, and PK endpoints
Biomarker Objective
The exploratory biomarker objective for this study is to identify biomarkers that can provide 
evidence of satralizumab activity (i.e., pharmacodynamic biomarkers), or can increase the 
knowledge and understanding of disease biology and/or related pathways, on the basis of the 
following endpoint:

Relationship between biomarkers in blood and efficacy, safety, PK, immunogenicity, or 
other biomarker endpoints
Health Status Utility Objective
The exploratory health status utility objective for this study is to evaluate health status utility 
scores of patients treated with satralizumab on the basis of the following endpoint:


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
12/Protocol WN42349, Version 1

Change in EuroQol 5-Dimension Questionnaire (3-level version; EQ-5D-3L) index-based 
and Visual Analogue Scale (VAS) scores
Study Design
Description of Study
This Phase IIIb study is a multicenter, single-arm, open-label study for approximately 
127 patients who completed the OLE period of Study BN40898 and Study BN40900, (i.e., were 
receiving ongoing treatment with satralizumab prior to study entry in this Study WN42349). The 
study aims to evaluate the long-term safety and efficacy of satralizumab in patients with 
NMOSD.
Informed consent should be obtained from participants while they are in the parent 
Studies BN40898 or BN40900.  Patients will be transitioned from their ongoing 
Study BN40898 or BN40900 at a planned dosing visit to allow for continuous dosing with
subcutaneous (SC) satralizumab at a dose of 120 mg (fixed dose) every 4 weeks (Q4W).
Safety and efficacy will be assessed at the baseline visit in this study. Efforts will be made to 
transition patients, at a 12-week or 24-week visit in their visit schedule in the parent study to 
reduce burden of assessments on patients.
Patients will receive satralizumab as monotherapy or in combination with one of the following 
background immunosuppressive treatments: azathioprine (AZA), mycophenolate mofetil (MMF),
or oral corticosteroids. Patients aged less than 18 years at the time of informed consent for 
Study BN40898 can continue treatment with a combination of oral corticosteroids and either 
AZA or MMF.  It is at the discretion of the investigator to modify the background treatment after
the baseline visit in this study.  For patients who experience a relapse during the study, 
appropriate acute relapse/rescue therapy will be initiated.
Patients who experience either a relapse or active infection or do not meet one of the 
retreatment criteria based on laboratory assessments in the parental study, should continue in 
the ongoing parental study and be transitioned to this study once the patient is stabilized after 
the relapse, the infection controlled, or the laboratory assessment allows retreatment.  If the 
patient cannot be enrolled within 12 weeks from the initial event preventing the transition to this 
study, the site should discuss with the Medical Monitor.
Number of Patients
This study includes patients with NMOSD who participated in Study BN40898 or 
Study BN40900 and are ongoing on satralizumab treatment in the OLE period of these studies 
prior to study entry in Study WN42349. Approximately 127 patients with NMOSD will be 
enrolled in this study.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Participated in Study BN40898 or Study BN40900 with satralizumab in NMOSD, are on 
ongoing satralizumab treatment and were aquaporin-4 (AQP4) IgG seropositive at 
screening in these studies.  Patients with NMOSD who were AQP4 IgG seronegative at 
screening in Study BN40898 or Study BN40900 can be enrolled if the investigator considers 
the continued treatment with satralizumab to be beneficial for the patient.

Signed Informed Consent Form (ICF)

Ability to comply with the study protocol

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use adequate contraception during the treatment period and 
for 3 months after the final dose of satralizumab.
A woman 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.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
13/Protocol WN42349, Version 1
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.  If required per local guidelines or 
regulations, locally recognized adequate methods of contraception and information 
about the reliability of abstinence will be described in the local ICF.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Use of prohibited medication.

Pregnant or breastfeeding, or intending to become pregnant during the study or within
3 months after the final dose of study drug.  Women of childbearing potential must have a 
negative urine pregnancy test result on the baseline visit prior to initiation of study drug.

Evidence of any 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, renal/urologic 
disease, digestive system disease, congenital or acquired severe immunodeficiency.

Known active infection that requires delaying the next satralizumab dose at the time of 
enrollmenta
a
In case of an active infection, the patient should remain in the parent study, as 
governed by that protocol, and may enroll in this study once the active infection is 
controlled.

NMOSD relapse at the time of enrollmentb
b
In case of a relapse, the patient should remain in the parent study, as governed by that 
protocol, and may enroll in this study once the patient is stable.

Laboratory abnormalities at the last assessment in Study BN40898 or Study BN40900 that 
preclude re-treatment with satralizumab c
c
If a patient does not meet the criteria to restart treatment with satralizumab based on 
laboratory assessments, the patient should remain in the parent study and the baseline visit 
should be delayed.  The last assessment before enrollment must meet the re-treatment
criteria.
End of Study
The end of this study is defined as the date when the last patient, last visit (LPLV), occurs.  The 
treatment period ends 3 years after the date the first patient enrolls in the study. The end of the 
study is expected to occur in second quarter of 2024.
In addition, the Sponsor may decide to terminate the study at any time.
Length of Study
The total length of the study, from enrollment of the first patient to the end of the study, is 
expected to be approximately 3 years and 3 months.
Investigational Medicinal Products
Test Product (Investigational Drug)
The investigational medicinal product (IMP) for this study is satralizumab.
Non-Investigational Medicinal Products
Acute relapse rescue therapy administered in case of a NMOSD relapse, and allowed 
background immunosuppressive therapy (IST) are considered non-investigational medicinal 
products (NIMP).


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Statistical Methods
Primary Analysis
All safety analyses will be performed on the Safety Population (SAF). Safety variables to be 
assessed are AEs, AESIs, SAEs, selected AEs, injection site reactions, patient withdrawals due 
to AEs, change in 12-lead ECGs, measurements of laboratory parameters, and vital signs 
(including body weight).
Summary tables for number and percentage of patients and rate of AEs per 100PY with 
adverse drug reactions (i.e., AEs related to study drug as assessed by the investigator) will be 
generated.
Adverse events will be summarized by System Organ Class (SOC) and Preferred Term (PT), 
based on Medical Dictionary for Regulatory Activities (MedDRA) coding, and grade of severity. 
The incidence of treatment emergent AEs will also be displayed by severity and relationship to 
the study drug, respectively. In addition, the incidence of AEs leading to withdrawal from 
treatment and SAEs will be tabulated.
Incidence of Selected AEs will be tabulated. AEs will be further analyzed according to whether 
they meet Sampson's criteria for diagnosis of anaphylaxis.
Laboratory values (including hematology, blood chemistry, and urinalysis), frequencies of 
laboratory abnormalities, vital signs (temperature, blood pressure, and pulse rate), 12-lead ECG, 
and suicidality (C-SSRS) will be summarized. Measurement and change from baseline in 
continuous laboratory parameters (hematology, clinical chemistry, and urinalysis), continuous 
ECG, vital signs (blood pressures and pulse rate), and body weight will be summarized with use 
of descriptive statistics. Body weight by change from randomization/first dose of satralizumab
of more than/less than 7% and 15% will also be analyzed descriptively.  When analyzing 
categorical data, the number and percentage of patients in each category will be presented. In 
addition, shift tables may be used to evaluate the number and percentage of patients having a 
different post-baseline status when compared with their baseline status. Numbers of patients 
who meet the marked abnormality criterion will also be presented.
Determination of Sample Size  
The sample size will include all eligible participants who consent to this study.  The sample size 
is expected to be no more than approximately 127 patients but will be determined by the 
number of patients who complete Studies BN40898 and BN40900 and enroll in this study.
All safety variables will be analyzed on the basis of the SAF. The SAF population will include all 
randomized or enrolled patients who have received at least one dose of study drug either during 
the parental studies or this study. It will encompass all patients from the parent studies, even if 
they do not participate in this study. Patients will be analyzed as treated for analysis purposes 
in the SAF.
Interim Analyses
No formal confirmatory effectiveness or safety interim analyses are planned.  Exploratory 
analyses of selected endpoints and in particular periodic analyses of safety data are planned to 
be performed during the course of the study.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADA
anti-drug (satralizumab) antibodies
AE
adverse event
AESI
adverse event of special interest
ALLSA
all-patients-treated (all satralizumab)
AQP4
aquaporin-4
AQP4-IgG
antiaquaporin-4 IgG antibody
ARR
annualized relapse rate
AZA
azathioprine
CCOD
clinical cutoff date
CI
confidence interval
CNS
central nervous system
CRP
C-reactive protein
CSF
cerebrospinal fluid
CSR
Clinical Study Report
C-SSRS
Columbia-Suicide Severity Rating Scale
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
EC
Ethics Committee
ECG
electrocardiogram
eCRF
electronic Case Report Form
EDC
electronic data capture
EDSS
Expanded Disability Status Scale
EOS
end of study
EOT
end of treatment
EQ-5D-3L
EuroQol 5-Dimension Questionnaire (3rd level version)
EU
European Union
FDA
Food and Drug Administration
Fc
fragment crystallizable
FSS
Functional System Score
HIPAA
Health Insurance Portability and Accountability Act
HR
hazard ratio
ICF
Informed Consent Form
ICH
International Conference On Harmonisation
IgG
immunoglobulin G
IL-6
interleukin-6


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Abbreviation
Definition
IL-6R
interleukin-6 receptor
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IRR
injection-related reaction
IST
immunosuppressive therapy/immunosuppressive treatment
ITT
intent-to-treat
IxRS
interactive voice or Web response system
LPLV
last patient, last visit
MMF
mycophenolate mofetil
MS
multiple sclerosis
NMO
neuromyelitis optica
NMOSD
neuromyelitis optica spectrum disorder
NSD
needle safety device
OLE
open-label extension
PD
pharmacodynamic(s)
PDR
protocol defined relapse
PFS
prefilled syringe
PK
pharmacokinetic(s)
PK-PPS
pharmacokinetic per-protocol set
Q4W
every 4 weeks
QTcF
QT interval corrected for heart rate with use of Fridericia’s 
Formula
RA
rheumatoid arthritis
RBR
Research Biosample Repository
SAE
serious adverse event
SAF
safety population
SAP
statistical analysis plan
SC
subcutaneous(ly)
SFU
safety follow-up
sIL-6R
soluble interleukin-6 receptor
TBL
total bilirubin
TFR
time to first relapse
ULN
upper limit of normal
US
United States
VAS
Visual Analogue Scale


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1.
BACKGROUND
1.1
BACKGROUND ON NEUROMYELITIS OPTICA SPECTRUM 
DISORDER
1.1.1
Introduction to Neuromyelitis Optica Spectrum Disorder
Neuromyelitis optica (NMO), originally named Devic’s disease, is a severe demyelinating 
inflammatory autoimmune disorder of the central nervous system (CNS). In 2015, the 
International Panel for Neuromyelitis Optica Diagnosis defined the unifying term 
“neuromyelitis optica spectrum disorder” (NMOSD), which includes serologic testing of 
antiaquaporin-4 IgG antibody (AQP4-IgG) and distinguishes aquaporin 4 (AQP4)
antibody seropositive or seronegative NMOSD. NMOSD is clinically characterized by 
optic neuritis and/or transverse myelitis (Wingerchuk et al. 2015), leading to disabling 
neurologic symptoms such as visual impairment (including blindness), disturbance of 
ambulation sensory disturbances, and/or bowel and bladder dysfunction. Fatigue and 
pain are common symptoms of NMOSD and significantly impact the patient’s quality of 
life. Disability in NMOSD is usually a consequence of relapses, which can be severe, 
even fatal, and result in residual disability.
Despite being clinically similar, NMOSD is distinct from MS radiologically, has a worse 
prognosis, and has a pathophysiology that is unresponsive to typical MS treatment 
(Weinshenker 2007; Oh and Levy 2012). Unlike in MS, secondary progression is 
uncommon in NMOSD. Other distinguishing features of NMOSD include an even 
stronger female preponderance, longitudinally extensive spinal cord lesions, and 
absence of oligoclonal IgG bands in the cerebrospinal fluid (CSF).
There are four aspects of NMOSD treatment in the current treatment algorithm: 1) acute 
treatment of relapses, 2) prevention of relapses, 3) symptom management, and 
4) rehabilitation.
Pulse steroids and plasma exchange are typically used for acute relapse treatment. 
Given that relapses often cause irreversible neurologic deficits, the goal for maintenance 
NMOSD therapy is relapse prevention. Since 2019, three medications for NMOSD have 
been approved in at least one country for the prevention of NMOSD relapses: 
satralizumab, eculizumab, and inebilizumab (for more information on satralizumab see 
Section 1.2). Prior to 2019 the standard maintenance therapy included oral 
corticosteroids and/or immunosuppressants (IST) such as azathioprine ( AZA) or 
mycophenolate mofetil (MMF). In some countries rituximab, although approved only for 
treatment of rheumatoid arthritis (RA) and non-Hodgkin lymphoma, is used as off-label 
NMOSD maintenance therapy. In addition, chemotherapies, such as methotrexate and 
mitoxantrone, are used. Residual symptoms during in the remission phase of NMOSD,
such as pain, fatigue, stiffness, and bladder and bowel symptoms, are common and are 
managed by symptomatic therapy.


