Clinical trial NCT02073279
Conditions: Neuromyelitis Optica (NMO) NMO Spectrum Disorder (NMOSD)
Sponsor: Hoffmann-La Roche
Start date: 2014-08-05; Completion date: 2022-01-31
Enrollment: 95 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objectives of this study are to evaluate the efficacy, safety, pharmacodynamic, pharmacokinetic and immunogenic profiles of satralizumab in participants with NMO and NMOSD.

Detailed description:

Arms: arm 1: Participants randomized to this arm for the double-blind period will receive satralizumab monotherapy. The double-blind period for the participant ends either when the participant experiences a Clinical Endpoint Committee (CEC) confirmed protocol-defined relapse, the total number of CEC confirmed protocol-defined relapses reaches 44, or 1.5 years after the last patient was randomized. In the open-label extension period, the participant will receive satralizumab SC injection at Weeks 0, 2, and 4, and Q4W thereafter, up to the end of the study. arm 2: Participants randomized to this arm for the double-blind period will receive placebo monotherapy. The double-blind period for the participant ends either when the participant experiences a Clinical Endpoint Committee (CEC) confirmed protocol-defined relapse, the total number of CEC confirmed protocol-defined relapses reaches 44, or 1.5 years after the last patient was randomized.. In the open-label extension period, the participant will receive satralizumab SC injection at Weeks 0, 2, and 4, and Q4W thereafter, up to the end of the study.
Interventions: intervention 1: Satralizumab intervention 2: Placebo
Intervention descriptions: intervention 1: Satralizumab will be administered subcutaneously (SC) at Weeks 0, 2, and 4, and thereafter once every 4 weeks (Q4W). intervention 2: Placebo will be administered subcutaneously (SC) at Weeks 0, 2, and 4, and thereafter once every 4 weeks (Q4W).

Protocol documents:
Prot_000.pdf: 
 
Official Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 
3 Study to Evaluate the Efficacy and Safety, of Satralizumab (SA237) 
as Monotherapy in Patients With Neuromyelitis Optica (NMO) and 
Neuromyelitis Optica Spectrum Disorder (NMOSD) 
NCT Number: NCT02073279 
Document Date: Protocol Version 10: 03-April-2020 
 
 


PROTOCOL AMENDMENT 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.
* 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 BN40900 (SA-309JG), Version 10
PROTOCOL
TITLE:
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND,
PLACEBO-CONTROLLED, PHASE 3 STUDY TO 
EVALUATE THE EFFICACY AND SAFETY, OF 
SATRALIZUMAB (SA237) AS MONOTHERAPY IN 
PATIENTS WITH NEUROMYELITIS OPTICA (NMO) AND 
NEUROMYELITIS OPTICA SPECTRUM DISORDER 
(NMOSD)
PROTOCOL NUMBER: BN40900 (SA-309JG)
VERSION NUMBER:
10
EUDRACT NUMBER:
2015-005431-41
IND NUMBER:
118183
TEST PRODUCT:
Satralizumab (SA237) (RO5333787)
MEDICAL MONITOR:
, M.D.
CO-SPONSORS:
F. Hoffmann-La Roche Ltd
Chugai Pharmaceutical Co. Ltd. *
DATE FINAL:
Version 1.0:  14 November 2013
DATES AMENDED:
Version 2.0:  18 February 2014
Version 3.0:  26 May 2014
Version 4.0:  2 September 2014
Version 5.0:  5 November 2015
Version 6.0:  1 March 2016
Version 6.1AB (Korea, Ukraine, Bulgaria, Others):  23 March 2016
Version 7.0:  13 July 2017
Version 7.1AB (Korea, Ukraine, Bulgaria, Others):  13 July 2017
Version 8.0:  14 June 2018
Version 8.1AB (Korea, Ukraine, Bulgaria, Others):  14 June 2018
Version 8.2AB (Korea, Ukraine, Bulgaria):  25 October 2018
Version 9:  5 March 2019
Version 10:  See electronic date stamp below.
 
03-Apr-2020 23:11:18
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd 
2/Protocol BN40900 (SA-309JG), Version 10 
 
PROTOCOL AMENDMENT, VERSION 10: 
RATIONALE 
Protocol BN40900 (SA-309JG) has been amended to reflect a change in Sponsor for 
South Korea and to increase the duration of the open-label extension (OLE) period until 
31 December 2021. In addition, specific measures were implemented to allow 
continuation of treatment and ensure patients’ safety during the SARS-CoV-2 
(COVID-19) pandemic. 
Changes to the protocol for all sites, along with a rationale for each change, are 
summarized below: 
• 
The open-label extension treatment period has been extended up to 31 December 
2021.  The management of neuromyelitis optica spectrum disorder (NMOSD) with 
satralizumab requires long-term treatment.  Extending the OLE treatment period to 
the end of December 2021 will ensure the continuation of treatment and provide 
additional long-term safety and efficacy data (Sections 1.3, 3.1.1, 4.3.2.2, and 
4.5.2.2). 
• 
The risks for satralizumab were updated based on the current available clinical trial 
data with satralizumab (Section 5.1).   
• 
F. Hoffmann-La Roche Ltd has taken over the future development of study drug 
satralizumab (SA237) in South Korea from Chugai Pharmaceutical Co., Ltd. 
(Chugai). Chugai will remain the Sponsor in Taiwan and Japan (Section 9.3).   
• 
Specific measures during emergency situations such as the SARS-CoV-2 
(COVID-19) pandemic were added to ensure treatment continuation and patient 
safety (Sections 4.3.2.2, 4.3.3, 4.5.1.10, 4.5.2.2, 4.5.3.2, and 5.1.1.7, and Appendix 
1, Table 8): 
– 
In the open-label extension period after Week 48, 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, 
home administration by a mobile nurse) will be allowed. 
– 
If patients cannot physically attend a visit at the study site for safety blood draw, 
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 adverse events (AEs) in the eCRF. 
– 
All efforts should be made to follow up with patients around the time of the 
scheduled visit by phone if they cannot physically attend a visit at the study site 
to collect any information on safety and/or neurological worsening the patient 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
3/Protocol BN40900 (SA-309JG), Version 10
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.

Following the implementation of Protocol Version 10 and in accordance with local 
regulations, administration of satralizumab outside of the study site may be allowed
to reduce the burden on patients traveling to study sites at defined visits. Patients 
will be followed up by study site personnel through phone calls (Sections 4.3.2.2, 
4.3.3, 4.5.2.2, and 5.1.1.7, and Appendix 1, Table 8). 
The following additional clarifications have also been made:

Medical History will include the first attack and date of diagnosis of neuromyelitis 
optica (NMO) or NMOSD to further characterize the enrolled patient population 
(Section 4.5.1.1).

Due to drifts in the Anti-AQP4 antibody cell-based assay over time confounding 
longitudinal assessment of anti-AQP4 antibody titers, samples will be analyzed by 
ELISA (Sections 4.5.3.2 and 6.7, and Appendix 1, Table 6).

Language has been added to clarify permitted and prohibited medications during the 
OLE period (Sections 4.4.1 and 4.4.2).

Patients who do not meet the criteria for childbearing potential during the OLE
period of the study (e.g., confirmed post-menopausal status) will not require further 
pregnancy testing (Section 4.5.1.10).

Patients who complete the OLE period with the last study drug administration on or 
before 31 December 2021 and decide to continue treatment with satralizumab
outside of this study will not have to complete the Last Observation Visit (Section 
4.5.2.3).

Reporting requirements for pregnancies in female patients have been clarified and 
aligned with the reporting requirements for pregnancies in female partners of male 
patients (Section 5.4.3.1).

The statistical considerations section has been updated to provide information on 
efficacy analyses done for the OLE period (Section 6).
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
4/Protocol BN40900 (SA-309JG), Version 10
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11
PROTOCOL SYNOPSIS .................................................................................... 12
1.
INTRODUCTION ........................................................................................ 22
1.1
Background on Neuromyelitis Optica (NMO) and 
Neuromyelitis Optica Spectrum Disorder 
(NMOSD)............................................................................... 22
1.1.1
Introduction to NMO and NMOSD ......................................... 22
1.1.2
Interleukin 6 as a Target Molecule for the 
Treatment of NMO and NMOSD............................................ 23
1.2
Background on Satralizumab................................................. 24
1.3
Study Rationale and Benefit–Risk Assessment..................... 26
2.
OBJECTIVES.............................................................................................. 28
2.1
Efficacy Objective .................................................................. 28
2.2
Safety Objective .................................................................... 29
2.3
Pharmacodynamic Objective................................................. 29
2.4
Pharmacokinetic Objective .................................................... 29
2.5
Immunogenicity Objective...................................................... 29
3.
STUDY DESIGN......................................................................................... 30
3.1
Description of Study .............................................................. 30
3.1.1
Overview................................................................................ 30
3.1.2
Investigational Patients and Sites.......................................... 31
3.1.3
Independent Data Monitoring Committee .............................. 31
3.1.4
Clinical Endpoint Committee (CEC)....................................... 31
3.2
Rationale for Study Design.................................................... 34
3.2.1
Rationale for Choice of Study Design Elements.................... 34
3.2.2
Rationale for Time to First Relapse Endpoint ........................ 34
3.2.3
Rationale for Test Product Dosage........................................ 35
3.2.4
Justification for Upper Age Limit............................................ 37
3.2.5
Justification for Placebo-Controlled Trial ............................... 37
3.3
Study Endpoints/Outcome Measures .................................... 39
3.3.1
Efficacy Outcome Measures.................................................. 39


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
5/Protocol BN40900 (SA-309JG), Version 10
3.3.1.1
Primary Endpoint................................................................... 39
3.3.1.2
Secondary Endpoints ............................................................ 39
3.3.2
Safety Outcome Measures .................................................... 39
3.3.3
Exploratory Endpoints ........................................................... 39
3.3.4
Pharmacodynamic Outcome Measures................................. 39
3.3.5
Pharmacokinetic Outcome Measures.................................... 40
3.3.6
Immunogenicity Outcome Measures ..................................... 40
4.
MATERIALS AND METHODS .................................................................... 40
4.1
Patients.................................................................................. 40
4.1.1
Inclusion Criteria.................................................................... 40
4.1.2
Exclusion Criteria................................................................... 41
4.2
Method of Treatment Assignment and Blinding..................... 42
4.3
Study Treatment.................................................................... 45
4.3.1
Formulation, Packaging and Handling................................... 45
4.3.1.1
Satralizumab and Placebo..................................................... 45
4.3.2
Dosage, Administration, and Compliance.............................. 46
4.3.2.1
Satralizumab and Placebo: Double-Blind Period................... 46
4.3.2.2
Satralizumab: Extension Period............................................. 47
4.3.3
Investigational Medicinal Product Accountability ................... 47
4.4
Concomitant Therapy ............................................................ 48
4.4.1
Major Permitted Therapies for NMO...................................... 49
4.4.2
Prohibited Therapy ................................................................ 49
4.5
Study Assessments ............................................................... 50
4.5.1
Description of Study Assessments ........................................ 50
4.5.1.1
Medical History and Demographic Data ................................ 50
4.5.1.2
Hepatitis B Screening ............................................................ 50
4.5.1.3
Hepatitis C Screening............................................................ 51
4.5.1.4
Screening for Tuberculosis.................................................... 51
4.5.1.5
Magnetic Resonance Imaging ............................................... 51
4.5.1.6
Vital Signs.............................................................................. 51
4.5.1.7
Physical Examination ............................................................ 51
4.5.1.8
Efficacy Assessments............................................................ 52


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
6/Protocol BN40900 (SA-309JG), Version 10
4.5.1.9
Columbia-Suicide Severity Rating Scale 
(C-SSRS)............................................................................... 55
4.5.1.10
Laboratory Assessments ....................................................... 56
4.5.1.11
Electrocardiograms................................................................ 58
4.5.1.12
Adverse Events ..................................................................... 59
4.5.2
Timing of Study Assessments ............................................... 59
4.5.2.1
Screening Assessments ........................................................ 59
4.5.2.2
Assessments During Treatment ............................................ 60
4.5.2.3
Assessments at Last Observation 
Visit/Withdrawal Visit ............................................................. 61
4.5.2.4
Follow-Up Assessments ........................................................ 61
4.5.2.5
Assessments at Extra Visits due to Relapse ......................... 62
4.5.2.6
Unscheduled Visits ................................................................ 62
4.5.3
Study Schedule ..................................................................... 62
4.5.3.1
Screening Period (Day -27 to 0 [Week -4  to -1])................... 62
4.5.3.2
Treatment Period................................................................... 63
4.6
Chugai Clinical Sample Repository (CCSR).......................... 87
4.6.1
Schedule of Assessments and Procedures ........................... 88
4.6.1.1
Study Procedures.................................................................. 88
4.6.1.2
Sampling Procedures ............................................................ 88
4.6.1.3
CCSR .................................................................................... 89
4.6.1.4
Biomarker Research Analysis Protocol ................................. 89
4.6.2
Sample Confidentiality and Sample Destruction.................... 89
4.6.3
Withdrawal of Patients from the CCSR Project...................... 89
4.6.4
Benefits to Donors................................................................. 90
4.7
Patient, Study and Site Discontinuation................................. 90
4.7.1
Patient Discontinuation.......................................................... 90
4.7.1.1
Discontinuation of Study Treatment....................................... 91
4.7.1.2
Withdrawal from Study........................................................... 92
4.7.2
Study and Site Discontinuation.............................................. 92
5.
ASSESSMENT OF SAFETY....................................................................... 92
5.1
Safety Plan ............................................................................ 92
5.1.1
Important Identified and Potential Risks of 
Satralizumab.......................................................................... 92