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1.1.2
Interleukin-6 as a Target Molecule for the Treatment of NMOSD
One of the key features of NMOSD is the presence of pathological autoantibodies 
against AQP4 (AQP4-IgG), a major water channel protein in the CNS (Lennon et al. 
2005).  Transfer of AQP4-IgG was shown to exacerbate experimental autoimmune 
encephalomyelitis in animal models.  Yamamura and co-workers identified the
CD19intCD27highCD38highCD180(and CD20) plasmablast B-cell subset, which is 
associated with production of AQP4-IgG in patients with NMOSD (Chihara et al. 2011).
Survival of plasmablasts is promoted by interleukin-6 (IL-6), and IL-6 was suggested to 
enhance antibody production by these plasmablasts; in vitro IL-6 receptor (IL-6R) 
blockade reduced survival of AQP4-IgG-producing plasmablasts.  IL-6 is a 
proinflammatory cytokine with pleiotropic functions, including inflammatory response, 
induction of the differentiation and proliferation of various types of cells, regulation of 
immune response, and thrombocytosis (Kishimoto 2010; Tanaka and Kishimoto 2012).
In addition to effects on B cells (e.g., AQP4-IgG production), IL-6 has also been 
suggested to contribute to NMOSD pathogenesis by promoting the differentiation of 
pro-inflammatory Th17 cells which, in turn, can also support B-cell differentiation to 
antibody-secreting plasmablasts (Lin et al. 2016); and by increasing blood-brain barrier
permeability, thus facilitating entry of pathological AQP4-IgG and inflammatory cells 
such as granulocytes (Takeshita et al. 2017) into the CNS.
1.2
BACKGROUND ON SATRALIZUMAB
Satralizumab (RO5333787; ENSPRYNG) is a humanized anti-human IL-6R blocking 
monoclonal antibody that was designed by application of recycling antibody technology.
Antibody engineering techniques were utilized to give satralizumab pH-dependent
binding affinity to IL-6R so that it binds to IL-6R under neutral conditions in plasma but 
dissociates under the slightly acidic conditions in endosomes, and is recycled to the 
plasma instead of being degraded in lysosomes, resulting in a longer plasma half-life.  In 
addition, satralizumab is a modified IgG2 isotype, which reduces Fc-mediated effector 
functions.
The Clinical Development Program of satralizumab in NMOSD currently consists of two 
ongoing pivotal placebo-controlled, randomized, double-blind Phase III studies: 
Study BN40898 in adult and adolescent patients treated with 120 mg subcutaneous (SC)
satralizumab in addition to background immunosuppressive therapy (IST) and 
Study BN40900 in adult patients treated with 120 mg SC satralizumab as a monotherapy. 
Both studies are ongoing in their open-label extension (OLE) periods.
Data from the completed double-blind periods of the pivotal Phase III Studies BN40898 
(Yamamura et al. 2019) and BN40900 (Traboulsee et al. 2020) in adult and adolescents 
with NMOSD demonstrated a substantial magnitude of clinical benefit.  Treatment with 
satralizumab led to significant reductions in the risk of protocol-defined relapse of 62% in 


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Study BN40898 (hazard ratio [HR]0.38; 95% CI: 0.16 to 0.88) and 55% in 
Study BN40900 (HR0.45; 95% CI: 0.23 to 0.89) compared with placebo.
Benefit was evident across multiple subgroups and was particularly high in the subgroup 
of patients who were AQP4-IgG seropositive, with risk reductions of 79% (HR0.21; 95% 
CI: 0.058 to 0.750; p0.0086) and 74% (HR0.26; 95% CI: 0.108 to 0.627; p0.0014) in 
Studies BN40898 and BN40900, respectively.  Evidence of benefit in the subgroup of 
patients who were AQP4-IgG seronegative was inconclusive.
Based on the results of the studies summarized above, satralizumab (ENSPRYNG) has 
been approved by multiple Health Authorities as monotherapy or in combination with IST
for the treatment of NMOSD in adult and adolescent patients who are anti-AQP4
seropositive, and is currently under review by other Health Authorities worldwide.
A multicenter, open-label, uncontrolled study to evaluate the pharmacokinetics, efficacy, 
safety, tolerability, and pharmacodynamic effects of satralizumab in children from 2 to 
less than 12 years of age is planned to start in the first quarter of 2021.
See the current Investigator's Brochure for details on nonclinical and clinical studies.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Satralizumab has been developed for the treatment of NMOSD, a serious condition that 
has substantial impact on day-to-day functioning of patients. Satralizumab has 
demonstrated a positive benefit/risk profile in the treatment of NMOSD in adult and 
adolescents patients who are AQP4 IgG seropositive.
The double-blind periods of both Study BN40898 and Study BN40900 have been 
completed (see summary of results in Section 1.2), and the studies remain ongoing in 
their OLE periods. Thus, patients ongoing in the OLE period can still benefit from the 
continuation of therapy with satralizumab in order to reduce the frequency and severity 
of NMOSD relapses.
Study WN42349 is an open-label, single-arm, rollover study of satralizumab that allows 
for patients ongoing in Study BN40898 and Study BN40900 to continue with long-term 
treatment with satralizumab for up to 3 years.  The study aims to collect longitudinal 
safety and efficacy data.  Analyzing the long-term safety and efficacy of satralizumab is 
of importance to help clinicians make informed decisions on the most appropriate 
therapy for their patients with NMOSD, a chronic disease requiring long-term 
maintenance relapse prevention therapy.
Although analysis of efficacy in the subgroup of patients who have AQP4-IgG 
seronegative NMOSD in Studies BN40898 and BN40900 was inconclusive, individual 
patients might benefit from continued treatment with satralizumab. Therefore, patients 
who were AQP4-IgG seronegative at screening in the pivotal studies may be enrolled in 


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this study, if the investigator considers continued treatment with satralizumab beneficial 
for the individual patient.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the long-term safety, efficacy, and pharmacokinetics/
pharmacodynamics of satralizumab and will provide continued treatment with 
satralizumab to patients with NMOSD who completed the OLE periods of the Phase III 
Studies BN40898 and BN40900.  Specific objectives and corresponding endpoints for 
the study are outlined below.
2.1
SAFETY OBJECTIVE
The primary safety objective for this study is:

To evaluate the long-term safety of satralizumab in patients with NMOSD
The secondary safety objective for this study is:

To further evaluate the risks of serious infections and hepatotoxicity in patients with 
NMOSD who are treated with satralizumab
Safety outcome measures:

Incidence and severity of adverse events (AE), adverse events of special interest 
(AESI), serious AEs (SAE), and selected AEs

Vital signs (temperature, blood pressure, and pulse rate), clinical laboratory tests 
(hematology, chemistry, and urinalysis), 12-lead electrocardiograms (ECG), and
suicidality (Columbia-Suicide Severity Rating Scale [C-SSRS])
2.2
EFFICACY OBJECTIVES
The efficacy objective for this study is to evaluate long-term efficacy of satralizumab on 
the basis of the following endpoints:

Time to first relapse (TFR) and proportion of patients who are relapse-free

Annualized relapse rate (ARR)

Change in Expanded Disability Status Scale (EDSS) score

Time to EDSS worsening and proportion of patients without EDSS worsening

Change in visual acuity
Further information on the efficacy endpoints is provided in Section 6.5.
2.3
PHARMACODYNAMIC OBJECTIVE
The pharmacodynamics (PD) objective for this study is to further characterize the target 
engagement in response to satralizumab treatment on the basis of the assessment of
IL-6, soluble IL-6R (sIL-6R) and C-reactive protein (CRP).


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2.4
PHARMACOKINETIC OBJECTIVES
The pharmacokinetic (PK) objective for this study is to further characterize the 
satralizumab PK profile on the basis of the following endpoint:

Serum concentration of satralizumab at specified timepoints
The exploratory PK objectives for this study are as follows:

To evaluate potential relationships between drug exposure and the efficacy and 
safety of satralizumab on the basis of the following endpoints:
–
Relationship between serum concentration or PK parameters for satralizumab
and efficacy endpoints
–
Relationship between serum concentration or PK parameters for satralizumab
and safety endpoints

To evaluate potential relationships between selected covariates and exposure to 
satralizumab on the basis of the following endpoint:
–
Relationship between selected covariates and serum concentration or PK 
parameters for satralizumab
2.5
IMMUNOGENICITY OBJECTIVES
The immunogenicity objective for this study is to evaluate the immune response to 
satralizumab on the basis of the following endpoint:

Incidence of anti-drug antibodies (ADAs) from the first dose of satralizumab in 
Studies BN40898 or BN40900 (parent studies)
The exploratory immunogenicity objective for this study is to evaluate potential effects of 
ADAs on the basis of the following endpoint:

Relationship between ADA status and efficacy, safety, and PK endpoints
2.6
BIOMARKER OBJECTIVE
The exploratory biomarker objective for this study is to identify biomarkers that can 
provide evidence of satralizumab activity (i.e., pharmacodynamic biomarkers), or can 
increase the knowledge and understanding of disease biology and/or related pathways, 
on the basis of the following endpoint:

Relationship between biomarkers in blood (listed in Section 4.5) and efficacy, safety, 
PK, immunogenicity, or other biomarker endpoints
2.7
HEALTH STATUS UTILITY OBJECTIVE
The exploratory health status utility objective for this study is to evaluate health status 
utility scores of patients treated with satralizumab on the basis of the following endpoint:

Change in EuroQol 5-Dimension Questionnaire (3-level version; EQ-5D-3L) index-
based and Visual Analogue Scale (VAS) scores


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3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
3.1.1
Overview of Study Design
This Phase IIIb study is a multicenter, single-arm, open-label study for approximately 
127 patients who completed the OLE period of Study BN40898 and Study BN40900, 
(i.e., were receiving ongoing treatment with satralizumab prior to study entry in this 
Study WN42349). The study aims to evaluate the long-term safety and efficacy of 
satralizumab in patients with NMOSD.
Informed consent should be obtained from participants while they are in the parent
Studies BN40898 or BN40900.  Patients will be transitioned from their ongoing 
Study BN40898 or BN40900 at a planned dosing visit to allow for continuous dosing with
SC satralizumab at a dose of 120 mg (fixed dose) every 4 weeks (Q4W). Safety and 
efficacy will be assessed at the baseline visit in this study. Efforts will be made to 
transition patients, at a 12-week or 24-week visit in their visit schedule in the parent 
study to reduce burden of assessments on patients.
Patients will receive satralizumab as monotherapy or in combination with one of the 
following background immunosuppressive treatments: AZA, MMF, or oral 
corticosteroids. Patients aged less than 18 years at the time of informed consent for 
Study BN40898 can continue treatment with a combination of oral corticosteroids and 
either AZA or MMF.  It is at the discretion of the investigator to modify the background
treatment after the baseline visit in this study (see Section 4.4.1).  For patients who 
experience a relapse during the study, appropriate acute relapse/rescue therapy will be 
initiated.
The treatment period with satralizumab will be 3 years from the date the first patient  
enrolls in this study. Patients who withdraw from treatment will be asked to complete an 
End of Treatment visit followed by a Safety Follow Up (SFU) period of 12 weeks from the 
last dose of study drug prior to the End of Study visit (see Section 4.6).
Patients who experience either a relapse or active infection or do not meet one of the 
retreatment criteria based on laboratory assessments as specified in Section 5.1 in the 
parental study, should continue in the ongoing parental study and be transitioned to this 
study once the patient is stabilized after the relapse, the infection controlled, or the 
laboratory assessment allows retreatment (see Section 4.1 and Section 4.1.2). If the 
patient cannot be enrolled within 12 weeks from the initial event preventing the transition 
to this study, the site should discuss with the Medical Monitor.
Figure 1 presents an overview of the study design.  A schedule of activities is provided in 
Appendix 1.


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Figure 1
Study Design
BLbaseline; OLEopen-label extension; Q4Wevery 4 weeks
a Patients are to be discontinued from Studies BN40898 or BN40900 on the day of the BL visit 
and first subcutaneous injection with satralizumab in Study WN42349.
b The Treatment period lasts up to 3 years from the date of enrollment of the first patient.
c Safety follow up (SFU),12 weeks after the last injection for all patients who received at least 
one dose of satralizumab (except for patients who continue with satralizumab treatment 
outside of this study).
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.  The treatment period ends 3 years after the date the first patient enrolls in the 
study. The end of the study is expected to occur in second quarter of 2024.
In addition, the Sponsor may decide to terminate the study at any time.
The total length of the study, from enrollment of the first patient to the end of the study, is 
expected to be approximately 3 years and 3 months.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Satralizumab Dose and Schedule
Based on PK and PD assessments in the Studies BN40898 and BN40900, satralizumab 
120 mg SC, administered Q4W will be used as the maintenance dose in this study.
3.3.2
Rationale for Patient Population
This study will enroll patients with NMOSD who participated in 
Studies BN40898 or BN40900 with satralizumab and who are currently undergoing
ongoing satralizumab treatment in the OLE period of these studies, in order to evaluate 
the long-term safety, and efficacy of satralizumab treatment.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
 
 
 
  
  
 
 
              
 


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3.3.3
Rationale for Biomarker Assessments
The following biomarker assessments will be used to investigate the effects of continued 
satralizumab treatment on the underlying NMOSD pathology:

Exploratory Biomarker samples will be used for research purposes to identify 
pathway and/or disease biomarkers, including those that may be reflective of 
immune cell activity and CNS inflammation or damage.
4.
MATERIALS AND METHODS
4.1
PATIENTS
This study includes patients with NMOSD who participated in Study BN40898 or 
Study BN40900 and are ongoing on satralizumab treatment in the OLE period of these 
studies prior to study entry in Study WN42349. Approximately 127 patients 
with NMOSD will be enrolled in this study.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Participated in Study BN40898 or Study BN40900 with satralizumab in NMOSD, are 
on ongoing satralizumab treatment and were AQP4-IgG seropositive at screening in 
these studies. Patients with NMOSD who were AQP4-IgG seronegative at 
screening in Study BN40898 or Study BN40900 can be enrolled if the investigator 
considers the continued treatment with satralizumab to be beneficial for the patient.

Signed Informed Consent Form (ICF)

Ability to comply with the study protocol

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use adequate contraception during the treatment 
period and for 3 months after the final dose of satralizumab.
A woman 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.  
If required per local guidelines or regulations, locally recognized adequate


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methods of contraception and information about the reliability of abstinence will 
be described in the local ICF.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Use of prohibited medication (see Section 4.4.2).

Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 3 months after the final dose of study drug.  Women of childbearing potential 
must have a negative urine pregnancy test result on the baseline visit prior to 
initiation of study drug.

Evidence of any 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, renal/urologic disease, digestive system disease, congenital 
or acquired severe immunodeficiency.

Known active infection that requires delaying the next satralizumab dose at the time 
of enrollment a
a
In case of an active infection, the patient should remain in the parent study, as 
governed by that protocol, and may enroll in this study once the active infection is 
controlled.

NMOSD relapse at the time of enrollmentb
b
In case of a relapse, the patient should remain in the parent study, as governed 
by that protocol, and may enroll in this study once the patient is stable.

Laboratory abnormalities at the last assessment in Study BN40898 or
Study BN40900 that preclude re-treatment with satralizumab (see Section 5.1.1)c
c
If a patient does not meet the criteria to restart treatment with satralizumab
based on laboratory assessments, the patient should remain in the parent study and 
the baseline visit should be delayed.  The last assessment before enrollment must 
meet the re-treatment criteria.
4.2
TREATMENT ASSIGNMENT
This is a non-randomized open-label, single-arm study where patients who participated 
in either Study BN40898 or Study BN40900 continue treatment with open-label 
satralizumab. After initial written informed consent has been obtained and eligibility has 
been established for a patient, the study site will obtain treatment kit assignment from an 
interactive voice or Web-based response system (IxRS). The IxRS interaction 
(Studies BN40898 or BN40900 completion) should happen no more than 3 days prior 
the baseline visit.


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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.  Acute relapse
rescue therapy administered in case of a NMOSD relapse, and allowed background IST
are considered non-investigational medicinal products (see Section 4.4.1).
4.3.1
Study Treatment Formulation and Packaging
4.3.1.1
Satralizumab
Satralizumab will be supplied by the Sponsor as prefilled syringe (PFS) with a needle 
safety device (NSD).  For information on the satralizumab formulation, see the pharmacy 
manual and/or local prescribing information for Enspryng (satralizumab).
4.3.2
Dosage, Administration, and Compliance
Satralizumab 120 mg 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.
Patients will receive an SC injection of satralizumab at the baseline visit and every Q4W 
thereafter, with the last study drug administration on or before the date 3 years after the 
first patient was enrolled.
Patients who experience a relapse during the study will continue administration of 
satralizumab at the discretion of the investigator.
In accordance with local regulations, administration of satralizumab prefilled syringes 
outside of the study site (e.g., self-administration or administration by a caregiver after 
completing training) may be allowed on scheduled study drug administration days that 
do not require additional assessments that must be performed on site (Appendix 1).
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 14 days).
The treatment regimen is summarized in Section 3.1.
See the pharmacy manual for detailed instructions on study drug storage and 
administration.
Details on treatment administration (e.g., dose and timing) should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Cases of 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.


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Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Section 5.1.
4.3.3
Investigational Medicinal Product 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) 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, with use of 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 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, and only authorized staff may 
supply IMPs.
If patients are administered satralizumab outside of the study site, IMP may be given to 
the patient to take home during a study site visit, or may be shipped to the patient’s 
home from the study site (in special circumstances).  Patients will be asked to return all 
IMP boxes at their next on-site visit.
Either the study site will dispose of IMPs according to the study site's institutional 
standard operating procedure or the IMPs will 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.
See the pharmacy manual and/or or local prescribing information for information on IMP
handling, including preparation and storage, and accountability.


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4.3.4
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 NMOSD

The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
NMOSD

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
4.4
CONCOMITANT THERAPY
Data on medications reported as ongoing in Study BN40898 or Study BN40900 up to the 
day of enrollment in Study WN42349 (e.g., prescription drugs and over-the-counter 
drugs) will be transcribed into the Concomitant Medications section of the eCRF.
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 the day 
of the baseline visit and first administration of satralizumab in this study to the end of
treatment visit.  All such medications should be reported to the investigator and recorded
on the Concomitant Medications eCRF.


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4.4.1
Permitted Therapy
Patients are permitted to use the following therapies during the study:

Background IST with any of the drugs listed below is permitted. The dose must not 
exceed the dose defined below. Initiation, change or termination of background IST
is permitted.

AZAa: 3 mg/kg/day 

MMFa: 3000 mg/day 

Oral corticosteroids: 15 mg/day (prednisolone equivalent)
a Combination with oral corticosteroids (15 mg/day [prednisolone equivalent]) can be 
continued in patients who were aged 12 to 17 years at the time of informed consent
in Study BN40898.

Acute relapse (rescue) therapy for NMOSD relapse; pulse intravenous or oral
corticosteroids, intravenous IG, and/or apheresis (including plasma exchange and 
plasmapheresis).
Acute relapse therapy should be provided at the discretion of the Investigator after 
the EDSS/Functional System Score (FSS) assessment has been completed at a 
relapse assessment visit (except when urgent treatment is required before the 
patient can undergo this assessment). Satralizumab treatment can be continued as 
scheduled, concurrently with acute relapse therapy.

Treatment with corticosteroids (e.g., oral, nasal) for AEs (i.e., indications other than 
background IST or acute relapse therapy) is permitted; the treatment duration 
should be kept as short as possible.
4.4.2
Prohibited Therapy
Between the first administration of satralizumab in Study BN40900 or Study BN40898 
and the last administration of satralizumab in Study WN42349:

Other IL-6R inhibitory therapy (e.g., tocilizumab), alemtuzumab, eculizumab,
antiB-lymphocyte stimulator monoclonal antibody (e.g., belimumab), any other 
treatment for prevention of MS relapse (e.g., interferon, glatiramer acetate, 
fingolimod, natalizumab, teriflunomide, or dimethyl fumarate), anti-CD4, cladribine, 
mitoxantrone, anti-CD20 or anti-CD19 treatment (e.g., rituximab, ocrelizumab, 
ofatumumab, or inebilizumab)

Total body irradiation, bone marrow transplantation

Immunization with live or live attenuated vaccines

Treatment with any investigational agent (other than satralizumab)
4.5
STUDY ASSESSMENTS
4.5.1
Description of Study Assessments
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each patient.


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Assessments scheduled on the day of study drug administration should be performed 
prior to administration of study drug, unless otherwise noted in the schedule of activities 
(see Appendix 1).
If study drug cannot be administered on the scheduled visit, every effort should be made 
to perform the assessments at the visit.
If a patient misses a scheduled visit without notice, the Investigator and/or site staff 
should try to contact the patient via telephone or another way in order to confirm if there 
has been an AE or relapse.  The Investigator and/or site staff should encourage the 
patient to visit the study site for an assessment as soon as possible.
Administration of satralizumab prefilled syringes outside of the study site (home dosing)
may be allowed, in accordance with local regulations, only if no on-site assessments are 
scheduled for that dosing day.  Patients should be followed up by phone to monitor if 
there has been an AE or neurological worsening.
During extraordinary circumstances like the SARS-CoV-2 (COVID-19) pandemic, when 
patients cannot attend a study site for a scheduled visit, administration of satralizumab 
outside of the study site will be allowed for all scheduled dosing days.  Patients should 
be followed up by phone around the time of the scheduled visit to confirm patient 
compliance with study drug treatment, and to collect information on safety and/or 
neurological worsening the patient might experience.  Safety laboratory assessments 
may be performed at a local laboratory when possible and any clinically significant 
abnormal laboratory values reported as AEs in the eCRF as described in Section 5.3.
4.5.2
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures.  ICFs for enrolled patients and for patients 
who are not subsequently enrolled will be maintained at the study site.  All screening 
evaluations must be reviewed to confirm that patients meet all eligibility criteria before 
enrollment.  The investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable.
4.5.3
Medical History, Baseline Conditions, Concomitant Medication,
and Demographic Data
No new medical history will be collected. Medical history/baseline conditions, AEs,  
NMOSD relapses, and concomitant medication reported in 
Studies BN40898 or BN40900 that are ongoing at the baseline visit in Study WN42349,
will be transcribed into the eCRF.
Demographic data will include age, sex, and self-reported race/ethnicity.