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
7/Protocol BN40900 (SA-309JG), Version 10
5.1.1.1
Serious infection.................................................................... 93
5.1.1.2
Neutropenia and Potential Risk of Infection........................... 94
5.1.1.3
Thrombocytopenia and Potential Risk of 
Bleeding................................................................................. 95
5.1.1.4
Liver Enzyme and Bilirubin Elevations and 
Potential Risk of Hepatotoxicity ............................................. 96
5.1.1.5
Elevated Lipid Levels and Potential Risk of 
Cardiovascular/Cerebrovascular Events ............................... 97
5.1.1.6
Immunogenicity ..................................................................... 98
5.1.1.7
Serious Hypersensitivity Reactions ....................................... 98
5.1.1.8
CYP450 Enzyme Normalization ............................................ 99
5.1.1.9
Complications of Diverticulitis................................................ 99
5.1.1.10
Malignancies........................................................................ 100
5.1.1.11
Demyelinating Disorders...................................................... 100
5.1.2
Other Information................................................................. 100
5.2
Safety Parameters and Definitions ...................................... 101
5.2.1
Adverse Events ................................................................... 101
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 102
5.2.3
Non-serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) ............................ 103
5.2.4
Selected Adverse Events..................................................... 103
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 103
5.3.1
Adverse Event Reporting Period ......................................... 103
5.3.2
Eliciting Adverse Event Information..................................... 104
5.3.3
Assessment of Severity of Adverse Events ......................... 104
5.3.4
Assessment of Causality of Adverse Events ....................... 104
5.3.5
Procedures for Recording Adverse Events.......................... 105
5.3.5.1
Diagnosis versus Signs and Symptoms .............................. 105
5.3.5.2
Adverse Events Occurring Secondary to Other 
Events.................................................................................. 105
5.3.5.3
Persistent or Recurrent Adverse Events.............................. 106
5.3.5.4
Abnormal Laboratory Values ............................................... 106
5.3.5.5
Abnormal Vital Sign Values ................................................. 107


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
8/Protocol BN40900 (SA-309JG), Version 10
5.3.5.6
Abnormal Liver Function Tests............................................ 108
5.3.5.7
Deaths ................................................................................. 108
5.3.5.8
Preexisting Medical Conditions............................................ 109
5.3.5.9
Lack of Efficacy or Worsening of NMO................................ 109
5.3.5.10
Hospitalization or Prolonged Hospitalization........................ 109
5.3.5.11
Overdoses ........................................................................... 110
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 110
5.4.1
Emergency Medical Contacts.............................................. 111
5.4.2
Reporting Requirements for Serious Adverse 
Events and Non-serious Adverse Events of 
Special Interest.................................................................... 111
5.4.3
Reporting Requirements for Pregnancies............................ 111
5.4.3.1
Pregnancies in Female Patients.......................................... 111
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 112
5.4.3.3
Abortions ............................................................................. 112
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 112
5.4.4
Reporting Requirements for Medical Device 
Complaints........................................................................... 112
5.5
Follow-Up of Patients after Adverse Events ........................ 113
5.5.1
Investigator Follow-Up......................................................... 113
5.6
Post-Study Adverse Events................................................. 113
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 114
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 114
6.1
Analysis Populations ........................................................... 114
6.1.1
Efficacy Analysis Populations.............................................. 114
6.1.2
All-Patients-Treated Population........................................... 115
6.1.3
Safety Analysis Populations ................................................ 115
6.1.4
Pharmacokinetics Per-Protocol Set and 
Pharmacodynamics Analysis Population............................. 115
6.2
Determination of Sample Size ............................................. 115
6.3
Summary of Conduct of Study............................................. 116
6.4
Summary of Treatment Group Comparability ...................... 117


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
9/Protocol BN40900 (SA-309JG), Version 10
6.5
Efficacy Analyses ................................................................ 117
6.5.1
Primary Efficacy Endpoint.................................................... 117
6.5.2
Secondary Efficacy Endpoints............................................. 118
6.5.3
Further Analysis................................................................... 122
6.5.3.1
Sensitivity Analysis for Primary Endpoint............................. 122
6.5.3.2
Sensitivity Analysis for Key Secondary Endpoint................. 122
6.5.3.3
Subgroup Analysis............................................................... 122
6.6
Safety Analyses................................................................... 122
6.7
Pharmacokinetic/Pharmacodynamics Analyses .................. 123
6.8
Immunogenicity ................................................................... 124
6.9
Handling Missing Data......................................................... 124
7.
DATA COLLECTION AND MANAGEMENT ............................................. 124
7.1
Data Quality Assurance....................................................... 124
7.2
Electronic Case Report Forms............................................. 125
7.3
Source Data Documentation................................................ 125
7.4
Use of Computerized Systems ............................................ 126
7.5
Retention of Records........................................................... 126
8.
ETHICAL CONSIDERATIONS.................................................................. 127
8.1
Compliance with Laws and Regulations .............................. 127
8.2
Informed Consent................................................................ 127
8.3
Institutional Review Board or Ethics Committee.................. 128
8.4
Confidentiality...................................................................... 128
8.5
Financial Disclosure ............................................................ 129
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 129
9.1
Study Documentation .......................................................... 129
9.2
Site Inspections ................................................................... 129
9.3
Administrative Structure....................................................... 129
9.4
Publication of Data and Protection of Trade 
Secrets ................................................................................ 130
9.5
Protocol Amendments ......................................................... 130
10. REFERENCES ......................................................................................... 131


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
10/Protocol BN40900 (SA-309JG), Version 10
LIST OF TABLES
Table 1
Maximum Blood Volumes ........................................................... 58
Table 2
Neutropenia Risk Mitigation ........................................................ 95
Table 3
Thrombocytopenia Risk Mitigation.............................................. 96
Table 4
Hepatic Enzyme Risk Mitigation.................................................. 97
Table 5
Adverse Event Severity Grading............................................... 104
Table 6
Observation and Test Schedule in the Double-Blind Period ..... 133
Table 7
Observation and Test Schedule in the Extension Period 
(Week 0 – Week 48) ................................................................. 139
Table 8
Observation and Test Schedule in the Extension Period 
(After Week 48)......................................................................... 142
LIST OF FIGURES
Figure 1
Study Design............................................................................... 31
Figure 2
Assessment of Relapse .............................................................. 33
LIST OF APPENDICES
Appendix 1
Schedule of Assessments......................................................... 133
Appendix 2
EDSS/FSS Assessment Form .................................................. 145
Appendix 3
SF-36 Questionnaire................................................................. 150
Appendix 4
Visual Analogue Scale for Pain................................................. 151
Appendix 5
FACIT-Fatigue Scale ................................................................ 152
Appendix 6
Modified Rankin Scale .............................................................. 153
Appendix 7
Zarit Burden Interview............................................................... 154
Appendix 8
EuroQol-5D (EQ-5D)................................................................. 156
Appendix 9
CCSR Subject Withdrawal Form............................................... 159
Appendix 10
C-SSRS at Baseline.................................................................. 161
Appendix 11
C-SSRS since Last Visit ........................................................... 164
Appendix 12
Instruction for Tuberculosis (TB) Screening and Treatment...... 167


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
11/Protocol BN40900 (SA-309JG), Version 10
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND,
PLACEBO-CONTROLLED, PHASE 3 STUDY TO 
EVALUATE THE EFFICACY AND SAFETY, OF 
SATRALIZUMAB (SA237) AS MONOTHERAPY IN 
PATIENTS WITH NEUROMYELITIS OPTICA (NMO)
AND NEUROMYELITIS OPTICA SPECTRUM 
DISORDER (NMOSD)
PROTOCOL NUMBER:
BN40900 (SA-309JG)
VERSION NUMBER:
10
EUDRACT NUMBER:
2015-005431-41
IND NUMBER:
118183
TEST PRODUCT:
Satralizumab (SA237) (RO5333787)
MEDICAL MONITOR:
, M.D.
CO-SPONSORS:
F. Hoffmann-La Roche Ltd
Chugai Pharmaceutical Co. Ltd.
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the original 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
12/Protocol BN40900 (SA-309JG), Version 10
PROTOCOL SYNOPSIS
TITLE:
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, PHASE 3 STUDY TO EVALUATE THE EFFICACY 
AND SAFETY, OF SATRALIZUMAB (SA237) AS MONOTHERAPY 
IN PATIENTS WITH NEUROMYELITIS OPTICA (NMO) AND 
NEUROMYELITIS OPTICA SPECTRUM DISORDER (NMOSD)
PROTOCOL NUMBER:
BN40900 (SA-309JG)
VERSION NUMBER:
10
EUDRACT NUMBER:
2015-005431-41
IND NUMBER:
118183
TEST PRODUCT:
Satralizumab (SA237) (RO5333787)
PHASE:
Phase III
INDICATION:
Neuromyelitis optica and neuromyelitis optica spectrum disorder
CO-SPONSORS:
F. Hoffmann-La Roche Ltd
Chugai Pharmaceutical Co. Ltd.
Objectives
Primary Objective
The primary objective for this study is as follows:

To evaluate the efficacy and safety of satralizumab (also known as SA237) monotherapy in 
patients with neuromyelitis optica (NMO) and neuromyelitis optica spectrum disorder 
(NMOSD).
Study Design
Description of Study
This is a multicenter randomized, double-blind, placebo-controlled, parallel assignment study 
followed by an open-label extension period. Patients will be randomized to two groups 
(2:1, Group A or B) and will receive subcutaneous (SC) satralizumab 120 mg (Group A) or 
placebo (Group B) at weeks 0, 2 and 4, and every 4 weeks (Q4W) thereafter. The 
randomization will be stratified by prior therapy for prevention of NMO/NMOSD attack (B-cell 
depleting therapy or immunosuppressants/others) and the most recent attack in the last one 
year prior to screening (first attack or relapse). Patients who complete the double-blind period or 
experience a protocol-defined relapse which is adjudicated by Clinical Endpoint Committee 
(CEC) in the double-blind period can enter the open-label extension period and will receive 
subcutaneous satralizumab. In the extension period, patients can receive open-label treatment 
with 120 mg satralizumab SC at Weeks 0, 2 and 4 and Q4W thereafter, with the last study 
drug administration on or before 31 December 2021. For patients who experienced a protocol-
defined relapse which is adjudicated by CEC, satralizumab should start in the stable disease 
condition (Day 31 or later, where Day 1 is defined as the day of onset of a protocol-defined 
relapse which is adjudicated by CEC). For patients who completed the double-blind period, 
satralizumab should start after 4 weeks from the last dosing in the double-blind period.




Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
14/Protocol BN40900 (SA-309JG), Version 10
Exclusion Criteria Related to Previous or Concomitant Therapy:
2.
Any previous treatment with interleukin 6 (IL-6) inhibitory therapy (e.g., tocilizumab), 
alemtuzumab, total body irradiation or bone marrow transplantation at any time.
3.
Any previous treatment with anti-CD20, eculizumab, anti-BLyS monoclonal antibody 
(e.g., belimumab), any other treatment for prevention of multiple sclerosis (MS) relapse (e.g.,
interferon, natalizumab, glatiramer acetate, fingolimod, teriflunomide or dimethyl fumarate) 
within 6 months prior to baseline.
4.
Any previous treatment with anti-CD4, cladribine, cyclophosphamide or mitoxantrone within 
2 years prior to baseline.
5.
Treatment with any investigational agent within 3 months prior to baseline.
Exclusions for General Safety:
6.
Pregnancy or lactation.
7.
For patients of reproductive potential, a positive result from a serum pregnancy test at 
screening, or not willing to use reliable means of contraception (physical barrier [patient or 
partner] in conjunction with a spermicidal product, contraceptive pill, patch, injectables, 
intrauterine device or intrauterine system) during the treatment period and for at least 
3 months after the last dose of study drug.
8.
Any surgical procedure (except for minor surgeries) within 4 weeks prior to baseline.
9.
Evidence of other demyelinating disease or progressive multifocal leukoencephalopathy 
(PML).
10. Evidence of serious uncontrolled concomitant diseases that may preclude patient 
participation, as described;
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.
11. Known active infection (excluding fungal infections of nail beds or caries dentium) within 
4 weeks prior to baseline.
12. Evidence of chronic active hepatitis B or C.
13. History of drug or alcohol abuse within 1 year prior to baseline.
14. History of diverticulitis that, in the Investigator’s opinion, may lead to increased risk of 
complications such as lower gastrointestinal perforation.
15. Evidence of active tuberculosis (excluding patients receiving chemoprophylaxis for latent 
tuberculosis infection).
16. Evidence of active interstitial lung disease.
17. Receipt of any live or live attenuated vaccine within 6 weeks prior to baseline.
18. History of malignancy within the last 5 years, including solid tumors, hematologic 
malignancies and in situ carcinoma (except basal cell and squamous cell carcinomas of the 
skin, or in situ carcinoma of the cervix uteri that have been completely excised and cured).
19. History of severe allergic reaction to a biologic agent (e.g., shock, anaphylactic reactions).


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
15/Protocol BN40900 (SA-309JG), Version 10
20. Active suicidal ideation within 6 months prior to screening, or history of suicide attempt within 
3 years prior to screening.
21. History of Stevens-Johnson syndrome.
Laboratory Exclusion criteria (at screening):
22. Following laboratory abnormalities at screening*. 
a.
White blood cells < 3.0 x103/μL
b.
Absolute neutrophil count < 2.0 x 103/μL 
c.
Absolute lymphocyte count < 0.5 x 103/μL
d.
Platelet count < 10 x 104/μL
e.
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 1.5 times the 
upper limit of normal.
* If retest is conducted, the last value of retest before randomization must meet study criteria.
Length of Study
The end of the double-blind period is defined as the date of primary analysis when the total 
number of relapses reaches 44 or 1.5 years after the date of randomization of the last patient 
enrolled, whichever comes first. The extension period is expected to last until the Last 
Observation Visit.
End of Study
The end of the study is defined as the date when the last patient’s last visit occurs; this is 
expected to be 12 weeks after the last dosing in the extension period.
Efficacy Outcome Measures
Primary endpoint
i.
Time to first protocol-defined relapse (TFR) in the double-blind period
Secondary endpoints
i.
Change in Visual Analogue Scale (VAS) score for pain
ii.
Change in Functional Assessment Of Chronic Illness Therapy (FACIT) Fatigue score
iii.
Change in Short Form Generic Health Survey (SF-36) score
iv.
Change in EQ-5D score
v.
Change in Timed 25-Foot Walk (T25W)
vi.
The proportion of relapse-free patients
vii.
Annualized relapse rate (ARR)
viii.
Change in modified Rankin Scale (mRS) score
ix.
Change in Zarit Burden Interview (ZBI) score
x.
Change in EDSS scores
xi.
Change in visual acuity (Snellen chart)
xii.
Change in low-contrast visual acuity (low-contrast Sloan letter chart [LCSLC])
Exploratory endpoint
i.
MRI scans of the brain, optic nerve and spinal cord
MRI for exploratory evaluation is optional and will be conducted at selected sites.