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4.5.4
Physical Examinations
Limited, symptom-directed physical examinations should be performed at baseline and 
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.  In 
addition, height will be obtained at baseline and weight will be obtained at the specified 
visits.
4.5.5
Vital Signs
Vital signs will include measurements of pulse rate, temperature and blood pressure 
while the patient is in a seated position for at least 5 minutes. At dosing visits at the 
study site, vital signs will be measured. Measurement of pulse rate, temperature, and 
blood pressure should take place immediately before study drug administration.
Record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
4.5.6
Relapse Assessment
Patients should report all new or worsening neurological events compatible with NMOSD
immediately to the sites and a visit for relapse assessment should be scheduled as soon 
as possible. Patients who attend the study center for a protocol-specified study visit that 
includes an EDSS/FSS assessment (see Appendix 1) should be assessed to determine 
whether a clinical relapse has occurred or not. Any clinical relapse should be reported 
and assessed if it meets the criteria for protocol-defined relapse (see Section 4.5.6.2).
An EDSS/FSS assessment by an appropriately Neurostatus qualified examining 
assessor should be performed in every case of potential relapse.
4.5.6.1
Procedure for Detection of Potential Relapse
All patients with new or worsened neurological symptoms suggestive of a relapse should 
have the EDSS/FSS performed and entered into the eCRF.  If a patient becomes aware 
of signs or symptoms that might indicate a relapse, the patient will contact the site 
immediately and return to the site for a relapse assessment visit as soon as possible.
The EDSS/FSS assessment should be performed within 7 days after the patient reports 
the symptoms to the site.  The list of assessments to be obtained at the relapse 
assessment visit is listed in Appendix 1. The Investigator should treat the patient as 
necessary based on his/her evaluation of the symptoms after the completion of relapse 
assessments. Magnetic resonance imaging findings might be supportive for evaluation 
of a relapse.
If a patient has difficulty visiting the study site as a result of severity of the relapse, the 
patient can visit a local clinic/hospital for immediate management of a relapse, and then 
visit the study site as soon as possible (which may be during or immediately after acute 
relapse/rescue therapy).


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If the patient is seen at a clinical facility other than the study site, the patient should show 
the patient ID card, which includes the investigator’s contact information, to the treating 
physicians/nurses at the local clinic/hospital and the study site should make every effort 
to obtain medical records from the facility, including information on treatment 
administered and the nature of the symptoms and signs observed.
4.5.6.2
Protocol-Defined Relapse
Protocol-defined relapse is the occurrence of new or worsening neurological symptoms 
attributable to NMOSD. Symptoms must persist for 24 hours and should not be 
attributable to confounding clinical factors (e.g., fever, infection, injury, change in mood, 
or adverse reactions to medications). New or worsening neurological symptoms that 
occur less than 31 days following the onset of a protocol-defined relapse will be 
considered part of the same relapse (i.e., if two relapses have onset days that are within 
30 days of each another, they will be counted only as one relapse), and the onset date 
used in the analysis will be the onset date of the first relapse. The new or worsening 
neurologic symptoms must meet either of following:
1.
An increase of at least 1.0 point on the EDSS score, or a 2.0 point increase on the 
EDSS if the EDSS score at baseline in the parent study was zero
2.
An increase of at least 2.0 points on one of the appropriate FSS
3.
An increase of at least 1.0 point on two or more of the appropriate FSS if the score 
at baseline in the parent study was one or more
4.
An increase of at least 1.0 point in single eye FSS when the score at baseline in the 
parental study in that eye was one or more
The base of comparison for the increase is the score at the most recent scheduled 
EDSS/FSS assessment visit prior to the relapse. The appropriate FSS change must 
affect at least one of the following functional systems: pyramidal, cerebellar, brainstem, 
sensory, bowel/bladder, or visual (single eye). Sexual dysfunction and cerebral function
will not suffice to establish a protocol-defined relapse.
4.5.7
Expanded Disability Status Scale
The EDSS is frequently used as a quantitative measure of disability and for assessment 
of severity of relapse for patients with MS as well as NMOSD. It is a well-established 
scale that has been used in most major MS clinical trials for many years (Kurtzke 1983). 
Based on a standard neurological examination, the EDSS quantifies disability in 
functional systems and allows neurologists to assign an FSS in each of these. Each of 
the FSS is an ordinal clinical rating ranging from 0 to 5 or 6. These functional ratings are 
then used in conjunction with observations and information concerning gait and the use 
of assisting devices to rate the EDSS. The EDSS is an ordinal scale with values from 
0 points (normal neurological examination) up to 10 points (death), increasing in 
increments of 0.5 points.


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In addition to those FSS, the single eye FSS (see the material for EDSS/FSS scoring) is 
assessed to confirm whether a relapse has occurred.
The EDSS/FSS assessment (see Appendix 2) should be performed by the same
qualified assessor, whenever it is feasible. 
4.5.8
Visual Acuity/Function Testing
Visual function testing will be performed with eye charts.
Visual acuity will be measured by a Snellen 20-foot wall chart. The test will be 
performed monocularly and patients may use their habitual distance glasses or contact 
lenses.
The same visual acuity testing method is to be employed for all study visits for each 
patient.
Other visual function (e.g., visual fields) will be assessed for EDSS/FSS assessment as 
well as visual acuity.
4.5.9
EQ-5D-3L
The EQ-5D-3L scale is a generic measure of health related quality of life that rates 
patient health state looking at five specific dimensions such as mobility, self-care, usual 
activity, pain/discomfort and anxiety/depression and score their general health state.
4.5.10
Columbia-Suicide Severity Rating Scale 
The 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, see Appendix 4). The structured interview prompts recollection of suicidal ideation, 
including the intensity of the ideation, behavior, and attempts with actual or potential 
lethality. The C-SSRS baseline from the parent study will be used, and the C-SSRS 
since the last visit will be collected at subsequent visits as indicated in the schedule of 
activities (see Appendix 1).
4.5.11
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests (except urinalysis and pregnancy tests) will be 
sent to the Central Laboratory for analysis.  Instruction manuals and supply kits will be 
provided for all central laboratory assessments. If a patient cannot visit the study site in 
extraordinary circumstances like the SARS-CoV-2 (COVID-19) pandemic, laboratory 
tests may be performed at a local laboratory in accordance with local regulations.

Hematology (hemoglobin, hematocrit, platelet count, INR, RBC count, WBC count, 
absolute differential count [neutrophils, eosinophils, lymphocytes, monocytes, 
basophils, other cells])

Serum chemistry (sodium, potassium, chloride, calcium, phosphorous, ferritin, BUN, 
creatinine, total bilirubin (TBL), fibrinogen, total protein, albumin, ALT, AST, alkaline 


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phosphatase, gamma-glutamyl transpeptidase, LDH, total cholesterol, LDL 
cholesterol, HDL cholesterol, triglycerides, creatine kinase, uric acid) complement 
tests (C3, C4, and CH50)

CRP

For patients with positive total hepatitis B core antibody status and undetectable 
hepatitis B viral DNA at screening in Study BN40898 or Study BN40900, hepatitis B 
viral DNA measurements will be continued to be performed regularly at 
approximately 24-weekly intervals during Study WN42349.
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 dip stick.

Pregnancy test
All female patients of childbearing potential (including those who have had a tubal 
ligation) will have a urine pregnancy test at the study site at the baseline visit 
confirmed as negative before the administration of study drug. If a urine pregnancy 
test is positive, it must be confirmed by a serum pregnancy test. During the study 
pregnancy tests (serum or urine) must have a sensitivity of at least 25 mIU/mL. 
Patients who do not meet the criteria for childbearing potential during the study 
(e.g., confirmed postmenopausal status) will not require further pregnancy testing. In 
order to qualify for and to remain in the study, the patient must have a negative 
pregnancy test, evidence of surgical sterility or evidence of post-menopausal status. 
Postmenopausal status is defined as any of the following: natural menopause with 
menses 1 year ago; radiation-induced with last menses 1 year ago, or bilateral 
oophorectomy.
The following samples will be sent to central laboratories or to the Sponsor or a 
designee for analysis:

Serum samples for PK and PD analysis (IL-6, sIL-6R)

Serum samples for immunogenicity analysis (ADA)

Serum and plasma samples for exploratory research on biomarkers and biomarker 
assay development
Exploratory biomarker research may include, but will not be limited to, analysis of 
anti-AQP4 antibodies and GFAP over time.
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 4.5.13), biological samples will be destroyed 


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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.

Plasma and serum samples collected for biomarker research and biomarker assay 
development will be destroyed no later than 10 years after the final CSR has been 
completed.
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 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.
4.5.12
Electrocardiograms
ECGs should be performed prior to any blood draws. To minimize variability, it is 
important that patients be in a resting position for 10 minutes prior to each ECG 
evaluation. Body position should be consistently maintained for each ECG evaluation to 
prevent changes in heart rate. Environmental distractions (e.g., television, radio, 
conversation) should be avoided during the pre-ECG resting period and during ECG 
recording. ECGs for each patient should be obtained from the same machine whenever 
possible.
For safety monitoring purposes, the Investigator or designee must review, sign, and date 
all ECG tracings. Paper copies will be kept as part of the patient's permanent study file 
at the site. ECG characteristics, including heart rate, QRS duration, and RR, PR, and 
QT intervals, will be recorded on the eCRF. QT interval corrected for heart rate with use 
of Fridericia's formula (QTcF) will be calculated post hoc. Changes in T-wave and 
U-wave morphology and overall ECG interpretation will be documented on the eCRF.
4.5.13
Optional Samples for Research Biosample Repository
4.5.13.1
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, 


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solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, and 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.
Leftover serum and plasma 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
4.5.13.2
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 ICF by each site's 
Institutional Review Board or Ethics Committee (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 4.5.13) will not be applicable at that site.
4.5.13.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to satralizumab, NMOSD, or 
the development of disease related tests or tools:

Leftover blood (serum and plasma) samples and any derivatives thereof (e.g., DNA, 
RNA, proteins, peptides)
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via whole genome sequencing, whole exome sequencing, or other 
genomic analysis methods. Genomics is increasingly informing researcher's 
understanding of disease pathobiology.  Whole genome sequencing and whole exome 
sequencing 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 AEs.


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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.
The 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 ICF and applicable laws (e.g., health authority requirements).
4.5.13.4
Confidentiality
The 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 ICF (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.
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.
4.5.13.5
Consent to Participate in the Research Biosample Repository
The ICF 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.