 
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd 
16/Protocol BN40900 (SA-309JG), Version 10 
Safety Outcome Measures 
i. 
Incidence and severity of adverse events (AE), serious AEs (SAEs) and AEs of special 
interest (AESIs). 
ii. 
Vital signs (temperature, systolic and diastolic blood pressure and pulse rate), physical 
examination, clinical laboratory tests (hematology, chemistry, and urinalysis), 12-lead 
electrocardiogram (ECG), suicidality (Columbia-Suicide Severity Rating Scale [C-SSRS]). 
 
Pharmacokinetic/Pharmacodynamic Outcome Measures  
i. 
Serum satralizumab concentration, IL-6, soluble IL-6 receptor (sIL-6R), high sensitivity 
C-reactive protein (hsCRP), anti-AQP4 antibody, plasmablast 
 
Immunogenicity Outcome Measures  
i. 
Incidence of anti-drug antibodies 
ii. 
PK, PD, clinical response, and safety during the study by anti-drug antibody status 
 
Investigational Medicinal Products 
Test Product 
Satralizumab 120 mg/mL 
Dose and Mode of Administration: 120 mg SC at Weeks 0, 2 and 4, and Q4W thereafter in the 
double-blind period and extension period, respectively. 
Comparator 
Placebo 
Dose and Mode of Administration: Single-dose of placebo SC at Weeks 0, 2 and 4, and Q4W 
thereafter in the double-blind period. 
Concomitant medication/therapy for NMO and NMOSD 
Permitted medication/therapy  
Double-blind period 
1. Rescue therapy for clinical relapse; pulse IV corticosteroids, oral corticosteroids for tapering, 
intravenous immunoglobulin (IVIG) and/or apheresis (including plasma exchange and 
plasmapheresis) 
2. Pain medications (including but not limited to pregabalin, gabapentin, carbamazepine, 
clonazepam, duloxetine, tramadol/acetaminophen). 
Starting of pain medications is permitted; however, the dose should be stable during the 
double-blind period. In case pain control is insufficient, dose increase or change of pain 
medication is permitted. Dose decrease and temporary treatment suspension are permitted 
for only safety reasons. 
 
Extension period 
1. Rescue therapy for clinical relapse; pulse IV corticosteroids, oral corticosteroids for tapering, 
IVIG and/or apheresis (including plasma exchange and plasmapheresis) 
2. Pain medications (including but not limited to pregabalin, gabapentin, carbamazepine, 
clonazepam, duloxetine, tramadol/acetaminophen) 
 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
17/Protocol BN40900 (SA-309JG), Version 10
Statistical Methods
Primary Analysis
A stratified two-sided log-rank test using strata of prior therapy for prevention of NMO/NMOSD 
attack (B-cell depleting therapy or immunosuppressants/others) and the most recent attack in 
the last one year prior to screening (first attack or relapse) will be used. The Kaplan-Meier 
method will be used to estimate the TFR in the double-blind period distribution for each 
treatment group. Relapse-free rates and their 95% confidence intervals (CI), in addition to the 
hazard ratio, will be used every 6 months to describe TFR distribution.
Determination of Sample Size
The sample size considerations are based on the following assumptions: (1) A two-sided 
log-rank test; (2) At least 80% power at the 5% significance level; (3) The hazard ratio of 
satralizumab over placebo for an initial 2 months from randomization is 1.0. The hazard ratio
after an initial 2 months from randomization is 0.25; (4) TFR in the placebo arm following an
exponential distribution, with hazard rate for 1 year h(t) 1.1295; (5) A 2-year dropout rate 
of 10%.
Based on these assumptions, 44 TFR events are needed for the primary analysis. The 
90 patients enrolled over 33 months and followed an additional 5 months will provide 
44 TFR events.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
18/Protocol BN40900 (SA-309JG), Version 10
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADA
Anti-Drug (Satralizumab) Antibodies
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
ANCOVA
Analysis of Covariance
AQP4
Aquaporin-4
ARR
Annualized Relapse Rate
AST
Aspartate Aminotransferase
AUC
Area Under The Serum Concentration-time Curve
BAFF
B-cell Activating Factor
BOCF
Baseline Observation Carried Forward
BUN
Blood Urea Nitrogen
Ca
Calcium
CCSR
Chugai Clinical Sample Repository
CD
Cluster of Differentiation
CEC
Clinical Endpoint Committee
CK
Creatinine Kinase
Cl
Chloride
CL/F
Clearance
CNS
Central Nervous System
CRO
Contract Research Organization
CRP
C-reactive Protein
CSF
Cerebrospinal Fluid
C-SSRS
Columbia-Suicide Severity Rating Scale
Ctrough
Average Trough Serum Concentration
DBP
Diastolic Blood Pressure
DNA
Deoxyribose Nucleic Acid
DOW
Dose Outside The Visit Window
EC
European Commission
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EDSS
Expanded Disability Status Scale
ELISA
Enzyme Linked Immunosorbent Assay


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
19/Protocol BN40900 (SA-309JG), Version 10
Abbreviation
Definition
EQ-5D
EuroQol
EU
European Union
FACIT
Functional Assessment of Chronic Illness Therapy
FDA
Food and Drug Administration
Fc
Fragment Crystallizable
FPI
First Patient In
FSS
Functional System Score
GCP
Good Clinical Practice
γ-GTP
Gamma Glutamyl Transpeptidase
Hb
Hemoglobin
HBcAb
Total Hepatitis B Core Antibody
HbsAb
Antibody To Hepatitis B Surface Antigen
HbsAg
Hepatitis B Surface Antigen
HCVab
Hepatitis C Virus Antibody
HBV
Hepatitis B virus
β-hCG
Beta Human Chorionic Gonadotropin
HCT
Hematocrit
HDL
High Density Lipoprotein
HIPAA
Health Insurance Portability and Accountability Act
hsCRP
High Sensitivity C-Reactive Protein
ICF
Informed Consent Form
ICH
International Conference On Harmonisation
ID
Identification (number)
IDCC
Independent Data Coordinating Center
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IFN
Interferon
IgG
Immunoglobulin G
IL-6
Interleukin-6
IL-6R
Interleukin-6 Receptor
IMP
Investigational Medicinal Product
IND
Investigational New Drug
INR
International Normalized Ratio
IRB
Institutional Review Board
IRR
Injection-related Reaction


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
20/Protocol BN40900 (SA-309JG), Version 10
Abbreviation
Definition
IST
Immunosuppressive Therapy
ITT
Intent-To-Treat
IV
Intravenous(ly)
IVIG
Intravenous Immunoglobulin
IxRS
Interactive Voice or Web Response System
K
Potassium
LCSLC
Low-contrast Sloan Letter Chart
LDH
Lactate Dehydrogenase
LDL
Low Density Lipoprotein
LPLV
Last Patient Last Visit
MMRM
Mixed-effects Model Repeated Measures
MRI
Magnetic Resonance Imaging
mRS
Modified Rankin Scale
MS
Multiple Sclerosis
Na
Sodium
NMO
Neuromyelitis Optica
NMOSD
Neuromyelitis Optica Spectrum Disorder
NSD
Needle Safety Device
OLE
Open-Label Extension
P
Phosphorous
PD
Pharmacodynamic
PDR
Protocol Defined Relapse
PFS
Prefilled Syringe
PK
Pharmacokinetic
PK-PPS
Pharmacokinetic Per-Protocol Set
PML
Progressive Multifocal Leukoencephalopathy
PLT
Platelets
PPS
Per-Protocol Set
Q4W
Every 4 Weeks
QTcF
QT Interval Corrected For Heart Rate using Fridericia’s 
Formula
RA
Rheumatoid Arthritis
RBC
Red Blood Cell(s)
RNA
Ribonucleic Acid
SAE
Serious Adverse Event
SAF
Safety Population
SAP
Statistical Analysis Plan


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
21/Protocol BN40900 (SA-309JG), Version 10
Abbreviation
Definition
SBP
Systolic Blood Pressure
SC
Subcutaneous (Ly)
SD
Standard Deviation
SF-36
Short Form Generic Health Survey
SFU
Safety Follow-Up
SJS
Stevens-Johnson Syndrome
sIL-6R
Soluble Interleukin-6 Receptor
SOC
System Organ Class
Study treatment
Satralizumab or Placebo
T25W
Timed 25-Foot Walk
TB
Tuberculosis
TBL
Total Bilirubin
TNF
Tumor necrosis factor
TFR
Time To First Protocol-defined Relapse
ULN
Upper Limit of Normal
US
United States
VAS
Visual Analogue Scale
V/F
Distribution Volume
WBC
White Blood Cell(s)
ZBI
Zarit Burden Interview


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
22/Protocol BN40900 (SA-309JG), Version 10
1.
INTRODUCTION
1.1
BACKGROUND ON NEUROMYELITIS OPTICA (NMO) AND 
NEUROMYELITIS OPTICA SPECTRUM DISORDER (NMOSD)
1.1.1
Introduction to NMO and NMOSD
Neuromyelitis optica (NMO), originally named Devic’s disease, is a severe
demyelinating inflammatory autoimmune disorder. NMO and NMO spectrum disorder 
(NMOSD) are clinically characterized by optic neuritis and/or transverse myelitis
(Wingerchuk et al. 2007), leading to various disabilities, such as visual impairment 
(including blindness), disturbance of motility and sensory deficit. NMO usually has a 
worse prognosis than multiple sclerosis (MS). Optic neuritis may present as a unilateral 
or bilateral event depending upon the portion of the visual pathway that is affected.
Visual impairment is often severe with a poor recovery. In addition, the severe relapses 
often lead to difficulty walking, para/tetraparesis and pan-sensory loss. Disability in NMO 
is usually more severe than that in MS and is usually related to the severity of NMO 
relapses. Most disabilities arise from the often devastating discrete acute attacks and 
secondary progression is uncommon. Fatigue and pain are common and affect a 
broader body area than those in MS and significantly impact the patient’s quality of life.
NMO is distinct from MS, radiologically, and prognostically, and has a pathophysiology
unresponsive to typical MS treatment (Weinshenker 2007; Oh and Levy 2012). Other
distinguishing features of NMO include a strong female preponderance, longitudinally
extensive spinal cord lesions and absence of oligoclonal immunoglobulin G (IgG) bands
in the cerebral spinal fluid (CSF).
Currently, there is one licensed medication for NMOSD (eculizumab; approved by the 
Food and Drug Administration [FDA] on 27 June 2019 and by the European 
Commission [EC] on 27 August 2019).  There are four aspects of NMO treatment in the 
current treatment algorithm, including: 1) acute treatment of relapses, 2) prevention of 
relapses, 3) symptom management and 4) rehabilitation. 
Historically the distinction between NMO and MS has been extensively debated but 
following the discovery of NMO-IgG or aquaporin-4 (AQP4) antibody, which is a 
circulating antibody which targets the dominant water channel in the central nervous 
system (Lennon et al., 2005), separate classifications have been developed. The 2006 
Wingerchuk NMO diagnostic criteria have been established and shared globally 
(Wingerchuk et al 2006). NMOSD includes individuals manifesting with recurrent
myelitis or recurrent optic neuritis or with a variety of signature brain syndromes, such as 
intractable vomiting and hiccups, and is diagnosed by ‘Criteria 2007’ (Wingerchuk et al., 
2007). In the most recently published diagnostic criteria, the overarching term 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
23/Protocol BN40900 (SA-309JG), Version 10
NMOSD was selected to unify traditional NMO and modern NMOSD definitions
(Wingerchuk et al. 2015).
In light of the non-reversibility of the neurological deficit associated with relapses,
maintenance immunosuppression has become standard practice. The current
standard in the United States (US), European Union (EU), Canada and Pacific Rim
countries outside of Japan, is to achieve and maintain remission with corticosteroids 
and then gradually withdraw them in favor of a non-steroid immunosuppressant,
although some patients need a low dose of oral steroids to maintain remission.
Treatment with a variety of different agents has been described although no
randomized comparisons of different therapies exist. Treatment approaches for 
prevention of attacks include systemic immunosuppression with azathioprine or
mycophenolate mofetil. Methotrexate use has also been reported, as is use of
mitoxantrone chemotherapy. In terms of biologic agents, rituximab, which is not
approved for treatment of MS or NMO, is widely used by clinicians in some countries. 
The use of tocilizumab (Araki et al. 2012, Ayzenberg et al. 2013, Kieseier et al. 2013) in 
NMO has also been reported.
Limited observational evidence suggests that typical MS treatments, including
interferon (IFN)-β, natalizumab and fingolimod, are not effective in NMO and may be
harmful when used to treat these patients. Unlike MS, disability in NMO is directly
tied to the number and severity of relapses. There remains an unmet medical need to 
develop additional therapeutic options to reduce the likelihood of relapses. 
1.1.2
Interleukin 6 as a Target Molecule for the Treatment of NMO 
and NMOSD
One of the key features of NMO is the presence of NMO-IgG, specific antibodies
against AQP4, a major water channel protein in the central nervous system (CNS).
Transfer of anti-AQP4 antibody has been shown to exacerbate experimental
autoimmune encephalomyelitis in animal models (Lennon et al. 2005; Hinson et al.
2012). From this observation, the role of the humoral arm of the immune system in 
disease pathology for NMO has been developed. Yamamura and coworkers have 
identified a CD19intCD27hiCD38hiCD180- (and CD20-) plasmablast B-cell subset, 
which is associated with production of anti-AQP4 antibodies) (Chihara et al. 2011). Cell 
surface expression of cluster of differentiation 19 (CD19) in plasmablasts is lower than 
other B-cells. Survival of plasmablasts is promoted by interleukin-6 (IL-6), but not by
other B-cell survival factors such as a proliferation including ligand (APRIL), the related
or tumor necrosis factor (TNF) family B-cell activating factor (BAFF, known as BLyS). IL-
6, but not BLyS was suggested to enhance antibody production by these plasmablasts, 
and anti-IL-6 receptor (IL-6R) blockade selectively inhibited survival of AQP4