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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.
4.5.13.6
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.
4.5.13.7
Monitoring and Oversight
The 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 ICF.  
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.
4.5.14
Assessments at the Treatment Discontinuation and End of 
Study Visit
The treatment discontinuation (EOT) visit is for patients who discontinue from 
satralizumab treatment in this study. 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. Patients will be asked to attend an End of 


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Study (EOS) visit 12 weeks after the last dose of satralizumab to complete the SFU
period.
Patients who decide to continue treatment with satralizumab outside of this study have 
to complete the EOT visit, but they will not have to complete the SFU.
After the final study visit, AEs should be reported and followed as outlined in Section 5.5
and Section 5.6.
See Appendix 1 for the schedule of activities performed at the EOT and EOS visits.
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

Meet the discontinuation criterion in the risk mitigation strategy (see Section 5.1).

Continuation of treatment should be carefully assessed in case of multiple or severe 
relapses that are not in keeping with the patients NMOSD history or trajectory.
The investigator should consult with the Medical Monitor if these relapses meet this 
criterion.

Malignancy or a severe allergic or anaphylactic reaction to satralizumab.
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF page.  Patients who discontinue study treatment will not be replaced.
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

Loss to follow-up


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
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.
When participants complete the treatment period or discontinue early, every effort
should be made to ensure that the safety follow-up period and all related assessments
are completed. Patients will return to the clinic for a study discontinuation/EOS visit 
12 weeks after the final dose of satralizumab.
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 AEs 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:

Poor protocol adherence

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
The safety plan for patients in this study is based on clinical experience with 
satralizumab in completed and ongoing studies, as well as experience with molecules in 
the same class.  The anticipated safety risks for satralizumab are outlined below.  See
the current satralizumab Investigator's Brochure for a complete summary of safety 
information.


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Several measures will be taken to ensure the safety of patients participating in this study.  
Patients will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of AEs.  The safety risks for satralizumab or anti-IL-6R 
antibodies and recommendations for vigilance with signs and symptoms of particular 
safety events are summarized in the following sections.
5.1.1
Risks or Laboratory Abnormalities Associated with 
Satralizumab
5.1.1.1
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 infections and they may become more 
severe as a result of initial masking. In the double-blind period of Phase III 
Studies BN40909 and BN40900, the rates of overall infections and serious infections in 
patients treated with satralizumab monotherapy or in combination with IST were not 
higher than the placebo groups.
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.

The administration of satralizumab should be delayed until the active infection is 
controlled.

If a patient develops a serious infection, administration of satralizumab is to be 
interrupted until the infection is resolved. The treating physician should conduct a 
benefit-risk assessment before resuming treatment with satralizumab.

Live or live attenuated vaccines should not to be given during the course of the 
study as clinical safety has not been established.
For patients with NMOSD participating in this study, therapies used to treat NMOSD (i.e., 
corticosteroids, AZA, MMF) have been shown to be associated with infections, 
particularly serious infections.
5.1.1.2
Serious Hypersensitivity Reactions
Anaphylaxis and hypersensitivity reactions are considered a potential risk for all biologic 
medications, including satralizumab. As of February 2020, no anaphylaxis or serious 
hypersensitivity reactions have been reported in clinical trials with satralizumab.
The symptoms/signs of hypersensitivity include, but are not limited to, blood pressure 
decrease, dyspnea, loss of consciousness, dizziness, queasiness, vomiting, itchiness, 


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flushing, etc. A decision to continue/discontinue treatment with satralizumab should be 
made taking into account the risks and benefits if any of these events are observed:

If an anaphylactic reaction or other serious hypersensitivity reaction occurs, 
satralizumab should be discontinued.  At the study site, the SC injections should be 
administered under close supervision in a setting where medications 
(e.g., corticosteroid, antihistamine, and epinephrine) and resuscitation facilities are 
available

Patients should be instructed to seek medical attention if they experience symptoms 
of hypersensitivity reaction outside of the clinic.

Administration of satralizumab prefilled syringes outside of the study site might be 
allowed (see Section 4.3.2) if the investigator determines that it is appropriate.  
Patients/caregivers should be instructed to recognize the signs and symptoms of 
hypersensitivity reactions and instructed to seek immediate medical attention if the 
patient develops symptoms of serious allergic reactions.  Patients/caregivers should 
confirm with the investigator whether treatment with satralizumab may be continued.
5.1.1.3
Liver Enzyme Elevations and Potential Risk of Hepatotoxicity
It has been reported that IL-6 appears to have a hepato-protective effect on various 
forms of liver injury and promotes hepatocyte regeneration.
In the double-blind period of Studies BN40898 and BN40900, mild and moderate 
elevations of liver transaminases have been observed with satralizumab treatment.  
Most elevations were 5upper limit of normal (ULN) and resolved while on treatment 
with satralizumab.  Elevations of ALT or AST 3ULN were not associated with 
increases in TBL.
Liver function markers should be closely monitored especially when satralizumab is 
administered, concomitantly with hepatotoxic drugs, or administered in patients with 
elevated transaminases.
Recommended dose interruptions based on transaminases are shown in Table 1.


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Table 1
Hepatic Enzyme Risk Mitigation
AST or ALT 
values
Action
1 to 3ULN a

Reduction (if necessary, interruption) of concomitant hepatotoxic 
drugs could be considered.

For persistent increases in this range, satralizumab could be 
interrupted until AST and ALT is below ULN a.
3 to 5ULN
Laboratory tests (ALT, AST, ALP and TBL) should be repeated within 
72 hours to confirm value. The presence of clinical symptoms should be 
queried. Patients who are far away from the trial site may be retested 
locally if prompt return to the trial site is difficult
Satralizumab should be interrupted until AST and ALT is below 3ULN.  
If at least one of following associated, satralizumab should be discontinued:

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
Laboratory tests (ALT, AST, ALP, and TBL) should be repeated within 
72 hours.  If value is confirmed, satralizumab should be discontinued 
immediately and gastroenterology expert 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.
ALPalkaline phosphatase; ALTalanine aminotransferase; ASTaspartate aminotransferase; 
INRinternational normalized ratio; TBLtotal bilirubin; ULNupper limit of normal.
a
ULN or patient’s baseline value in the parent study, whichever is higher.
5.1.1.4
Neutropenia
In the completed Studies BN40898 and BN40900 double-blind period of the Phase III
studies, decreases in neutrophil counts have occurred following treatment with 
satralizumab. These episodes of neutropenia were not associated with serious 
infections. The majority of neutrophil decreases were transient or intermittent.
Recommended dose interruption based on ANC results is shown in Table 2.
Table 2
Neutropenia Risk Mitigation
ANC (/µL)
Action
1,000
Maintain dose
5001,000

If neutropenia persists, satralizumab should be interrupted until ANC is 
above 1,000/µL.

If ANC was under 1,000/µL at the previous laboratory test, ANC must 
be checked before treatment with the satralizumab (e.g., ANC test at 
site).
500
Satralizumab should be discontinued.
ANCabsolute neutrophil count.


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5.1.1.5
Thrombocytopenia
In the double-blind period of Studies BN40898 and BN40900, decreases in platelet 
counts have occurred following treatment with satralizumab. The majority of the 
decreased platelets were transient and not below 75109/L.  Treatment-related reduction 
in platelets was not associated with bleeding events in clinical trials.
Recommended dose interruption based on platelet counts are shown in Table 3.
Table 3
Thrombocytopenia Risk Mitigation
Platelet Count (/L）
Action
75,000
Maintain dose
50,00075,000
If thrombocytopenia persists, satralizumab should be interrupted 
until platelet count is above 75,000/µL.
50,000
Satralizumab should be discontinued.
5.1.1.6
Elevations in Lipid Parameters
In the double-blind period of Studies BN40898 and BN40900, elevations in total 
cholesterol and triglycerides were observed more often in patients treated with 
satralizumab compared with placebo.  The elevations in lipid parameters did not require 
dose interruption. Patients should be managed according to local guidelines.
5.1.1.7
Laboratory Findings Associated with Pharmacodynamic
Effects
In addition to the above abnormal laboratory values, decreases in CRP, fibrinogen, and 
complement (C3, C4, and CH50) were observed in Studies BN40898 and BN40900. 
These are anticipated PD effects of satralizumab.
5.1.1.8
CYP450 Enzyme Normalization
No interaction studies have been performed. Population PK analyses did not detect any 
effect of AZA, OCs, or MMF 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. Although modestly raised IL-6 levels have been reported in 
patients with NMOSD, mainly during times of increased disease activity, this was not 
evident in patients enrolled in Studies BN40898 and BN40900.
However, caution should be exercised when starting or discontinuing satralizumab 
treatment in patients also receiving substrates of CYP450 3A4, 1A2, 2C9 or 2C19, 
particularly those with a narrow therapeutic index (such as warfarin, carbamazepine, 
phenytoin, and theophylline), and doses adjusted if needed.
Given the prolonged terminal half-life of satralizumab, the effect of satralizumab may 
persist for several weeks after stopping therapy.


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5.1.2
Other Risks Associated with IL-6R Inhibitors
5.1.2.1
Gastrointestinal Perforations (Complications of Diverticulitis)
As of February 2020, gastrointestinal (GI) perforations have not been reported in clinical 
trials with satralizumab treatment, with the exception of one patient who developed a GI 
perforation as a complication of a surgery.
Gastrointestinal perforations have been reported rarely in patients with RA administered 
with other anti IL-6R antibodies. Anti-IL6R antibodies may suppress the acute 
symptoms (abdominal pain, pyrexia, etc.) associated with diverticulitis, etc., causing 
delayed diagnosis and progression to perforation.

Patients presenting with symptoms potentially indicative of complicated diverticulitis, 
such as abdominal pain, should be evaluated (X-ray, computerized tomography [CT] 
scan, etc.) promptly for early identification of gastrointestinal perforation and 
appropriate measures taken.

Patients should be made aware of the symptomatology potentially indicative of 
complicated diverticular disease, and they should be instructed to alert their 
healthcare provider as soon as possible if these symptoms arise.

In patients who receive corticosteroids 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 appreciably increase in the 
occurrence of malignancies. No increased risk of malignancies has been observed in 
clinical trials with satralizumab treatment.
Satralizumab 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
Other Demyelinating Disorders
Demyelination-related diseases have been reported in patients with RA administered
another antiIL-6R antibody, but it is not known whether there is a causal relationship. If
symptoms suggestive of a demyelination-related disease, other than NMOSD, are 
observed, differential diagnosis of the patient should be performed.
5.1.3
Concomitant Immunosuppressive Treatment
Patients receiving background treatment with allowed ISTs should also be informed of 
the risks associated with taking corticosteroids, AZA, or MMF. For additional safety data, 
see the local prescribing information.


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5.1.4
Management of Patients Who Experience Adverse Events
5.1.4.1
Treatment Interruption
Satralizumab treatment may be temporarily suspended in patients who experience an 
AE or abnormal laboratory values (see Section 5.1).  If satralizumab has been withheld 
for 12 weeks, resumption of treatment should be discussed with the Medical Monitor.  
Satralizumab treatment may be suspended for reasons other than toxicity (e.g., surgical 
procedures) with Medical Monitor approval.  The investigator and the Medical Monitor 
will determine the acceptable length of treatment interruption.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording AEs, including SAEs and 
AESIs, 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 AE is any untoward 
medical occurrence in a clinical investigation subject administered a pharmaceutical 
product, regardless of causal attribution.  Therefore, an AE can 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 Section 5.3.5.9, and 
Section 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, X-ray) 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)
Acute, new, or worsening neurological symptoms considered to be an NMOSD relapse 
will not be reported as Adverse Events. NMOSD relapses will be recorded only on a 
pre-specified eCRF “NMOSD relapse” form.