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
24/Protocol BN40900 (SA-309JG), Version 10
antibody-producing plasmablasts in vitro. Based on these ex vivo studies, there are also 
now reports from several different global Investigators that have used anti-IL-6R 
blockade to treat patients with NMO.
This suggests that immunomodulatory agents that specifically target the humoral
immune system could potentially have an effect in treatment of patients with NMO.
Complement activation by NMO-IgG binding to AQP4 has been suggested. An agent
that targets production of AQP4-Ab, would be upstream of the complement activation
step.
IL-6 which is secreted by T-cells and macrophages during infection and trauma acts as 
both a pro-inflammatory and anti-inflammatory cytokine, Anti-IL-6R blockade may have
a direct effect on B cells in NMO. Survival of plasmablasts is promoted by IL-6, and
IL-6 was suggested to enhance antibody production by the selective plasmablasts, and
anti-IL-6R blockade selectively inhibited survival of AQP4 antibody-producing
plasmablasts in vitro.
Araki et al. 2013, reported initial positive results with IL-6R blockade in a 36-year-old 
female patient with NMO and multiple relapses, who had been previously diagnosed with 
MS. The patient experienced relapses with two different treatment regimens (IFN-β plus 
low-dose oral prednisolone and subsequently prednisolone plus azathioprine). Following 
treatment with intravenous (IV) tocilizumab 8 mg/kg monthly for 6 months, relapses 
ceased (apart from one minor case) and the patient’s Expanded Disability Status Scale 
(EDSS) score improved to 2.0 from 3.5.
Kieseier et al. 2013 reported a case study of a 34-year old female who was diagnosed 
with NMO. Therapy with rituximab and alemtuzumab did not prevent relapses. After 
starting IV treatment with tocilizumab 8 mg/kg body weight every 4 weeks, EDSS score 
was reduced from 8.0 to 4.0 within 2 months, and the patient was ambulatory with an 
EDSS score of 2.5 after 1 year.
Ayzenberg et al. 2013 reported a case series of three patients with aggressive NMO 
unresponsive to rituximab therapy. The patients continued to experience relapses 
despite complete cluster of differentiation CD20-cell depletion. After starting treatment 
with tocilizumab 6 mg/kg every 4 or 6 weeks, the median annualized relapse rate (ARR) 
decreased from 3.0 (range 2.3-3.0) to 0.6 (range 01.3).
1.2
BACKGROUND ON SATRALIZUMAB
Satralizumab is a humanized anti-human IL-6R neutralizing monoclonal antibody that
was designed by application of recycling antibody technology to the approved anti-IL6
receptor antibody, tocilizumab, which is currently marketed as a treatment for


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
25/Protocol BN40900 (SA-309JG), Version 10
rheumatoid arthritis (RA), systemic juvenile idiopathic arthritis, polyarticular juvenile 
idiopathic arthritis and Castleman's disease. 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,
imparting a longer plasma half-life. In addition, satralizumab is an IgG2 isotype which
reduces fragment crystallizable (Fc) receptor effector functions compared with 
tocilizumab (which is an IgG1 antibody). The longer plasma half-life of satralizumab
compared with tocilizumab was confirmed based on the result of nonclinical study and
Phase 1 study in healthy volunteers (SA-001JP).
Like tocilizumab, satralizumab achieves its pharmacological effects by inhibiting IL-6
signaling. Compared with tocilizumab, satralizumab was designed to have:
1)
A longer plasma half-life due to pH-dependent binding to the IL-6R, a lower antibody 
molecule isoelectric point and stronger binding to neonatal Fc receptor, and
2)
Lower effector activities (e.g., antibody dependent cellular cytotoxicity and 
complement-dependent cytotoxicity) owing to its lower binding affinity to
Fcγ receptor and the adoption of an IgG2 backbone.
The pharmacological effects and safety of satralizumab are expected to be comparable 
or superior to those of tocilizumab, and because of its longer plasma half-life, it is 
expected to show pharmacological efficacy at a lower dosing frequency.
The safety, tolerability, pharmacokinetics and bioavailability of subcutaneously (SC) 
administered satralizumab were investigated in Japanese and Caucasian healthy adult 
male volunteers (SA-001JP) in Japan. In this Phase 1 (single-dose) study, 48 Japanese 
subjects were given satralizumab by SC injection or IV, and 24 Caucasian subjects were 
given satralizumab by SC. This study demonstrated comparable safety and 
pharmacokinetic (PK) profiles with a single administration of satralizumab within no 
ethnic effects observed other than body weight. A single SC dose of satralizumab up to 
240 mg and an IV dose of satralizumab up to 120 mg were safe and well tolerated.
SA-105JP is a Phase 1b, open-label, randomized, parallel group, multiple dosing study 
in patients with RA. The objectives of the study are to assess safety, immunogenicity, 
PK/pharmacodynamics (PD), and efficacy of satralizumab as a monotherapy. All 
patients were given 120 mg of satralizumab as a loading dose at Week 0, 2 and 4 to 
induce high dose tolerance at the beginning of the study. Patients were then randomized 
to satralizumab 120 mg (Group A; 11 patients), 60 mg (Group B; 11 patients) or 30 mg 
(Group C; 11 patients) and received 3 doses of randomized treatment at Weeks 8, 12 
and 16. In total, during the primary evaluation period, 45 adverse events (AEs) were 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
26/Protocol BN40900 (SA-309JG), Version 10
reported in 22 patients, 17 events in Group A, 14 in Group B and 14 in Group C. The 
most frequent AEs by system organ class (SOC) were infections and infestations (15 
AEs in 12 patients), and most frequently reported individual AE was upper respiratory 
tract infection (4 events). The next most frequent AEs by SOC were skin and 
subcutaneous tissue disorders (7 AEs in 5 patients). The majority of AEs were mild in 
severity and there was no apparent difference in incidence of AEs between the groups. 
Two serious adverse events (SAEs) were reported in the primary evaluation period: one 
patient in Group A developed interstitial pneumonia after the second injection and 
discontinued due to this SAE. Following treatment in hospitalization, this event resolved. 
One patient in Group B developed bronchopneumonia after the first injection. Injection at 
Week 2 was interrupted due to the SAE. Following treatment in hospitalization, this 
event resolved. See the Investigator’s Brochure for details on nonclinical and clinical 
studies with satralizumab.
1.3
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT
Satralizumab is being developed for the treatment of NMO and NMOSD, which is a
serious condition that has substantial impact on day-to-day functioning of the patient.  
Satralizumab has the potential to treat this serious disease and fulfills an unmet medical
need. Patients diagnosed with NMO and NMOSD remain poorly served by existing 
treatments and experience a series of catastrophic relapses culminating in worsening 
disability including paraplegia and blindness. Treatment options are limited to the use of 
high dose corticosteroids at the time of relapse and chronic immunosuppression most 
commonly with azathioprine, mycophenolate, low dose oral corticosteroids and B-cell 
depleting agents, but none of these are approved. The evidence supporting the use of 
these therapies is limited to small single arm studies. More recently there have been 
small series of patients who experienced a dramatic reduction in relapse rate following 
inhibition of IL-6 signaling following treatment with the humanized antibody tocilizumab. 
Satralizumab is the first of a new class of monoclonal antibodies which following its 
uptake is recycled from within the cell permitting infrequent dosing. Satralizumab binds 
potently to the alpha-subunit of the IL-6 receptor preventing signaling via this receptor. 
Satralizumab has been studied in healthy volunteers and subjects with rheumatoid 
arthritis. 
In addition to the safety information for satralizumab, the safety information obtained
for tocilizumab is considered to be useful in predicting the safety of satralizumab since
tocilizumab has essentially the same mechanism of action as satralizumab. The
following risks have been identified following treatment with tocilizumab: serious
infections; gastrointestinal perforation; hypersensitivity.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
27/Protocol BN40900 (SA-309JG), Version 10
In order to address the potential risks for the patients, the following safety precautions are 
included in the study design:
In addition to regular standard safety evaluations (laboratory measures, physical 
examinations, vital signs and electrocardiogram [ECG]), a special focus will be 
placed on the above-noted risks.
An Independent Data Monitoring Committee (IDMC) will periodically review AEs
during the double-blind period in an un-blinded manner. The study will be stopped
prematurely if there are any critical safety concerns.
An independent Clinical Endpoint Committee (CEC) will review all cases of relapses and 
adjudicate each to see if it meets the protocol-defined relapse in the double-blind period.
In order to ensure that no relapse events are missed by the Investigator, the adjudication 
process will include a concurrent review of all cases to determine if a possible relapse 
event has been missed.
In summary, treatment with satralizumab is an approach for a specific therapeutic 
strategy in NMO with possible advantages for patients. All necessary measures are 
taken to closely monitor the safety of the treatment and thus to protect the patients 
enrolled in this study. The possible benefits are deemed to outweigh the potential risks 
involved in participation in this study.
The Clinical Development Program of satralizumab in NMOSD currently consists of 
two ongoing pivotal placebo-controlled randomized, double-blind Phase 3 studies. The 
double-blind periods of both studies have been completed (please refer to the latest 
Investigator’s Brochure for a summary of the study results), and the studies are 
currently ongoing in their open-label extension (OLE) periods.
A multicenter, open-label, uncontrolled study to evaluate the pharmacokinetics, safety, 
tolerability, and pharmacodynamic effects of satralizumab in children from 2 to less 
than 12 years of age is planned to start in Q4 2020.
The first study described here (Study BN40900, also known as Study SA-309JG, the 
monotherapy study) is a multicenter, randomized, double-blind, placebo-controlled, 
Phase 3 study of satralizumab monotherapy for treatment of NMOSD that was 
recommended by FDA at the meeting of 11 July 2013.
In addition, the Sponsor is conducting a second study (Study BN40898, also known as 
Study SA-307JG, the add-on study), a multicenter, randomized, double-blind, placebo-
controlled, Phase 3 study of satralizumab as an add-on to widely used baseline 
immunosuppressive therapies (ISTs) for the treatment of NMOSD.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
28/Protocol BN40900 (SA-309JG), Version 10
To date, a Phase 1 single ascending dose study in healthy subjects (SA-001JP), and a 
Phase 1 multiple dose study in patients with rheumatoid arthritis (SA-105JP) have been 
conducted.
Long-term safety information and data supporting durability of efficacy in patients with 
NMOSD will be derived from the open-label extension period of the ongoing Phase 3 
studies. Additional long-term safety information is supplied from Phase 1 multiple dose 
study in Japanese patients with rheumatoid arthritis (SA-105JP).
2.
OBJECTIVES
2.1
EFFICACY OBJECTIVE
The efficacy objective for this study is:

To evaluate the efficacy of satralizumab monotherapy compared with placebo in 
patients with NMO and NMOSD
The primary efficacy endpoint:
i.
Time to first protocol-defined relapse (TFR) in the double-blind period
The secondary efficacy endpoints are:
i.
Change in visual analog scale (VAS) score for pain
ii.
Change in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue score
iii.
Change in Short Form generic health survey (SF-36) score
iv.
Change in EQ-5D score
v.
Change in Timed 25-Foot Walk (T25W)
vi.
The proportion of relapse-free patients
vii.
Annualized relapse rate (ARR)
viii.
Change in modified Rankin Scale (mRS) score
ix.
Change in Zarit Burden Interview (ZBI) score
x.
Change in EDSS score
xi.
Change in visual acuity (Snellen chart)
xii.
Change in low-contrast visual acuity (Low-contrast Sloan letter chart [LCSLC])
Exploratory endpoints
i.
Magnetic resonance imaging (MRI) scans of the brain, optic nerve and spinal cord 
MRI for exploratory evaluation is optional and conducted at selected sites. 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
29/Protocol BN40900 (SA-309JG), Version 10
2.2
SAFETY OBJECTIVE
The safety objective for this study is:

To evaluate the safety of satralizumab monotherapy compared with placebo in
patients with NMO and NMOSD.
Safety outcome measures:

Incidence and severity of AEs, adverse events of special interest (AESIs) and SAEs, 
vital signs (temperature, systolic blood pressure [SBP], diastolic blood pressure 
[DBP] and pulse rate), physical examinations, clinical laboratory tests (hematology, 
chemistry, and urinalysis), 12-lead ECGs, suicidality (Columbia-Suicide Severity 
Rating Scale [C-SSRS]).
2.3
PHARMACODYNAMIC OBJECTIVE
The pharmacodynamic objective for this study is as follows:

To examine the PD of satralizumab
Pharmacodynamics Endpoints:

IL-6, soluble IL-6R (sIL-6R), high-sensitivity C-reactive protein (hsCRP), anti AQP4
antibodies and plasmablasts.
2.4
PHARMACOKINETIC OBJECTIVE
The pharmacokinetic objective for this study is as follows:

To examine the pharmacokinetics (PK) of satralizumab
Pharmacokinetics Endpoint:

Serum satralizumab concentration
2.5
IMMUNOGENICITY OBJECTIVE
The immunogenicity objective for this study is as follows:

To examine the immunogenicity of satralizumab.
Immunogenicity Endpoint:

Incidence of anti-drug antibodies.

PK, PD, clinical response, and safety during the study by anti-drug antibody status.
Study endpoints relating to these objectives are described in Section 3.3.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
30/Protocol BN40900 (SA-309JG), Version 10
3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
3.1.1
Overview
This Phase 3 pivotal study is a multicenter randomized, double-blind, placebo-controlled 
parallel assignment study followed by an open-label extension period. Patients will be 
randomized to two groups (2:1, Group A or B) and will receive subcutaneous 
satralizumab (Group A) or placebo (Group B) at Weeks 0, 2 and 4, and Q4W thereafter. 
The number of patients who are negative for anti-AQP4 antibody at screening will be 
limited to 30% of total study population. The randomization will be stratified by prior 
therapy for prevention of NMO/NMOSD attack (B-cell depleting therapy or 
immunosuppressants/others) and the most recent attack in the last one year prior to 
screening (first attack or relapse).
Patients who experience a protocol-defined relapse which is adjudicated by the CEC in 
the double-blind period or complete the double-blind period (see the section “Length of 
Study” in PROTOCOL SYNOPSIS) can enter the open-label extension period. In the
extension period, patients will receive open-label treatment with 120 mg satralizumab
SC at Weeks 0, 2 and 4 and every 4 weeks (Q4W) thereafter, with the last study 
drug administration on or before 31 December 2021. For patients who experience a 
relapse in the double-blind period, appropriate rescue therapy for relapse will be 
conducted. For patients who experienced a protocol-defined relapse which is 
adjudicated by CEC, satralizumab should start in the stable disease condition (Day 31 
or later, where Day 1 is defined as the day of onset of a protocol-defined relapse which 
is adjudicated by CEC). For patients who completed the double-blind period, 
satralizumab should start after 4 weeks from the last dosing in the double-blind period.
The extension period is expected to last until the Last Observation Visit. 
Those patients who experience 2 relapses in the extension period, both with a more 
severe intensity than the last relapse prior to baseline must be discontinued from 
treatment (See Section 4.7.1.1). It is the Investigator’s decision whether the patient can 
continue in the extension period. If the relapses aren’t as severe as the relapse prior to 
baseline they can remain in the extension period without being limited to the total 
number of relapses.
Study design is summarized in Figure 1.




Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
32/Protocol BN40900 (SA-309JG), Version 10
responsibilities and the process of adjudication of relapses are described on in detail in 
the CEC charter.
Screening for a Possible Relapse During the Study
During the screening period patients will be trained on the possible symptoms and signs 
of a potential relapse of optic neuritis or myelitis, or a relapse involving other locations. A 
Relapse Assessment Form, including the time and content of every report of a possible 
event, will be prepared. All reports of potential relapses from patients regardless of the 
time of the report will be described in the Relapse Assessment Form. Patients will be 
instructed to remember accurately the time and content of every symptom of a possible 
relapse and to contact the study site if they have such symptoms. During the double-
blind period, the site will contact the patient weekly by phone calls between the
scheduled site visits, to query any change in symptoms or other signs of a potential 
relapse. Additionally, the site will contact the patient, at the discretion of the Investigator,
between the scheduled site visits if necessary.
The site staff will also be trained on signs and symptoms that may be indicative of a 
potential relapse. 
If a patient becomes aware of signs or symptoms which might indicate relapse, the 
patient will return to the site for an extra visit as soon as possible with a target date set
for no more than three days after reporting the symptoms to the site. The examining 
Investigator must perform an EDSS/FSS assessment within seven days after the patient 
reports the symptoms to the site. The list of assessments to be obtained at the extra visit 
at relapse 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. MRI findings might be supportive for evaluation of relapse.
If a patient has difficulty visiting the study site within three days, the patient can visit a 
local clinic/hospital to receive rescue therapy for clinical relapse, and then visit the study 
site during or immediately after rescue therapy for clinical relapse. Alternatively, the 
examining Investigator may visit the local clinic/hospital to conduct the EDSS/FSS 
assessment during rescue therapy for clinical relapse.
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 must make every effort to 
obtain medical records from the facility, including information on treatment administered 
and the nature of the symptoms and signs observed.
Assessment of relapse is summarized in Figure 2.




Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
34/Protocol BN40900 (SA-309JG), Version 10
3.2
RATIONALE FOR STUDY DESIGN
3.2.1
Rationale for Choice of Study Design Elements
A Phase 3 study with a sample size of 90 evaluable patients is considered to be 
adequate to demonstrate efficacy for this rare disease population. As no 
proof-of-concept Phase 2 studies have been conducted for satralizumab in NMO or 
NMOSD, the magnitude of the treatment effect is not known a priori, although there are 
some case reports of treatment with tocilizumab reducing the relapse rate.
The proportion of patients who are negative for anti-AQP4 antibody is expected to 
increase because this study allows enrolling such patients. In order to avoid a big 
difference between the study population and population in real world, percentage of the 
patients who are negative status for anti-AQP4 will be capped at 30% based on 
published data (Jarius et al. 2012, Lennon et al. 2004, Marignier et al. 2013, 
Takahashi et al. 2007).
The end of the study is defined as the date when the last patient, last visit (LPLV) occurs. 
LPLV is expected to occur 12 weeks after the last dosing in the extension period.
3.2.2
Rationale for Time to First Relapse Endpoint
There are currently no validated endpoints to evaluate the efficacy of agents for the 
treatment of NMO or NMOSD. In the absence of such endpoints, TFR was selected as 
the primary efficacy measure in this study. TFR is proposed rather than ARR because of 
the devastating nature of relapses and standard clinical approach of changing therapy 
following a relapse which prevents a more prolonged study period. TFR is alternative to
ARR, of which is precedent for selection as the primary endpoint in MS clinical trial, as a 
statistical measure of the frequency of relapse and has been used as the secondary 
endpoint in several large MS studies (Giovannoni et al. 2010, Cohen et al 2010, Kappos 
et al 2010, O’Connor et al 2011). Furthermore, for NMO, the natural history of the 
disease is such that any relapse is potentially catastrophic to the patient and is often 
accompanied by long lasting neurological impairment.
One of the primary advantages of using TFR is from the ethical perspective, particularly 
dealing with the clinical consequences of relapse experienced by NMO and NMOSD 
patients. Time to first relapse allows patients who experience a relapse during the 
double-blind period to receive acute therapy. This mitigates the ethical concern of 
keeping patients with NMO/NMOSD on a potentially ineffective therapy for a fixed period 
of time and reflects current clinical practice in NMO/NMOSD, that when a patient 
experiences a relapse, treatment choice is often changed.


 
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd 
35/Protocol BN40900 (SA-309JG), Version 10 
3.2.3 
Rationale for Test Product Dosage 
Based on PK and PD assessments in Phase I studies with satralizumab and anecdotal 
efficacy data from investigational studies of tocilizumab, 120 mg Q4W will be used as 
the maintenance dose of satralizumab in this study. 
The mean trough level of satralizumab 120 mg SC Q4W in steady state in study 
SA-105JP was 20.3 ±6.13 μg/mL and the computed mean trough level of tocilizumab 
8 mg/kg IV Q4W in steady state was 9.7 ±11 μg/mL (Frey N et al. 2010). Based on these 
data, the PK of satralizumab 120 mg SC Q4W was higher than that of tocilizumab 
8 mg/kg IV Q4W. However, the patients enrolled to the Phase 1b (SA-105JP) were all 
Japanese RA patients and mean body weight of the patients was 54.1 ±10.8 kg. On the 
other hand, the mean body weight of patient in the Phase 3 studies of tocilizumab was 
67 to 73 kg. The computed PK of satralizumab 120 mg SC Q4W in RA patients (based 
on a body weight of 75 kg) is 8.2 μg/mL, which is comparable to tocilizumab 8 mg/kg IV 
Q4W. 
This dose is appropriate based on the following considerations: 
Results from Phase 1 single-dose study in healthy subjects and multiple dose study in 
patients with rheumatoid arthritis showed that satralizumab 120 mg Q4W inhibited IL-6 
signaling completely, whereas lower doses (30, 60 mg Q4W) did not. 
Systemic inflammatory condition is not expected in patients with NMO and NMOSD 
compared to RA patients, therefore, inflammatory parameter such as C-reactive protein 
(CRP) and IL-6 is within normal range in patients with NMO and NMOSD.  
Therefore, satralizumab 120 mg Q4W is expected to inhibit IL-6 signaling completely in 
patients with NMO and NMOSD.  
IV tocilizumab 8 mg/kg Q4W, trough level of which is comparable to satralizumab 
120 mg Q4W, showed preliminary clinical efficacy in the investigational case reports in 
patients with NMO and NMOSD. In addition, the PK/PD correlation between tocilizumab 
and satralizumab is comparable.  
Satralizumab has been investigated in 2 studies, including one Phase 1 single 
ascending dose study in Caucasian and Japanese healthy volunteer (SA-001JP) and 
one Phase 1b multiple dose study in Japanese RA patients (SA-105JP). 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
36/Protocol BN40900 (SA-309JG), Version 10
For the NMO Studies BN40890 and BN40900 (SA-307JG and SA-309JG), satralizumab
120 mg SC Q4W was selected based on the assumptions below.

The sIL-6R complex in plasma, which is a PD marker of satralizumab's mechanism 
of action increased in a dose dependent manner in the Phase 1 study in healthy 
subjects. However the increase reached a plateau at higher doses, which 
suggesting that sIL-6R was saturated and trans-signaling of sIL-6R was completely 
inhibited.

The sIL-6R increased also in RA patients and the increase reached a plateau 
following satralizumab 120 mg SC Q4W. In addition, CRP, which is a PD marker of 
classical signaling of IL-6, showed sustained decreases, meaning that 
trans-signaling and classical signaling of IL-6 was completely inhibited by 
satralizumab 120 mg SC Q4W.

Based on the hypothesis that the quantity of sIL-6R in NMO is not apparently 
different from that in, healthy volunteer and RA patients, the elimination rate of 
satralizumab from circulating blood in NMO patients is not expected to be different 
from healthy volunteer or RA patients. Therefore, PK in NMO patients is expected to 
be comparable to healthy volunteer and RA patients.

The mean trough of satralizumab 120 mg SC in steady state was comparable to 
tocilizumab 8 mg/kg IV Q4W. Furthermore, the inhibition effect of IL-6 signaling was 
also comparable between both.

The exposure dependent safety issues of satralizumab are not expected as long as 
IL-6 signaling is completely inhibited. Satralizumab 120 mg SC Q4W is the dose 
which completely inhibits IL-6 signaling in RA patients. In fact, dose-dependent 
safety issue was not observed in Phase 1b study in RA patients.
Based on above, satralizumab 120 mg Q4W is expected to be an optimal dose in 
patients with NMO and NMOSD.
PD Response
The assay of sIL-6R can measure free sIL-6R and satralizumab-sIL-6R complex. 
Therefore, the value of sIL-6R was measured as total of free sIL-6R and the sIL-6R 
complex (Nishimoto et al., 2008). The sIL-6R complex which is a PD marker of the 
mechanism of action of satralizumab increased with dose dependent manner in Phase 1 
in healthy subjects. However the increase reached to plateau in higher dose, meaning 
that sIL-6R was saturated and trans-signaling of sIL-6R was completely inhibited. 
Validation data indicates that the assay for sIL-6R is not inhibited by satralizumab (drug 
on board).


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
37/Protocol BN40900 (SA-309JG), Version 10
3.2.4
Justification for Upper Age Limit
For the NMO study BN40900 (SA-309JG), the inclusion criteria allow enrollment of 
patients 18-74 years inclusive. The upper age limit is based on safety data from patients 
enrolled in the Phase 1b RA Study SA-105JP. In that study, 13 of 33 patients enrolled in 
the study were 65 years or older. Preliminary analysis of data from that study suggests 
that the overall safety profile of satralizumab in patients age 65 or older may be similar to 
that of patients younger than 65 years.
3.2.5
Justification for Placebo-Controlled Trial
A placebo-controlled superiority trial comparing satralizumab monotherapy to placebo 
has been designed in this study. There are several key points to justify design of a 
placebo-controlled monotherapy study for approval of satralizumab:

One of the primary rationales for a placebo-controlled study is the risk of mandating 
exposure of patients to unapproved drugs with safety profiles that are not well 
characterized based on results of randomized studies. 

Patients will be randomized in a 2:1 ratio to active treatment and placebo groups. 
This study design decreases the probability that on randomization a patient will 
receive placebo.

The results of comparing satralizumab monotherapy to placebo would enable the 
evaluation of the safety and efficacy of satralizumab itself.
The need for placebo for scientific reasons:
A control treatment is generally considered necessary to demonstrate efficacy in various 
types of clinical trials, including NMO trials.
Placebo controls are needed to differentiate the pharmacologic and PD effects of a drug 
from the nondrug effects that patients experience in clinical trials. For example, the 
systematic attention by repeated examinations and frequent visits in a clinical study may 
lead to noteworthy placebo effects that patients are not exposed to in routine medical 
practice. Without a placebo group, these non-pharmacologic effects in the artificial 
environment of a clinical study cannot be distinguished from a real drug effect. 
Furthermore, many AEs seen in clinical trials are complaints that patients experience 
independent of drug therapy (e.g., headache, respiratory infections). Thus, the real 
safety and tolerability profile of a drug can best be evaluated by comparing the incidence 
of reported AEs with a placebo group.
Placebo controls offer a clear reference point, and they increase the likelihood of 
attaining statistical significance with a smaller sample size; this means that trials may be 
done more quickly and with a smaller number of patients. 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
38/Protocol BN40900 (SA-309JG), Version 10
Finally, the validity of the whole study as a measurement instrument can be proven by 
showing the difference of active drug versus placebo. If a study that has only active 
treatment arms does not show a difference between treatments, it cannot be known 
whether there actually was no treatment difference or if the study just failed to detect the 
difference (e.g., by poor design or conduct).
Protocol features to minimize the risk of placebo exposure:

To further reduce the risk of harm to the patients in the placebo group, the following 
safety measures will be implemented in this study:

Patients who have conditions indicating a higher risk as per exclusion criteria (e.g., 
cardiovascular, CNS disease, hematologic/hematopoiesis disease, respiratory 
disease, muscular disease, endocrine disease, renal/urologic disease, digestive 
system disease, congenital or acquired severe immunodeficiency, known active 
infection, history of diverticulitis, active tuberculosis (TB), malignancy) will be 
excluded from participation in the study.

The study design uses TFR rather than ARR to minimize the number of risk events; 
important when using a placebo.

Proactive screening for potential relapses will include a contact with the patient
between the scheduled site visits, if required in the judgment of the Investigator. The 
site staff will query the patient for any change in symptoms or other signs of a 
potential relapse. If such a symptom is reported, the patient will be instructed to 
return to the site as soon as possible for an extra visit following relapse.
During the screening period patients will be trained on the possible symptoms and signs 
of a potential relapse of optic neuritis or myelitis, or a relapse involving other locations. 
Patients will be instructed to contact the site if they have symptoms or signs of a 
potential relapse. The patient will be instructed to return to the site as soon as possible 
for an extra visit following relapse, but no more than three days after reporting the 
symptoms to the site. This is to allow for a rapid decision on rescue therapy.

Resources will be put in place to focus on blinding, proactive screening for relapses, 
and minimizing drop-out. To ensure patients can conveniently return for visits, 
appointments would be scheduled according to the patient’s schedule as much as 
possible, and objective independent clinical measures of global disability (see
Appendix 6). The effectiveness of blinding procedures will be monitored during the 
trial. 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
39/Protocol BN40900 (SA-309JG), Version 10

A process for proactive screening for possible attacks, documentation of the time 
and content of every report of a possible event by a patient, and a list of sequential 
tests and procedures to be followed when a patient reports a potential event 
described above (see Section 3.1.4). 

The adjudication process includes concurrent systematic ongoing data review of all 
cases to determine if a possible relapse event is missed.
3.3
STUDY ENDPOINTS/OUTCOME MEASURES
3.3.1
Efficacy Outcome Measures
3.3.1.1
Primary Endpoint
i.
TFR in the double-blind period
3.3.1.2
Secondary Endpoints
i.
Change in VAS score for pain
ii.
Change in FACIT fatigue score
iii.
Change SF-36 score
iv.
Change in EQ-5D score
v.
Change in T25W score
vi.
The proportion of relapse-free patients
vii.
ARR
viii.
Change in mRS score
ix.
Change in ZBI score
x.
Change in EDSS score
xi.
Change in visual acuity (Snellen chart)
xii.
Change in low-contrast visual acuity (by LCSLC)
3.3.2
Safety Outcome Measures
i.
Incidence and severity of AEs, SAEs and AESIs
ii.
Vital signs (temperature, SBP and DBP and pulse rate), physical 
examinations, clinical laboratory tests (hematology, chemistry, and 
urinalysis), 12-lead ECG, suicidality (C-SSRS)
3.3.3
Exploratory Endpoints
i.
MRI scans of the brain, optic nerve and spinal cord 
MRI for exploratory evaluation is optional and will be conducted at selected 
sites. 
3.3.4
Pharmacodynamic Outcome Measures
i.
IL-6
ii.
sIL-6R
iii.
hsCRP
iv.
Anti-AQP4 antibodies


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
40/Protocol BN40900 (SA-309JG), Version 10
v.
Plasmablasts
3.3.5
Pharmacokinetic Outcome Measures
i.
Serum satralizumab concentration
3.3.6
Immunogenicity Outcome Measures
i.
Incidence of anti-drug antibodies
ii.
PK, PD, clinical response, and safety during the study by anti-drug
antibody status
4.
MATERIALS AND METHODS
4.1
PATIENTS
This study includes patients with NMO or NMOSD. The proportion of patients who are 
negative for anti-AQP4 antibody at screening will be capped at 30% of total number of 
patients.
4.1.1
Inclusion Criteria 
Patients must meet the following criteria for study entry:
1. Patients must be diagnosed as either:
a.
NMO as defined by Wingerchuk 2006 criteria*, or
b.
NMOSD as defined by either of the following criteria with anti-AQP4 antibody 
seropositive status at screening.
i.
Idiopathic single or recurrent events of longitudinally extensive myelitis 
(≥3 vertebral segment spinal cord MRI lesion)
ii.
Optic neuritis, single, recurrent or simultaneous bilateral
2. Clinical evidence of at least 1 documented relapse (including first attack) in the last 
12 months prior to screening.
3. EDSS score from 0 to 6.5 inclusive at screening.
4. Age 18 to 74 years, inclusive at the time of informed consent.
5. Ability and willingness to provide written informed consent and to comply with the 
requirements of the protocol.
*According to Wingerchuk et al. 2006, a diagnosis of NMO requires all of following 
criteria:
I.
Optic neuritis
II. Acute myelitis
III. At least two of three supportive criteria:

Contiguous spinal cord lesion identified on an MRI scan extending over 
3 vertebral segments

Brain MRI not meeting diagnostic criteria for multiple sclerosis


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
41/Protocol BN40900 (SA-309JG), Version 10

NMO-IgG seropositive status
4.1.2
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry:
Exclusion Criteria Related to Neuromyelitis Optica:
1.
Clinical relapse onset (including first attack) within 30 days prior to baseline.
Exclusion Criteria Related to Previous or Concomitant Therapy:
2.
Any previous treatment with IL-6 inhibitory therapy (e.g., tocilizumab), alemtuzumab, 
total body irradiation or bone marrow transplantation at any time.
3.
Any previous treatment with anti-CD20, eculizumab, anti-BLyS monoclonal antibody 
(e.g., belimumab), any other treatment for prevention of MS relapse (e.g., interferon, 
natalizumab, glatiramer acetate, fingolimod, teriflunomide or dimethyl fumarate) 
within 6 months prior to baseline.
4.
Any previous treatment with anti-CD4, cladribine, cyclophosphamide or 
mitoxantrone within 2 years prior to baseline.
5.
Treatment with any investigational agent within 3 months prior to baseline.
Exclusions for General Safety:
6.
Pregnancy or lactation.
7.
For patients of reproductive potential, a positive result from a serum pregnancy test 
at screening, or not willing to use reliable means of contraception (physical barrier 
[patient or partner] in conjunction with a spermicidal product, contraceptive pill,
patch, injectables, intrauterine device or intrauterine system) during the treatment 
period and for at least 3 months after the last dose of study drug.
8.
Any surgical procedure (except for minor surgeries) within 4 weeks prior to baseline.
9.
Evidence of other demyelinating disease or progressive multifocal 
leukoencephalopathy (PML).
10. Evidence of serious uncontrolled concomitant diseases that may preclude patient 
participation, as described;
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.
11. Known active infection (excluding fungal infections of nail beds or caries dentium) 
within 4 weeks prior to baseline.
12. Evidence of chronic active hepatitis B or C.
13. History of drug or alcohol abuse within 1 year prior to baseline.
14. History of diverticulitis that, in the Investigator’s opinion, may lead to increased risk 
of complications such as lower gastrointestinal perforation.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
42/Protocol BN40900 (SA-309JG), Version 10
15. Evidence of active TB (excluding patients receiving chemoprophylaxis for latent TB
infection).
16. Evidence of active interstitial lung disease.
17. Receipt of any live or live attenuated vaccine within 6 weeks prior to baseline.
18. History of malignancy within the last 5 years, including solid tumors, hematologic 
malignancies and in situ carcinoma (except basal cell and squamous cell 
carcinomas of the skin, or in situ carcinoma of the cervix uteri that have been 
completely excised and cured).
19. History of severe allergic reaction to a biologic agent (e.g., shock, anaphylactic 
reactions).
20. Active suicidal ideation within 6 months prior to screening, or history of suicide 
attempt within 3 years prior to screening.
21. History of Stevens-Johnson syndrome (SJS).
Laboratory exclusion criteria (at screening):
22. Following laboratory abnormalities at screening*. 
a.
White blood cells (WBC) < 3.0 x103/μL
b.
Absolute neutrophil count (ANC) < 2.0 x 103/μL
c.
Absolute lymphocyte count < 0.5 x 103/μL
d.
Platelet count < 10 x 104/μL
e.
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 1.5 
times the upper limit of normal (ULN).
* If retest is conducted, the last value of retest before randomization must meet study 
criteria.
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
Randomization will be stratified by prior therapy for prevention of NMO/NMOSD attack 
(B-cell depleting therapy or immunosuppressants/others) and the most recent attack in 
the last one year prior to screening (first attack or relapse). If a patient was administered
B-cell depleting therapies (e.g., anti-CD20 antibody [e.g., rituximab], anti-CD19 antibody) 
at least once in the year prior to baseline, the patient will be stratified into “B-cell 
depleting therapy group” and otherwise into the “immunosuppressants/others group”
(e.g., oral corticosteroids, azathioprine, mycophenolate mofetil, cyclosporine, 
methotrexate, tacrolimus). Patients will be randomized in a 2:1 ratio to one of the two 
treatment groups. Administration of study treatment should occur on same day as
randomization. For the randomization of patients, the Investigator will use Interactive 
Web Response and Voice Response Systems (IxRS). Details can be found in the study 
manual The IxRS will assign patients to a treatment group based on the pre-defined 
randomization list.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
43/Protocol BN40900 (SA-309JG), Version 10
During the double-blind period, the study is performed in a double-blind manner. Study 
treatments (satralizumab and placebo) are supplied in identical vials and are similar in 
color and appearance, thereby enabling double-blind conditions.
Patients and all study site personnel are blinded to treatment assignment until all 
patients have either completed the double-blind period, discontinued early from the 
study or as described below regarding un-blinding.
Patients, Investigator staff, persons performing the assessments, and data analysts 
remain blinded to the identity of the treatment, from the time of randomization until 
database lock, using the following methods: (1) Randomization data are kept strictly 
confidential until the time of un-blinding, and are not accessible by anyone else involved 
in the study, (2) The identity of the study treatments (i.e., satralizumab and placebo) is 
concealed by the use of study treatments that are all identical in packaging, labeling, 
schedule of administration and appearance, (3) Relapse is assessed separately from the 
treating Investigator, who is responsible for the patient care.
There will be a treating Investigator and an examining Investigator at each site – the 
treating Investigator responsible for the patient care and the examining Investigator 
responsible for the administration of the EDSS/FSS. The examining Investigator must be 
appropriately qualified to assess EDSS/FSS. The treating Investigator will have access 
to both safety and efficacy data and will make treatment decisions based on the patient’s 
clinical response and laboratory findings. The examining Investigator will have access 
via the paper form only to the EDSS/FSS data (including Relapse Assessment Form)
except in an emergency (such as there is no physician other than for EDSS/FSS 
assessment in study site) and will not consult the patient medical records. Patients will 
be instructed not to discuss any symptoms with the examining Investigator in order to 
avoid potential un-blinding of the examining Investigator; the examining Investigator 
should remind the patient at the start of the examination. At the protocol-specified study 
visit that includes an EDSS/FSS assessment (see Appendix 1) from baseline in the 
double-blind period, the examining Investigator will complete and sign a form which 
includes the kind of assessment form examining Investigator used for assessment and 
the confirmation of blinding the patient medical record, the study-related data apart from 
EDSS/FSS and information apart from neurological findings since the last EDSS/FSS 
assessment visit.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
44/Protocol BN40900 (SA-309JG), Version 10
In addition, site personnel, study monitor, the Sponsor and the study team will be blinded 
for some of the laboratory results (including serum satralizumab concentration, hsCRP, 
IL-6, sIL-6R, anti-drug antibody [ADA], anti-AQP4 antibodies [except screening], 
plasmablasts and complement [C3, C4, and CH50]) before the primary analysis.
The study blind should not be broken except in a medical emergency (where knowledge 
of the study treatment received would affect the treatment of the emergency), due to 
regulatory requirement (e.g., for SAE reporting), IDMC/IDCC or sample management at 
laboratory for pharmacokinetic and immunogenicity objectives.
The blind for each patient must only be broken following discussion between the 
Investigator and the PAREXEL Medical Monitor on a case-by-case basis.
The Investigator should notify the Medical Monitor prior to contacting IxRS for 
un-blinding. All calls resulting in an un-blinding event will be recorded and reported by 
the IxRS to the Medical Monitor. If an Investigator, site personnel performing 
assessments, or patient, is un-blinded, this must be listed as major protocol violation. 
The medical monitor and Investigator should consult each other to decide whether a 
patient who had his/her emergency key code broken can enter the open-label extension 
period.
Serious unexpected suspected adverse reactions (SUSARs), which are subject to 
expedited reporting, should be un-blinded by authorized personnel of the Sponsor who 
are not involved in the satralizumab clinical trial program before submission to the 
Regulatory Authorities.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
45/Protocol BN40900 (SA-309JG), Version 10
4.3
STUDY TREATMENT
4.3.1
Formulation, Packaging and Handling
4.3.1.1
Satralizumab and Placebo
Satralizumab
Investigational product name:
Satralizumab (also known as SA237-120)
Appearance:
Colorless to slightly yellow liquid
Formulation
Liquid for SC injection
Manufacturing process:
The drug substance manufacturing process consists of a cell 
culture process and a purification process. The cell line used 
for the cell culture process is generated from a Chinese 
Hamster Ovary cell line using recombinant deoxyribose 
nucleic acid (DNA) technology
Manufacturer:
Drug product in vial:
Chugai Pharma Manufacturing Co., Ltd.
5-1, Ukima, 5-Chome, Kita-ku
Tokyo, 115-8543, Japan
Drug product in plastic prefilled syringe (PFS) with needle 
safety device (NSD):
Chugai Pharma Manufacturing Co., Ltd.
16-3 Kiyohara-Kogyodanchi, Utsunomiya 
Tochigi, 321-3231, Japan
Composition:
The drug product is a vial or a plastic PFS with NSD filled 
with 1.0 mL of solution, which contain 120 mg of 
satralizumab. As excipients, it contains L-histidine, 
L-arginine, L-aspartic acid and polyoxyethylene (160) 
polyoxypropylene (30) glycol, and it has a pH of 5.5 to 6.5.
Storage conditions:
The drug product is stored at 2-8°C, protected from light until 
use
Satralizumab PFS with NSD can be used in the extension period.
For further details on satralizumab, see the current Investigator's Brochure.
Placebo
Satralizumab placebo vial is identical in composition to satralizumab vial, but does not 
contain the satralizumab active ingredient. It is identical in appearance and packaging to 
satralizumab.
Kit ID, lot number and expiry date will be labeled. Local labeling may be different in 
some countries according to local regulatory guidelines. Packaging will be the same for 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
46/Protocol BN40900 (SA-309JG), Version 10
all countries. All satralizumab vials, placebo vials and satralizumab PFS with NSD must 
be stored at a controlled temperature of 2-8°C, and handled according to Good 
Manufacturing Practice and Good Clinical Practice (GCP) procedures. A temperature log 
must be kept recording the storage temperature of the satralizumab vials, placebo vials 
and satralizumab PFS with NSD, and be available for regular review by the study 
monitor. 
Please refer to the pharmacy section of the study manual for details.
4.3.2
Dosage, Administration, and Compliance
All study centers will be provided with a supply of satralizumab and placebo after all the 
necessary documentation is in place for the study but before the first administration of 
study treatment. If a patient is found to be eligible for the study, the Investigator or 
designated person will be informed via the IxRS as to which coded study treatment to 
use for injection.
Satralizumab 120 mg or placebo 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 for that visit. Choice of needle and syringe sizes is left 
to the discretion of the Investigator. This will be performed at the study center in a setting 
where medications for treatment of anaphylaxis and resuscitation facilities are available. 
Patients should remain at the study center for at least 1 hour in order to receive 
medication immediately if anaphylaxis occurs.
If study drug is not 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). Site staff should 
consult with the Medical Monitor if in doubt as to how to schedule dosing in such 
circumstances.
4.3.2.1
Satralizumab and Placebo: Double-blind period
The patient will receive an SC injection of satralizumab or placebo at Weeks 0, 2 and 4, 
and Q4W thereafter during the double-blind period. The double-blind period ends when 
either the patient has a protocol-defined relapse which is adjudicated by CEC, the total 
number of registered relapses is 44 or 1.5 years after the date of randomization of the 
last patient enrolled, whichever comes first. 
Patients who experienced a relapse during the double-blind period should continue the 
double-blind period regardless of rescue therapy unless the patient experiences a 
relapse which is adjudicated by CEC as a protocol-defined relapse, and will continue 
administration of study treatment at the discretion of the Investigator.