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5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
An SAE is any AE that meets any of the following criteria:

Fatal (i.e., the AE actually causes or leads to death)

Life threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death)
This does not include any AE 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)

Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions)

Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

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 exception to this definition of an SAE is in the rare event that a patient is 
hospitalized following an NMOSD relapse, as long as the reason for hospitalization is to 
receive standard treatment with rescue therapy for clinical relapse.
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of 
an AE (rated as mild, moderate, or severe] criteria; 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 AE recorded on 
the eCRF.
Serious adverse events are required to be reported by the Investigator to the Sponsor 
within 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:


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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.
5.2.4
Selected Adverse Events
Additional data will be collected for the following selected AEs.  The data should be 
recorded in the eCRF on the AE page and on the special form for that particular AE.

Infections that require treatments with intravenous antibiotics, antifungals, or 
antivirals

Opportunistic infections that require treatments with oral antibiotics, antifungals, or 
antivirals 

Injection-related reaction (IRR; an AE that occurs within 24 hours after study drug 
injection except where the event is not considered an allergic reaction)
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all AEs (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 AE 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
Adverse Events with onset prior to the baseline visit will be reported in the eCRF of 
either Study BN40898 or Study BN40900.
Investigators will seek information on AEs at each patient contact.  All AEs, 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 initiation of study drug, all AEs will be reported until 3 months after the final dose of 
study drug.
Instructions for reporting AEs that occur after the AE reporting period are provided in 
Section 5.6.


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5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting AE
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?"
5.3.3
Assessment of Severity of Adverse Events
Table 4 provides guidance for assessing AE severity.
Table 4
Adverse Event Severity Grading Scale
Severity
Description
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating with inability to work or to perform normal daily activity
Note:  Regardless of severity, some events may also meet seriousness criteria.  
Refer to definition of a serious adverse event (see 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 
increase the occurrence of the event

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 AEs on 
the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one AE term should be recorded in the event field on the Adverse Event eCRF.


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5.3.5.1
Injection Related Reactions
Injection-related reaction is defined as the event that occurs within 24 hours after study 
drug injection. An IRR should be recorded on the IRR page of the eCRF as 
“injection-related reaction”, and individual signs and symptoms should also be captured 
on the IRR page of the eCRF.
But exceptive conditions are as follows:

Anaphylaxis or anaphylactic shock:
If the event is judged as anaphylaxis or anaphylactic shock by Investigator’s 
discretion, it will be recorded on the Adverse Event page of the eCRF.

Obviously not allergic reaction (e.g., infection):
If the event is judged not to be an allergic reaction or injection related reaction, it will 
be recorded on the Adverse Event page of the eCRF
5.3.5.2
Diagnosis versus Signs and Symptoms
For AEs, 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, AEs 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.

If a severe gastrointestinal 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.


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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
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events.
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.
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 


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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 or 
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 
TBL (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 TBL 2ULN

Treatment-emergent ALT or AST3ULN in combination with clinical jaundice
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).


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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 NMOSD.
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 NMOSD, "Neuromyelitis optica 
spectrum disorder 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 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 NMOSD
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on relapse related clinical data.  In rare cases, the 
determination of clinical progression will be based on symptomatic deterioration.  
However, every effort should be made to document progression through use of objective 
criteria.  If there is any uncertainty as to whether an event is due to disease progression, 
it should be reported as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE (per the definition of SAE in Section 5.2.2), except as outlined 
below.


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The following hospitalization scenarios are not considered to be SAEs:

Hospitalization because of NMOSD relapse

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.
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.
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, 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 


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satralizumab, 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, 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.

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.


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
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 Outcome Data
Adverse event reports will not be derived from PRO data by the Sponsor.  Sites are not 
expected to review the PRO data for adverse events.
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)

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 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


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
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
The contact details for the Emergency Medical Contacts will be provided in the 
Investigator (Site) File. Medical Monitor names and contact information will be included.
Contact Information for All Sites
Medical Monitor
 M.D.
Telephone No.:
Mobile Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center will be 
available 24 hours per day, 7 days per week, in case the above-listed contacts cannot 
be reached.  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
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 3 months 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 
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 Serious Adverse 
Event/Adverse Event of Special Interest Reporting 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 with use of 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 3 months after the final
dose of study treatment are provided in Section 5.6.


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5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed 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 with use of 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
Male patients will be instructed through the ICF to immediately inform the investigator if 
their partner becomes 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 
with use of the fax number or email address provided to investigators.  Attempts should 
be made to collect and report details of the course and outcome of any pregnancy in the 
partner of a male patient exposed to study drug.  When permitted by the site, the 
pregnant partner would need to sign an Authorization for Use and Disclosure of 
Pregnancy Health Information to allow for follow-up on her pregnancy.  If the 
authorization has been signed, the investigator should submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.  An investigator who is contacted by the male patient or his pregnant 
partner may provide information on the risks of the pregnancy and the possible effects 
on the fetus, to support an informed decision in cooperation with the treating physician 
and/or obstetrician.
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).
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, 


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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).  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, a PFS with an NSD is considered a medical device.  The investigator must 
report all medical device 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; see the pharmacy manual for further details).  If the medical 
device results 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 
3 months [see Section 5.3.1] 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 Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form with use of 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.
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:

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 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The purpose of this study is to assess safety and efficacy of long-term administration of 
satralizumab.  Patients who are on treatment with satralizumab and ongoing in the OLE 
period of Study BN40898 or BN40900 can be enrolled in this study. For analysis 


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purposes, data of both parental studies and this study will be combined, where 
appropriate.
This section outlines the statistical analysis strategy and procedures for the study. A 
detailed methodology for statistical analyses of the data collected in this trial and the 
analyses in conjunction with the parental trials will be documented in a Statistical 
Analysis Plan (SAP).
6.1
ANALYSIS POPULATIONS
6.1.1
Efficacy Analysis Populations
The intent-to-treat (ITT) population, which will serve as the primary population for the 
analysis of efficacy, consists of all randomized patients in the double-blind period of the 
parent Studies BN40898 and BN40900. The ITT population will encompass all patients 
from the parent studies, even if they do not participate in this study. Patients will be 
analyzed as randomized for analysis purposes in the ITT, even if patients randomized to 
placebo received satralizumab in the OLE period of the parent study.
In addition, all efficacy analyses will be conducted from the first dose of satralizumab in 
the parent studies.  This analysis population is in line with the All-Patients-Treated (All 
satralizumab [ALLSA]) Population. Patients that were directly enrolled in the extension 
period of the parental studies will also be included in these analyses.
6.1.2
All-Patients-Treated Population
The ALLSA population will be defined as all enrolled patients who received at least one 
dose of satralizumab at any time either during the parent studies or this study.
6.1.3
Safety Analysis Populations
All safety variables will be analyzed on the basis of the Safety Population (SAF). The 
SAF population will include all randomized or enrolled patients who have received at 
least one dose of study drug either during the parental studies or this study. It will 
encompass all patients from the parent studies, even if they do not participate in this 
study. Patients will be analyzed as treated for analysis purposes in the SAF.
6.1.4
Pharmacokinetics Per-Protocol Set and Pharmacodynamics 
Analysis Population
The Pharmacokinetics Per-Protocol (PK-PPS) and immunogenicity (ADA) Set will 
include all patients in the SAF with at least one valid post-dose concentration or ADA 
titer result with a dosing record and sampling time. Pharmacodynamics variables (e.g., 
IL-6, sIL-6R, CRP) will be analyzed with use of the SAF population. 
6.2
DETERMINATION OF SAMPLE SIZE
The sample size will include all eligible participants who consent to this study. The 
sample size is expected to be no more than approximately 127 patients but will be 


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determined by the number of patients who complete Studies BN40898 and BN40900 
and enroll in this study.
6.3
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll, discontinue, or complete the study will be 
summarized.  Reasons for premature study discontinuation 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.
6.4
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics (including age, sex, region, race, AQP4-IgG
serostatus, and EDSS) will be summarized with use of means, standard deviations, 
medians, and ranges for continuous variables and proportions for categorical variables, 
as appropriate.  Summaries will be presented for all enrolled patients.  In addition, 
descriptive summaries for the demographic and baseline characteristics at the baseline 
of the parental trials and at the time point of the first satralizumab dose for all originally 
randomized or enrolled patients will be presented.
6.5
EFFICACY ANALYSES
All efficacy analyses will be based on the ITT population and the ALLSA population. For 
both populations, data from Study WN42349 will be combined with data from the 
Studies BN40898 and BN40900.
All efficacy endpoints are secondary endpoints. The definitions are in line with 
Studies BN408989 and BN40900 to investigate long-term efficacy by summarizing the 
data of the parental studies and this Study WN42349.
Time to First Relapse
The time to first relapse (TFR) efficacy endpoint is based on several endpoint definitions 
to accommodate different estimand strategies.  The most important intercurrent event is 
the use of therapy for the treatment of an acute NMOSD relapse (rescue therapy).
For the treatment policy strategy, the use of rescue therapy is ignored. Therefore, in the 
analysis for the treatment policy estimand the TFR is defined as the time from 
randomization in ITT or first dose of satralizumab in ALLSA to the first protocol-defined 
relapse as assessed by the investigator (iPDR).
The time point of relapse onset is defined as the time at which the patient experiences 
any new or worsening neurological symptoms representing NMOSD clinical relapse(s). 
For patients who have not relapsed at the time of analysis, the TFR will be censored at 
the clinical cutoff date (CCOD) or at time of withdrawal from study. There are no other 
censoring reasons.


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For the composite strategy estimand, the use of rescue therapy (as defined in
Section 4.4.1) for the treatment of acute relapses will be considered as an event in 
addition to the iPDR. Therefore, in the analysis for the composite estimand, the TFR is 
defined as the time from randomization in ITT or first dose of satralizumab in ALLSA to 
the iPDR or first use of rescue therapy, whatever comes first. Patients are either 
censored at the CCOD or at the time of withdrawal from study if they did not have an 
iPDR or did not receive rescue therapy. There are no other censoring reasons.
In addition, four further definitions of relapse are also analyzed:

For the time to first clinical relapse, the TFR is defined as the time from 
randomization in ITT or first dose of satralizumab in ALLSA to the first clinical 
relapse. Clinical relapses are all relapses that occurred during the parental studies
or this study, even if they did not meet the PDR definition. Patients are censored at 
the CCOD or at the time of withdrawal from study if they did not have a clinical 
relapse. There are no other censoring reasons.

For the time to first treated clinical relapse, the TFR is defined as the time from 
randomization in ITT or first dose of satralizumab in ALLSA to the first treated 
clinical relapse. Treated clinical relapses are all relapses that occurred during the 
parental studies or this study and that were treated with rescue therapy. The 
relapses do not need to meet the PDR definition. Patients are censored at the 
CCOD or at the time of withdrawal from study if they did not have a treated clinical 
relapse. There are no other censoring reasons. This definition is similar to the time 
to iPDR or rescue therapy definition and another way of incorporating the 
intercurrent event of rescue therapy.

For the time to first clinical relapse with EDSS change from randomization/first dose 
of satralizumab, the TFR is defined as the time from randomization in ITT or first 
dose of satralizumab in ALLSA to the first clinical relapse that has an EDSS change 
from baseline in line with the change definition for the PDR. For the PDR definition, 
the EDSS at relapse is compared with the EDSS at the last regular visit. In this 
definition the EDSS at relapse is compared with the EDSS at the time of 
randomization in ITT or at the time of first dose of satralizumab in ALLSA. Patients 
are censored at the CCOD or at the time of withdrawal from study if they did not 
have a clinical relapse that fulfills the EDSS change criteria. There are no other 
censoring reasons.