 
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd 
47/Protocol BN40900 (SA-309JG), Version 10 
4.3.2.2 
Satralizumab: Extension period 
Patients who complete the double-blind period (see the section “Length of Study” in 
PROTOCOL SYNOPSIS) or experience a protocol-defined relapse which is adjudicated 
by the CEC in the double-blind period can enter the open-label extension period. In the 
open-label extension period, the patient will receive an SC injection of satralizumab at 
Week 0, 2 and 4, and Q4W thereafter, with the last study drug administration on or 
before 31 December 2021. 
For patients who experienced a protocol-defined relapse which is adjudicated by CEC, 
satralizumab should start in the stable disease condition (Day 31 or later, where Day 1 is 
defined as the day of onset of a protocol-defined relapse which is adjudicated by CEC). 
For patients who completed the double-blind period, satralizumab should start after 
4 weeks (± 7 days) from the last dosing in the double-blind period. 
Patients who experience a relapse during the extension period will continue 
administration of satralizumab at the discretion of the Investigator. 
In the OLE period after Week 48, and 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, or home administration by a 
mobile nurse) will be allowed in emergency situations such as the SARS-CoV-2 
(COVID-19) pandemic. 
Following the implementation of Protocol Version 10 and 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, or 
home administration by a mobile nurse) may be allowed on scheduled study drug 
administration days that do not require additional assessments that must be performed 
on site (Appendix 1).   
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1. 
4.3.3 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study 
(satralizumab or placebo) will be provided by the Sponsor or its designee. The 
investigational site will acknowledge receipt of IMPs, using the IxRS to confirm the 
shipment condition and content. See the study manual for details of procedures for 
handling temperature excursions. Any damaged shipments will be replaced.  




Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
49/Protocol BN40900 (SA-309JG), Version 10
4.4.1
Major Permitted Therapies for NMO
Permitted Medication/Therapy During the Double-Blind Period
1.
Rescue therapy for clinical relapse; pulse IV corticosteroids, oral corticosteroids for 
tapering, intravenous immunoglobulin (IVIG) and/or apheresis (including plasma 
exchange and plasmapheresis)
2.
Pain medications (including but not limited to pregabalin, gabapentin, 
carbamazepine, clonazepam, duloxetine, tramadol/acetaminophen).
Starting of pain medications is permitted; however, the dose should be stable during 
the double-blind period. In case pain control is insufficient, dose increase or change 
of pain medication is permitted. Dose decrease and temporary treatment 
suspension are permitted for only safety reasons.
Permitted Medication/Therapy During the Extension Period
1.
Rescue therapy for clinical relapse; pulse IV corticosteroids, oral corticosteroids for 
tapering, IVIG and/or apheresis (including plasma exchange and plasmapheresis)
2.
Pain medications (including but not limited to pregabalin, gabapentin,
carbamazepine, clonazepam, duloxetine, tramadol/acetaminophen)
3.
During the OLE period: Treatment with corticosteroids (e.g., oral, nasal) for AEs 
(i.e., indications other than a relapse) is permitted; the treatment duration should 
be kept as short as possible
Rescue therapy should proceed at the discretion of the treating Investigator after the 
examining Investigator or rater has completed EDSS/functional system score (FSS) 
assessment except in an emergency. Rescue therapy can be started based on 
Investigator’s decision.
4.4.2
Prohibited Therapy
1.
Prior to and throughout the study

IL-6 inhibitory therapy (e.g., tocilizumab), alemtuzumab, total body irradiation, 
bone marrow transplantation.
2.
From 2 years prior to baseline to the end of the study.

Anti-CD4, cladribine, cyclophosphamide, mitoxantrone.
3.
From 6 months prior to baseline to the end of the study.

Eculizumab, anti-BLyS monoclonal antibody (e.g., belimumab), anti-CD20 
treatment (e.g., rituximab, ocrelizumab, ofatumumab), any other treatment for 
prevention of MS relapse (e.g., interferon, natalizumab, glatiramer acetate, 
fingolimod, teriflunomide, dimethyl fumarate).
4.
From 3 months prior to baseline to the end of the study.

Treatment with any investigational agent (other than satralizumab).


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
50/Protocol BN40900 (SA-309JG), Version 10
5.
From 6 weeks prior to baseline to the end of the study.

Immunization with live or live attenuated vaccine.
6.
From baseline to the end of the study.

Immunosuppressants (e.g., cyclosporine, methotrexate, tacrolimus), and 
during the double-blind period, azathioprine and mycophenolate mofetil.

Treatment with azathioprine or mycophenolate mofetil in the OLE period 
should only be initiated after consultation with the Medical Monitor.

Corticosteroids, IVIG excepting for rescue therapy for clinical relapse. For 
treatment with corticosteroids for indications other than relapse therapy in the 
OLE period, see Section 4.4.1.
4.5
STUDY ASSESSMENTS 
4.5.1
Description of Study Assessments
4.5.1.1
Medical History and Demographic Data
Medical history refers to clinically significant diseases, including but is not limited to 
medication allergies, anaphylaxis, cancer, demyelinating disease other than NMO and 
NMOSD, neurologic disorders, psychiatric disorders, rheumatologic disorders, 
musculoskeletal diseases, cardiovascular disease, pulmonary disease, gastrointestinal 
diseases including hepatic diseases, hematologic disorders and renal disease.
Demographic data will include age (date of birth), sex and race/ethnicity. These data are 
required in order to perform subgroup analyses to evaluate the consistency of the results 
across race/ethnic groups. Previous relapse (including first attack) and date of NMO or 
NMOSD diagnosis will be recorded in the eCRF. Height will be recorded at baseline and 
body weight will be recorded at baseline and every 24 weeks thereafter.
4.5.1.2
Hepatitis B screening
Patients who are hepatitis B surface antigen (HBsAg) positive will be excluded from the 
study.
Patients for whom a positive result for antibody to HbsAg (HBsAb) is clearly associated 
with hepatitis B virus (HBV) vaccination can be enrolled. If not, hepatitis B viral DNA will 
be measured at a central laboratory.
If total hepatitis B core antibody (HBcAb) status is positive, hepatitis B viral DNA will be 
measured at a central laboratory.
If hepatitis B viral DNA is detectable, the patient must be excluded. If undetectable, the 
patient may be enrolled. In these cases hepatitis B viral DNA measurements must be 
performed regularly at approximately 12 weekly intervals during the study.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
51/Protocol BN40900 (SA-309JG), Version 10
4.5.1.3
Hepatitis C screening
Patients with negative hepatitis C serology can be enrolled. Patients with positive 
hepatitis C serology will be excluded from the study. However, if hepatitis C virus (HCV) 
ribonucleic acid (RNA) is undetectable 12 weeks after HCV treatment completion, the 
patient can be enrolled.
4.5.1.4
Screening for Tuberculosis
For entry into this study, patients should be screened for TB at site according to local
guidance (or instruction for TB screening if none exist). Result of screening tests will be 
reported on the eCRFs. If the patient is positive for latent TB, then the patient must be 
treated with appropriate anti-mycobacterial therapy for at least 3 weeks prior to initiating 
study treatment administration.
For further details on screening for TB, see Appendix 12.
4.5.1.5
Magnetic Resonance Imaging
During the screening period, patients who are classified as PML based on the local 
imaging assessment will be excluded. If patients who show lesions suspicious for PML 
by brain MRI, JC virus in the CSF will be measured - if “detectable” or “undetectable with 
high clinical suspicion”, the patient must be excluded. Patients who are anti-AQP4 
antibody negative and have an MRI with classic MS features on T2 weighted imaging 
with Dawson’s fingers, adjacent to lateral ventricles, juxtacortical and/or cortical lesions 
must also be excluded.
4.5.1.6
Vital Signs
Vital signs will include measurements of pulse rate, temperature and SBP and DBP 
while the patient is in a seated position for at least 5 minutes. At the injection visit, vital 
signs will be measured before and after study treatment administration. Measurement of 
pulse rate, temperature, SBP and DBP should take place immediately before and then at 
15 (±5) and 60 (±5) minutes after study treatment administration.
4.5.1.7
Physical Examination
A complete physical examination should include an evaluation of the head, neck, eyes, 
ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal and
respiratory, gastrointestinal and genitourinary systems. There should be a detailed 
examination of neurological systems. Any abnormality identified at baseline should be 
recorded on the General Medical History and Baseline Conditions eCRF.
At subsequent visits, limited, symptom-directed physical examinations should be 
performed. Changes from baseline abnormalities should be recorded in patient notes. 
New or worsened abnormalities should be recorded as AEs on the Adverse Event page 
of the eCRF.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
52/Protocol BN40900 (SA-309JG), Version 10
4.5.1.8
Efficacy Assessments
Relapse Assessment
All new or worsening neurological events compatible with NMO representing a clinical 
relapse are to be reported in the eCRF. 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 clinical relapse has occurred or not. Clinical 
relapse should be confirmed whether it meets the criteria for protocol-defined relapse or 
not. There will be a treating Investigator and an examining Investigator at each site to 
keep blindness of relapse assessment – the treating Investigator responsible for the 
patient care and the examining Investigator responsible for the administration of the 
EDSS/FSS. The examining Investigator must be appropriately qualified to assess 
EDSS/FSS. The treating Investigator will have access to both safety and efficacy data 
and will make treatment decisions based on the patient’s clinical response and 
laboratory findings. The examining Investigator will have access via the paper form only 
to the EDSS/FSS data (including Relapse Assessment Form) except in an emergency
(such as there is no physician other than for EDSS/FSS assessment in study site) and 
will not consult the patient medical records. The EDSS assessment should always be 
performed by the same examining Investigator from baseline whenever it is feasible and, 
in the double-blind period, will be performed with the assessor blinded to the patient’s 
treatment assignment. The examining Investigator must perform EDSS/FSS assessment 
within seven days after the patient reports the symptoms to the site.
The separation of the role of the treating and examining Investigator should be 
maintained during the OLE extension period whenever possible.
Patients will be instructed not to discuss any symptoms, other than those to EDSS/FSS
assessment, with the examining Investigator; the examining Investigator should remind 
the patient at the start of the examination to discuss any symptoms, other than those to 
EDSS/FSS assessment, with the treating Investigator. Please see Section 3.1.4 for 
procedure of screening for a possible relapse.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
53/Protocol BN40900 (SA-309JG), Version 10
Protocol-defined relapse is the occurrence of new or worsening neurological 
symptoms attributable to NMO or NMOSD. Symptoms must persist for >24 hours and 
should not be attributable to confounding clinical factors (e.g., fever, infection, injury, 
change in mood, 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 2 relapses have onset days that are 
30 days of one another, they will be counted only as 1 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 any of the following:

An increase of at least 1.0 point on the EDSS score excepting increase to 1.0 or 1.5 
from zero (i.e., a 2.0 point increase on the EDSS is required if the baseline was zero)

An increase of at least 2.0 points on one of the appropriate FSS

An increase of at least 1.0 point on two or more of the appropriate FSS if the 
baseline score was one or more

An increase of at least 1.0 point in single eye FSS when the baseline score in that 
eye is one or more
The base of comparison for the increase is the score in the most recent EDSS/FSS 
assessment visit. 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. All patients with new neurological symptoms suggestive of 
relapse should have EDSS/FSS performed during an unscheduled visit. In addition to 
eCRF, a separate Relapse Assessment Form and accompanying necessary data will be 
completed by the site and sent to the PAREXEL Pharmacovigilance department (please 
refer to the instructions in the study manual) during the double-blind period. Relapse 
Assessment Form will be completed in case of the occurrence of any new or worsening 
neurologic symptoms or EDSS/FSS change shown above at EDSS/FSS assessment 
visit. During the double-blind period, the form and the data will be reviewed by a CEC. 
Details regarding the CEC responsibilities and the process of adjudication are described 
in the CEC charter (see Section 3.1.4).
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 NMO, and is included as a 
secondary endpoint in this study. 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 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
54/Protocol BN40900 (SA-309JG), Version 10
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 assisted 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.
A reference to the EDSS/FSS is included in Appendix 2.
Health Status Measurements Using Short Form-36
The SF-36 is a multi-purpose, short-form health survey with 36 questions. It yields an 
8-scale profile (vitality, physical functioning, bodily pain, general health, role-physical, 
role-emotional, social role functioning and mental health) of functional health and 
well-being scores as well as psychometrically-based physical and mental health 
summary measures and a preference-based health utility index. It is a generic measure, 
as opposed to one that targets a disease, or treatment group. 
A reference to the SF-36 questionnaire is included in Appendix 3.
Visual Analogue Scale for Pain
The VAS for pain is a scale 100 mm in length that the patient uses to rate the intensity of 
the pain they experience, from no pain to pain as bad as it could be.
A reference to the VAS for pain is included in Appendix 4.
Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale
The FACIT fatigue scale is a short, 13-item tool that measures and individual’s level of 
fatigue during their usual daily activities over the past 7 days (Webster et al. 2003). The 
level of fatigue is measured on a five-point scale (0not at all to 4very much). 
A reference to the FACIT Fatigue questionnaire is included in Appendix 5.
Visual Function Testing
Visual function testing will be performed with eye charts. Visual acuity will be measured 
by a Snellen chart and LCSLC.
Visual acuity measured using a Snellen chart will be assessed monocularly. Visual 
acuity of LCSLC will be binocularly assessed using 100%, 2.5% and 1.25% contrast 
charts, from a distance of 2 meters.
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.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
55/Protocol BN40900 (SA-309JG), Version 10
Disability Testing using Modified Rankin Scale
The mRS is a commonly used scale for measuring the degree of disability or 
dependence in the daily activities of people who have suffered a stroke or other causes 
of neurological disability. The mRS is scored from 0 (no symptoms at all) to 6 (death).
A reference to the mRS is included in Appendix 6.
Zarit Burden Interview
The ZBI is a popular caregiver self-report measure that originated as a 29-item 
questionnaire (Zarit et al, 1980). The revised version contains 22 items. Each item on 
the interview is a statement which the caregiver is asked to endorse using a 
5-point scale. 
The ZBI should be conducted for the patient’s caregiver (e.g., family, relative) (when 
there is one), if the Investigator considers the caregiver to be reliable by in supporting 
the patient's daily life. The caregiver has knowledge of the patient's condition and 
symptoms, and is acting in an informal or unpaid capacity. Caregivers will be asked to 
sign a separate written informed consent for the collection of data using the ZBI. If a 
caregiver withdraws from the study, the assessment of ZBI is terminated.
A reference to the ZBI questionnaire is included in Appendix 7.
EQ-5D
The EQ-5D scale is a generic measure of health related quality of life that rates subject 
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.
A reference to the EQ-5D questionnaire is included in Appendix 8.
Timed 25-Foot Walk (T25W)
The T25W is a quantitative measure of lower extremity function and is the component of 
the Multiple Sclerosis Functional Composite (MSFC) (Fischer et al., 1999). The patient is 
directed to one end of a clearly marked 25-Foot course and is instructed to walk 25 feet 
as quickly as possible, but safely. The task is immediately administered again by having 
the patient walk back the same distance. Patients may use assistive devices when doing 
this task. The 25-foot lane will be certified by the study coordinator or nurse.
4.5.1.9
Columbia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is a tool used to assess the lifetime suicidality of a patient and to track 
suicidal events through the treatment. The scale will be administered at the time points 
indicated in the Schedule (see Appendix 1) for prompt recollection of suicidal ideation, 
including the intensity of the ideation, behavior and attempts with actual/potential 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
56/Protocol BN40900 (SA-309JG), Version 10
lethality. The “C-SSRS at baseline” should be collected at baseline and the “C-SSRS 
since last visit” should be collected at subsequent visits.
References to the C-SSRS form are included in Appendix 10 (C-SSRS at baseline) and
Appendix 11 (C-SSRS since last visit).
4.5.1.10
Laboratory Assessments
Samples for the following laboratory tests will be sent to the Central Laboratory for 
analysis (except urinalysis and pregnancy tests). Instruction manuals and supply kits will 
be provided for all central laboratory assessments. If a patient cannot visit the study 
site in emergency situations 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, international normalized ratio 
(INR), red blood cell (RBC) count, WBC count, absolute differential count 
[neutrophils, eosinophils, lymphocytes, monocytes, basophils, other cells]).