For the time to first treated clinical relapse with EDSS change from 
randomization/first dose of satralizumab, the TFR is defined as the time from 
randomization in ITT or first dose of satralizumab in ALLSA to the first treated 
clinical relapse that has an EDSS change from baseline in line with the change 
definition for the PDR.  For the PDR definition, the EDSS at relapse is compared 
with the EDSS at the last regular visit.  In this definition the EDSS at relapse is 
compared with the EDSS at the time of randomization in ITT or at the time of first 
dose of satralizumab in ALLSA.  Patients are censored at the CCOD or at the time 
of withdrawal from study if they did not have a clinical relapse that fulfills the EDSS 
change criteria. There are no other censoring reasons.


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In the analyses from randomization, the goal is to test the equality of the TFR distribution 
in the satralizumab (SA237) and Placebo arms:
H0: TFRSA237TFRplacebo versus H1: TFRSA237 ≠ TFRplacebo
A stratified two-sided log-rank test with use of strata of study ID of the parental study and 
geographical region will be used.
The KaplanMeier method will be used to estimate the TFR distribution for each 
treatment group. The KaplanMeier curve will provide a visual description of the 
differences across treatment groups. In addition, estimates of the treatment effect will 
be expressed as HR and 95% confidence intervals (CIs) with use of a stratified study ID 
of the parental study and geographical region) Cox proportional-hazards model. The 
Median TFR is not expected to be reached in this study at the time of the primary 
analysis; hence, every 6-months, relapse-free rates and their 95% CI will be used to 
describe TFR distribution in addition to the HR. 
In the analyses from first dose of satralizumab no comparator is available to the 
satralizumab arm. Therefore only the KaplanMeier curves will be provided together
with relapse-free rates and corresponding 95% CI at every 6 months.
Annualized Relapse Rate
All relapses for each eligible patient in the parental studies and in this study will be 
recorded throughout all study periods (parent study DB and OLE periods and this study).
The ARR will be analyzed from randomization in ITT and from first dose of satralizumab 
in ALLSA. In both analyses the ARR is calculated as the total number of relapses 
experienced divided by the person-years of the whole study period. The unadjusted 
95% CI will be presented based on the Poisson distribution.
For comparing the difference between the two treatment arms, negative binomial 
regression model will be used with ARR as response variable and treatment group,
study ID of the parental study, and geographical region as covariates. In the ALLSA 
analyses, treatment group will not be included because all patients will receive 
satralizumab in this analysis.
In addition, the ARR by year of exposure will be estimated with use of a GEE Poisson 
regression model with repeated measurements and an unstructured covariance matrix, 
adjusted by Study Identifier of the parental study, and exposure year. Log-transformed 
patient years are included as an offset variable. In these analyses the overall ARR for 
the whole period is additionally estimated by a Poisson regression model. When 
comparing the difference between the randomized treatment arms of the parental 
studies, treatment is included as an additional covariate and the adjusted ARR and 
corresponding 95% Cis are presented for each arm and year.


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All ARR analyses will be conducted for iPDRs, clinical relapses and treated clinical 
relapses.
Change in Expanded Disability Status Scale Score
The EDSS score will be assessed on scheduled visits during the study. The mean 
change in EDSS scores from randomization/first dose of satralizumab to every 24 weeks 
after the randomization/first dose of satralizumab visit will be analyzed.
Time to EDSS worsening based on the definition for PDR is estimated with a Cox 
regression with treatment group, and Study Identifier of the parental study as covariates.  
The HR and 95% CI for the treatment groups are estimated in this model, the p value is 
calculated on the basis of the stratified log rank test.  In addition, Kaplan-Meier estimate 
of event-free rates will be provided for every 24 weeks and Kaplan-Meier curved will be 
estimated.
These analyses are done for the double-blind period and the combined double-blind and 
OLE periods.  When all randomized patients of both periods are analyzed together, 
patients are analyzed as randomized, even if patients randomized to placebo receive 
satralizumab in the OLE period. In addition, all patients are analyzed from first dose of 
satralizumab.  In this case, only KaplanMeier estimate of event-free rates will be 
provided for every 24 weeks and KaplanMeier curved will be estimated since no 
comparison can be made.
In the same way, time to severe EDSS worsening is analyzed. Severe EDSS worsening 
is defined as a change of at least 2 points on the EDSS scale from randomization/first 
dose of satralizumab.
Change in Visual Acuity (Snellen Chart)
Visual acuity will be measured by a Snellen 20-foot wall chart. The test will be 
performed monocularly and patients may use their habitual distance glasses or contact 
lenses.
The same visual acuity testing method is to be employed for all study visits for 
each patient.
The mean change in logMAR Visual Acuity scores from randomization/first dose of 
satralizumab to every 24 weeks after the randomization/first dose of satralizumab visit 
will be analyzed.
Use of Acute Relapse/Rescue Therapy
The use of rescue therapy is based on treated clinical relapses.  If a patient has at least 
one treated clinical relapse, then this patient is counted as a patient with rescue therapy
use.  The use of rescue therapy will be analyzed with a logistic regression model with 
treatment group, Study Identifier of the parental study and geographical region as 
covariates.  The odds ratio, corresponding 95% CI, and p value for the treatment group 


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will be reported.  This analysis will be conducted for the entire study period of each 
patient and also for the period after the first dose of satralizumab. In the analysis from 
first dose of satralizumab, treatment group will not be included as a covariate.
6.5.1
Further Analyses
6.5.1.1
Subgroup Analysis
The subgroup summary tables for TFR based on iPDRs will be presented by AQP4-IgG 
serostatus at screening (positive/negative), age (adolescents/adults) at randomization, 
geographical region (Asia, Europe, North America), weight at randomization, first dose of 
satralizumab, ARR at randomization (less than one/one/more than one), most recent 
attack at randomization (first attack vs relapse), prior therapy at randomization (B-cell 
depleting therapy/immunosuppressants/others), EDSS at randomization/first dose of 
satralizumab (2.5:  no or minimal disability/2.5), race, and Study Identifier of parental 
study. ARR was a stratification factor in Study BN40898 and is calculated on the basis 
of the relapses entered in the medical history for Study BN40900. Most recent attack 
and prior therapy were stratification factors in Study BN40900 and are only available for 
patients enrolled from this trial.
Further details will be described in the SAP.
6.6
SAFETY ANALYSES
All safety analyses will be performed on the SAF. Safety variables to be assessed are 
AEs, AESIs, SAEs, selected AEs, injection site reactions, patient withdrawals due to AEs, 
change in 12-lead ECGs, measurements of laboratory parameters, and vital signs 
(including body weight).
Summary tables for number and percentage of patients and rate of AEs per 100PY with 
adverse drug reactions (i.e., AEs related to study drug as assessed by the investigator)
will be generated.
Adverse events will be summarized by System Organ Class (SOC) and Preferred Term
(PT), on the basis of Medical Dictionary for Regulatory Activities (MedDRA) coding, and
grade of severity. The incidence of treatment emergent AEs will also be displayed by 
severity and relationship to the study drug, respectively. In addition, the incidence of 
AEs leading to withdrawal from treatment and SAEs will be tabulated.
Incidence of Selected AEs (see Section 5.2.4) will be tabulated. AEs will be further 
analyzed according to whether they meet Sampson's criteria for diagnosis of 
anaphylaxis (Sampson et al. 2006).
Laboratory values (including hematology, blood chemistry, and urinalysis), frequencies 
of laboratory abnormalities, vital signs (temperature, blood pressure, and pulse rate), 
12-lead ECG, and suicidality (C-SSRS) will be summarized. Measurement and change 
from baseline in continuous laboratory parameters (hematology, clinical chemistry, and 


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urinalysis), continuous ECG, vital signs (blood pressures and pulse rate), and body 
weight will be summarized with use of descriptive statistics. Body weight by change 
from randomization/first dose of satralizumab of more than/less than 7% and 15% will 
also be analyzed descriptively. When analyzing categorical data, the number and 
percentage of patients in each category will be presented. In addition, shift tables may 
be used to evaluate the number and percentage of patients having a different 
post-baseline status when compared with their baseline status. Numbers of patients
who meet the marked abnormality criterion will also be presented.
6.7
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES
The PK analysis population is described in Section 6.1.  The trial will evaluate the 
PK characteristics of satralizumab treatment by summary statistics and non-linear mixed 
effects analysis (population PK).
The serum concentration at each sampling timepoint will be described irrespective of 
whether patients receive acute relapse/rescue therapy, change background (baseline)
treatment for NMOSD, miss a dosing or if the study drug administration is delayed. 
Individual and mean serumconcentration-versus-time curves will be plotted.
Descriptive statistics, such as geometric mean, geometric coefficient of variance and the 
95% CI for the geometric mean for the serum satralizumab concentration, as well as 
arithmetic mean, standard deviation, median, minimum, and maximum on the measured 
serum satralizumab concentration, IL-6, sIL-6R, and CRP will be calculated by visit and 
per defined time window post-dose for the PK-PPS.
An exploratory analysis to identify any potential relationship among serum satralizumab
concentration and PD (CRP, IL-6, sIL-6R) will be performed. These results will be 
described and reported in a separate analysis report.
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 volunteers and adult/adolescent 
patients with NMOSD (Satralizumab Simulation Report; available upon request).  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 on the basis of the model.  The results of the population PK analysis will 
be reported separately from the CSR.
Further details are described in a separate Data Analysis Plan.
6.8
IMMUNOGENICITY ANALYSES
The percentage of patients who have positive or negative ADA results will be tabulated.
PK/PD, efficacy parameter and safety will be summarized by anti-drug antibody status.


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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 are ADA negative or have missing 
data at baseline but develop an ADA response following study drug exposure 
(treatment-induced ADA response), or if they are ADA positive at baseline and the titer 
of one or more post-baseline samples is greater than fourfold of the titer of the baseline 
sample (treatment-boosted 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 that is greater than fourfold than the titer of the baseline sample (treatment 
unaffected).
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
may be analyzed and reported via descriptive statistics.
6.9
BIOMARKER ANALYSES
Although no formal statistical analysis of exploratory biomarkers will be performed, data 
may be analyzed in the context of this study and in aggregate with data from other 
studies.
6.10
HEALTH STATUS UTILITY ANALYSES
Change from baseline in EQ-5D-3L health utility index-based will be calculated at 
specified timepoints.
The EQ-5D-3L is a participant-answered questionnaire measuring 5 dimensions of 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression with 
3 possible response categories: 1) no problems; 2) some problems; 3) severe problems.
Therefore, EQ-5D-3L is able to represent 243 (35) distinct health states. These states 
may then be converted into a single index value by with use of the time trade-off (TTO) 
based tariff methods. The best possible answer would be (1,1,1,1,1) and the worst 
possible answer would be (3,3,3,3,3). A shift table will be used to evaluate the number 
and percentage of patients having a different post-baseline status when compared with
their baseline status. The mean change in EQ-5D-3L score will be analyzed from 
randomization/first dose of satralizumab to every 24 weeks after the randomization/first 
dose of satralizumab visit.
I 


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6.11
INTERIM ANALYSES
No formal confirmatory effectiveness or safety interim analyses are planned.
Exploratory analyses of selected endpoints and in particular periodic analyses of safety 
data are planned to be performed during the course of the study.
6.12
HANDLING OF MISSING DATA
For TFR, patients who have not experienced relapses according to the respective 
relapse definition, the TFR will be censored at the CCOD or study withdrawal.
For all other efficacy endpoints missing data will not be imputed.
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 
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 and specialty laboratory data will 
be sent directly to the Sponsor, with use of 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 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.


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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, patient-reported outcomes, 
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.
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 data (if applicable), ICFs, 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 


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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.
Roche 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.
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 Directive (2001/20/EC)
and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor's sample ICF (and ancillary sample ICFs such as an Assent Form or 
Mobile Nursing ICF, 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 ICFs 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 ICF 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.


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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 
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 
with use of 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 ICFs, 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 


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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
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 ICF (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 9.5).
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 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 CSRs and other summary reports will be provided upon request (see 
Section 9.5).
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, ICFs, 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.  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.  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
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.


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Approximately 56 sites globally will participate to enroll approximately 127 patients.  
Enrollment will occur through an IxRS.
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in Section 4.5.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected.
9.6
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 healthcare professionals and to the public, at scientific 
congresses, in clinical trial 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 CSRs and other summary reports will be made available upon request.  For 
more information, see the Roche Global Policy on Sharing of Clinical Trials Data at the 
following Website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
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 CSR.  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.


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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.
9.7
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 (e.g., change in Medical Monitor or contact information).
10.
REFERENCES
Chihara N, Aranami T, Sato W, et al. Interleukin 6 signaling promotes anti-aquaporin 4 
autoantibody production from plasmablasts in neuromyelitis optica. Proc Natl Acad 
Sci USA 2011;108:37016.
Kishimoto T. IL-6: from its discovery to clinical applications. Int Immunol 2010; 
22:34752.
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability 
status scale (EDSS). Neurology 1983;33:144452.
Lennon VA, Kryzer TJ, Pittock SJ, et al. IgG marker of optic-spinal cord multiple 
sclerosis binds to the aquaporin-4 water channel. J Exp.Med 2005;202:4737.
Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of 
neuromyelitis optica: distinction from multiple sclerosis. Lancet 2004;364:210612.
Lin J, Li X, and Xia J. Th17 cells in neuromyelitis optica spectrum disorder: a review. Int 
J Neurosci. 2016;126:105160.
Oh J and Levy M. Neuromyelitis optica: an antibody-mediated disorder of the central 
nervous system. Neurol Res Int 2012;2012:460825.
Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the 
definition and management of anaphylaxis: summary report--Second National 
Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
Symposium. J Allergy Clin Immunol 2006;117:3917.
Takeshita Y, Obermeier B, Cotleur AC, et al. Effects of neuromyelitis optica-IgG at 
theblood-brain barrier in vitro. Neurol Neuroimmunol Neuroinflamm 2016; 4:e311.
Tanaka T and Kishimoto T. Immunotherapeutic implication of IL-6 blockade. 
Immunotherapy 2012;4:87105.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
77/Protocol WN42349, Version 1
Traboulsee A, Greenberg BM, Bennett JL, et al. Safety and efficacy of satralizumab 
monotherapy in neuromyelitis optica spectrum disorder: a randomised, 
double-blind, multicentre, placebo-controlled phase 3 trial. Lancet Neurol 
2020;19:40212.
Weinshenker BG. Neuromyelitis optica is distinct from multiple sclerosis. Arch Neurol 
2007;64:899901.
Wingerchuk DM, Banwell B, Bennett JL et al. International consensus diagnostic criteria 
for neuromyelitis optica spectrum disorders. Neurology 2015;85:177-89.
Yamamura T, Kleiter I, Fujihara K, et al.Trial of satralizumab in neuromyelitis optica 
spectrum disorder. N Engl J Med. 2019;381:211424.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
78/Protocol WN42349, Version 1
Appendix 1
Schedule of Activities
Week (Window in days)
Screening a
Treatment Period b
Safety 
follow-up 
period
BL a
Every 
4 weeksc
Every 
12 weeks
Every 
24 weeks
Delayed 
dosing d
Relapse 
assessment
Unscheduled
assessments e
End of 
treatment f
End of 
study g
While in 
parent study 
to –1
Day 1
(7)
(7)
(7)
-
-
-
-
(7)
Informed consent
x
Inclusion/exclusion 
criteria
x
x
Demographic data
x
Satralizumab injection 
(SC)
x
x h
x h
x h
x h
Body weight and height i
x
x
x
x
Physical examination
x
x
x
x
x
x
x
x
Vital signs j
x
x
x
x
x
x
x
x
ECG k
x
x
x
x
x
Pregnancy test l
x
x
x
x
x
x
Laboratory tests m
x
x
x
x
x
x
Hepatitis B viral DNA n
x
x
x
x
x
C-SSRS
x
x
x
x
x
EQ-5D
x
x
x
x
x
EDSS/FSS
x
x
x
x
x
x
Adverse events
Monitor and record throughout the study


Appendix 1: Schedule of Activities (cont.)
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
79/Protocol WN42349, Version 1
Week (Window in days)
Screening a
Treatment period b
Safety 
follow-up 
period
BL a
Every 
4 weeks c
Every 
12 weeks
Every 
24 weeks
Delayed 
dosing d
Relapse 
assessment
Unscheduled
assessments e
End of 
treatment f
End of 
study g
While in parent 
study to –1
Day1
(7)
(7)
(7)
-
-
-
-
(7)
Concomitant medications
Monitor and record throughout the study
Relapse Assessment
Monitor and record throughout the study
Visual acuity/ function o
x
x
x
x
x
PK sample
x
x
x
x
x
x
PD sample p
x
x
x
x
x
x
ADA sample
x
x
x
x
x
x
Biomarker sample q
x
x
x
x
x
x
ALPalkaline phosphatase: BLbaseline; BUNblood urea nitrogen; CKcreatine kinase; C-SSRSColumbia-Suicide Severity Rating Scale; DBPdiastolic 
blood pressure; ECGelectrocardiogram; EDSSExpanded Disability Status Scale; FSSfunctional status scale; γ-GTPgamma glutamyl transpeptidase; 
Hbhemoglobin; hCGhuman chorionic gonadotropin; HCThematocrit; HBcAbtotal hepatitis B core antibody; HBsAbantibody to hepatitis B surface antigen; 
HBVhepatitis B virus; CRPC-reactive protein; IL-6Interleukin-6; INRinternational normalized ratio; IUInternational Units; NMOSDneuromyelitis optica 
spectrum disorder; PKpharmacokinetics; PLTplatelet; sIL-6Rsoluble IL-6 receptor; SBPsystolic blood pressure; SCsubcutaneous; SFUsafety follow-up;.
a Patients ongoing on treatment with satralizumab in Studies BN40898 and BN40900 will have their study completion in Study BN40898 or BN40900 on the 
same day as the BL visit in this study to allow continuous treatment. Patients will complete the BL visit and complete the next following visit on the visit
schedule the patient was on in the parent study prior to study entry. To reduce the burden on patients and sites, the optimal timepoint to transition the 
patient is when the patient’s visit schedule in the parental study falls on either a 12 or 24 week visit.
b If patients cannot physically attend a visit at the study site, e.g. in extraordinary circumstances such as the SARS-CoV-2 (COVID-19) pandemic, all efforts 
should be made to follow up with patients around the time of the scheduled visit by phone to collect any information on safety and/or neurological worsening 
the patient might experience and to confirm patient compliance with study treatment.  Any issues occurring during the dosing period outside of the study site 
should be reported.


Appendix 1: Schedule of Activities (cont.)
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
80/Protocol WN42349, Version 1
c In accordance with local regulations, administration of satralizumab outside of the study site (home dosing) is allowed.  Patients will be followed up by study 
site personnel through phone calls to monitor compliance and perform safety assessments.
d Delayed dosing visit, in the event that the study drug cannot be administered at the scheduled visit but all other planned assessments are performed at the 
scheduled visit. Minimum dosing interval should be 14 days.
e Unscheduled assessments performed at unscheduled (non-dosing) visits will depend on the clinical need of the patient. Tests/assessments may be done 
as appropriate.
f
A treatment discontinuation (EOT) visit will be performed for patients who permanently discontinue from satralizumab treatment in this study. 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
SFU: Patients will be asked to attend an EOS Visit 12 weeks after the final dose of satralizumab to complete the safety follow up period. Patients who 
decide to continue treatment with satralizumab outside of this study will not have to complete the SFU.
h In accordance with local regulations, administration of satralizumab prefilled syringes outside of the study site (e.g., self-administration or administration by a 
caregiver after completing training, administration by the patient’s [local] general physician) will be allowed at all dosing visits in extraordinary circumstances
such as the SARS-CoV-2 (COVID-19) pandemic.
i
Body weight is to be determined to the nearest 0.1 kg.  For body weight measurements, the patient should wear clothes, without any shoes, outerwear, or 
accessories.  Height will be recorded at baseline only.
j
Body temperature, systolic and diastolic blood pressure and pulse rate are measured just before dosing and while the patient is in a seated position for at 
least 5 minutes
k ECG should be performed prior to blood draws.
l
For females of child-bearing potential urine dipstick pregnancy test [sensitivity of at least 25 mIU/mL β-hCG] will be performed.
m RBC, Hb, Ht, WBC, WBC differentiation, PLT, INR, fibrinogen, total protein, albumin, total bilirubin, ALP, AST, ALT, γ-GTP, LDH, total cholesterol, LDL, HDL, 
triglyceride, ferritin, BUN, creatinine, CK, Na, Cl, K, Ca, P, complement (CH50, C3, C4), uric acid, urinary glucose, urinary protein, urinary occult blood, 
urobilinogen. If patients cannot physically attend a visit at the study site for safety blood draw in extraordinary circumstances such as the SARS-CoV-2 
(COVID-19) pandemic, safety lab tests should be performed, in accordance with local regulations, at a local laboratory when possible and any clinically 
significant abnormal laboratory values reported as AEs in the eCRF as described in Section 5.4.
n Hepatitis B viral DNA must be monitored in patients for whom a positive result for HBsAb was not clearly associated with vaccination against hepatitis B 
virus and HBV DNA was negative at screening or for whom HBcAb was positive and HBV DNA was negative at screening in BN40898 or BN40900.
o Separate visual function testing is not required if it is implemented with FSS assessment.
p IL-6, sIL-6R, CRP
q Biomarker sample (e.g., including, but not limited to, anti-AQP4-Ab)


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
81/Protocol WN42349, Version 1
Appendix 2
EDSS/FSS Assessment Form
The actual forms will be provided to the sites and should be used for assessment.
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Appendix 2: EDSS/FSS Assessment Form (cont.)
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
82/Protocol WN42349, Version 1
 
 
 
 
 
 
 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
83/Protocol WN42349, Version 1
Appendix 3
EuroQol-5D (EQ-5D)
The actual forms will be provided to the sites and should be used for assessment.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 


Appendix 3: EuroQol-5D (EW-5D)
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
84/Protocol WN42349, Version 1
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


Appendix 3: EuroQol-5D (EW-5D)
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
85/Protocol WN42349, Version 1
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Appendix 3: EuroQol-5D (EW-5D)
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
86/Protocol WN42349, Version 1
EQ-5D questionnaire references:
Brooks R. EuroQol: the current state of play. Health Policy 1996;37:5372.
EuroQol Group. EuroQol--a new facility for the measurement of health-related 
quality of life. Health Policy 1990;16:199208.
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the 
new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011;20:172736.
Janssen MF, Pickard AS, Golicki D, et al. Measurement properties of the
EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a 
multi-country study. Qual Life Res 2013;22:171727.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
87/Protocol WN42349, Version 1
Appendix 4
C-SSRS since Last Visit
The actual forms will be provided to the sites and should be used for assessment.
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
  
  
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Appendix 4:   C-SSRS since Last Visit (cont.)
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
88/Protocol WN42349, Version 1
 
 
  
   
 
 
  
 
 
 
 
  
 
 
  
   
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
     
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
   
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Appendix 4:   C-SSRS since Last Visit (cont.)
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
89/Protocol WN42349, Version 1
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
   
  
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Appendix 4:   C-SSRS since Last Visit (cont.)
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
90/Protocol WN42349, Version 1