Serum chemistry (sodium, potassium, chloride, calcium, phosphorous, ferritin, blood 
urea nitrogen (BUN), creatinine, total bilirubin, fibrinogen, total protein, albumin, ALT, 
AST, alkaline phosphatase, gamma-glutamyl transpeptidase (γ-GTP), lactate 
dehydrogenase (LDH), total cholesterol, low density lipoprotein (LDL) cholesterol, 
high density lipoprotein (HDL) cholesterol, triglycerides, creatine kinase (CK), uric 
acid).

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 serum pregnancy test at the study site at the screening visit. 
During the study, serum or urine pregnancy tests will be performed at site, and 
confirmed as negative before the administration of study treatment (except Week 2 
of double-blind and extension period). 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 OLE period of the study (e.g., 
confirmed postmenopausal status) will not require further pregnancy testing.
Postmenopausal status is defined as any of the following: natural menopause with 
last menses 1 year ago; radiation induced with last menses 1 year ago, or due 
to bilateral oophorectomy.

Complement tests (C3, C4 and CH50).

Plasmablasts.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
57/Protocol BN40900 (SA-309JG), Version 10

hsCRP.
Samples for the following laboratory tests will be sent to Sponsor’s designee for analysis.

Pharmacokinetic/Pharmacodynamic assessments.
–
Serum satralizumab concentration, IL-6, sIL-6R, anti-AQP4 antibody.

Immunogenicity assessments.
–
Anti-drug antibodies.

Chugai Clinical Sample Repository (CCSR) (blood/serum/plasma).
The maximum blood volumes that may be taken at each visit, depending upon the 
assessments the patient has opted into, are summarized in Table 1.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
58/Protocol BN40900 (SA-309JG), Version 10
Table 1
Maximum Blood Volumes
Visit(s)
Maximum 
blood volume 
taken (mL) [1]
Double-blind period
Screening
35.5
Week 0
46
Week 2
32.5
Weeks 4 & 8
44
Weeks 5 & 6, Dose outside the visit window
3.5
Weeks 12, 24 & 48, every 24 weeks after Week 48 and at the withdrawal 
visit
47
Weeks 16, 20, 28, 32, 40, 44, every 4 weeks after Week 48
26.5 [2]
Week 36
29.5
At extra visit on relapse
42
Extension period
Weeks 0, 24, 48
32.5
Week 2
16 
Weeks 4, 8, 16, 20, 28, 32, 40, 44
26.5
Every 12 weeks after Week 48
21
Weeks 12, 36 & every 24 weeks after Week 48
29.5
Dose outside the visit window
3.5
At extra visit on relapse
27.5
Last observation visit and withdrawal visit
29.5
[1]
Blood volumes of TB test with using blood sample and serum pregnancy test are calculated 
as 3.0 and 2.0 respectively. These values are depending on the study site.
[2]
29.5 mL every 12 weeks after Week 48.
Assessment of hsCRP, PK, IL-6, sIL-6R, anti-drug antibody, anti-AQP4 antibodies
(except screening), plasmablasts and complement (C3, C4, and CH50) will be 
performed in a blinded manner during the double-blind period of the study.
For details on name and address of laboratory, sampling procedures, sample storage 
and shipment, see the materials in the Site Laboratory Binder.
4.5.1.11
Electrocardiograms
For all patients who consent to the study, ECGs should be performed prior to any blood 
draws. To minimize variability, it is important that patients be in a resting position for 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
59/Protocol BN40900 (SA-309JG), Version 10
≥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 those patients who consent to additional PK testing, triplicate digital ECG recordings 
will be obtained with approximately 25 minutes between each ECG recording at each 
specified time point from baseline. The average of the three readings will be used to 
determine ECG intervals (e.g., PR, QT and QT intervals).
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 using 
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.
For those patients who consent to additional PK testing, triplicate digital ECG should be 
also performed at Weeks 5 and 6, and copies of ECG tracings will be collected at 
baseline and Weeks 5, 6, 24 and 48 by PAREXEL and sent to the Sponsor.
4.5.1.12
Adverse Events
The reporting of AEs is detailed in Section 5.3.
4.5.2
Timing of Study Assessments
4.5.2.1
Screening Assessments
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations. Signed Informed Consent 
Forms (ICFs) for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site.
Screening tests and evaluations will be performed within 28 days prior to baseline, 
unless otherwise specified. All screening evaluations must be completed and reviewed 
to confirm that patient meets all eligibility criteria before randomization. The Investigator 
will maintain a screening log to record details of all patients screened and to confirm 
eligibility or record reasons for screening failure, as applicable.
If a patient fails any laboratory inclusion/exclusion criteria at screening, the test can be 
repeated within 28 days of screening period.


 
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd 
60/Protocol BN40900 (SA-309JG), Version 10 
If a patient has not met all inclusion/exclusion criteria within 28 days of the original 
screening visit, rescreening which refers to repeating whole screening process can be 
conducted twice. Each patient must be re-consented before rescreening occurs. As part 
of the rescreening process, a TB test, an X-ray, hepatitis tests, MRI and anti-AQP4 
antibodies testing are not required if each of them are conducted within 12 weeks prior 
to baseline. Patients may be eligible for rescreening up to two additional times. A retest 
is defined as any assessment repeated within 28 days of screening. 
If relapse occurs during screening period, the patient should be treated as a screening 
failure and should receive the site-specific acute relapse treatment. The patient can be 
rescreened with a new ICF. 
Please see Appendix 1 for the schedule of screening assessments. 
4.5.2.2 
Assessments During Treatment 
Assessment during treatment applies to both double-blind and extension period. All 
assessments must be performed on the day of the specified visit, unless a time window 
is specified in the schedule of assessments (see Appendix 1). Assessments scheduled 
on the day of study treatment administration should be performed prior to administration 
of study treatment, unless otherwise noted in the schedule of assessments.  
If study drug cannot be administered on the scheduled dosing day, 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 
the scheduled study visit assessments. 
Following the implementation of Protocol Version 10, administration of satralizumab 
prefilled syringes outside of the study site may be allowed, in accordance with local 
regulations, only if no on-site assessments are scheduled for that dosing day 
(Appendix 1).  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 
during the OLE period after Week 48 (Appendix 1).  Patients should be followed up by 
phone around the time of the scheduled visit to confirm patient compliance with study 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
61/Protocol BN40900 (SA-309JG), Version 10
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 5.3.5.
Please see Appendix 1 for the schedule of assessments performed during the treatment 
period.
4.5.2.3
Assessments at Last Observation Visit/Withdrawal Visit
The Withdrawal Visit is for patients who withdraw from the study. Every effort should be 
made to conduct the visit at 12 weeks after the last dosing. At the Withdrawal Visit of the 
double-blind period, a complete set of the assessments performed every 24 weeks after 
Week 48 of the double-blind period is to be performed including a chest X-ray. At the 
Withdrawal Visit of the extension period, a complete set of the assessments performed 
every 24 weeks from Week 0 to Week 48 of the extension period is to be performed 
(including a chest X-ray) with the exception of the anti-AQP4 antibody assay.
Patients who complete the double-blind period or experience a protocol-defined relapse 
which is adjudicated by CEC in the double-blind period can enter the open-label 
extension period. Patients completing the open-label extension period will attend a Last 
Observation Visit 12 weeks after the last dose of satralizumab. 
The Last Observation Visit will be conducted 12 weeks after the last dose of 
satralizumab for patients who complete the open-label extension period. At this visit, a 
complete set of the assessments performed at Week 0 of the extension period is to be 
performed (including a chest X-ray) with the exception of the anti-AQP4 antibody assay.  
Patients who complete the OLE period with the last study drug administration on or 
before 31 December 2021 and decide to continue treatment with satralizumab outside of 
this study will not have to complete the Last Observation Visit. 
After the Last Observation Visit or Withdrawal Visit, AEs should be followed as outlined 
in Sections 5.5 and 5.6.
Please see Appendix 1 for the schedule of assessments performed at the Withdrawal 
Visit and the Last Observation.
4.5.2.4
Follow-Up Assessments
Safety Follow-Up will be conducted for patients who withdraw from the study in the 
double-blind period due to clinical relapse and will last for 24 weeks from the last dosing. 
A telephone interview will be conducted by site personnel every 4 weeks from last 
dosing to record details of any medications and treatments NMO/NMOSD the patient is


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
62/Protocol BN40900 (SA-309JG), Version 10
taking and to identify any new or worsening neurological symptoms and data will be 
entered into the relevant pages of the eCRF. 
Please see Appendix 1 for the schedule of follow-up assessments.
4.5.2.5
Assessments at Extra Visits due to Relapse
If patients develop new or worsening neurological symptoms they will attend for an extra 
visit within the shortest reasonable timeframe to have a relapse assessment at the 
investigational site. Please see Appendix 1 for assessments that are required to be 
performed in case of such extra visits.
4.5.2.6
Unscheduled Visits
Any unscheduled visits during the study apart from those mentioned above should be 
captured in the unscheduled visits module in the eCRF.
Regular phone calls to patients will be conducted in order to ensure that relapses are not 
missed. 
4.5.3
Study Schedule
The observation and tests listed in Table 6 (Observation and Test Schedule in the 
Double-Blind Period), Table 7 and Table 8 (Observation and Test Schedule in the 
Extension Period) will be performed.
4.5.3.1
Screening Period (Day -27 to 0 [Week -4 to -1])
All participants must sign an informed consent form before any study-specific 
procedures are performed. All screening procedures are to be conducted within 28 days
of first drug administration, except as noted below:
Day -27 to 0 (Week -4 to -1)

Complete informed consent [Informed consent must be obtained prior to first 
screening assessment, but if informed consent is obtained before the 28-day 
screening period (i.e., before Day -27), all screening assessments must be 
completed within 28 days prior to baseline (i.e., from Day -27 to 0).

Review the study inclusion/exclusion criteria

Record medical history

Physical examination

Record vital signs including body temperature, systolic and diastolic blood pressure 
and pulse rate

ECG should be performed prior to blood draws.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
63/Protocol BN40900 (SA-309JG), Version 10

TB test (e.g., tuberculin test and or/ Quantiferontest) should be conducted 
according as local guidance.

Perform Chest X-ray

Perform pregnancy test for females of child-bearing potential. Serum beta human 
chorionic gonadotropin (β-hCG) must be performed at screening. During the study, 
serum or urine [sensitivity of at least 25 mIU/mL] β-hCG will be performed.

Perform laboratory test: RBC, hemoglobin (Hb), hematocrit (HCT), WBC, WBC 
differentiation, platelets (PLT), INR, fibrinogen, total protein, albumin, total bilirubin, 
alkaline phosphatase (ALP), AST, ALT, γ-GTP, LDH, total cholesterol, LDL, HDL, 
triglyceride, ferritin, BUN, creatinine, CK, sodium (Na), chloride (Cl), potassium (K), 
calcium (Ca), phosphorus (P), complement (CH50, C3, C4), uric acid, urinary 
glucose, urinary protein, urinary occult blood, urobilinogen.

Hepatitis test includes HBsAg, HBcAb, HBsAb, hepatitis C virus antibody (HCVAb). 
If a positive result for HBsAb is not clearly associated with vaccination against 
hepatitis B virus or HBcAb status is positive, hepatitis B viral DNA will be measured.
Efficacy

Conduct EDSS

Brain MRI for screening is required for excluding PML or MS. If PML cannot be 
excluded by MRI, JC virus in the CSF will be measured. Performing an MRI 
scan for exploratory evaluation is optional, will be conducted at selected sites, 
and will require a separate signature on the informed consent.
Exploratory Biomarker

Collect sample for Anti-AQP4 antibody (enzyme linked immunosorbent assay 
[ELISA]).
4.5.3.2
Treatment Period
Safety including adverse events and concomitant medications and efficacy including 
relapse assessment will be monitored and recorded throughout the treatment period of 
the study. During the double-blind period, the site will contact the patient weekly by 
phone calls between the scheduled site visits, to query any change in symptoms or other 
signs of a potential relapse.
Day 1 (Week 0-Baseline)

Review the study inclusion/exclusion criteria

Administer study treatment injection (SC) after all other study-related procedures 
have been performed.

Record body height and weight


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
64/Protocol BN40900 (SA-309JG), Version 10

Physical exam

Record vital signs including body temperature, systolic and diastolic blood pressure 
and pulse rate which are to be measured before dosing and 15 min (±5 min) and 
60 min (±5 min) after dosing in case of study treatment injection visit

Perform ECG (PAREXEL will collect copies of ECG tracings of those patients who 
provided informed consent for additional PK sampling). ECG should be performed 
prior to blood draws.

Perform pregnancy test

Perform laboratory test: RBC, Hb, HCT, 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

Perform C-SSRS (C-SSRS at baseline scale should be used)
Efficacy

Perform EDSS/FSS, Visual Function Testing (Visual function testing includes 
visual acuity tests of Snellen and Low-contrast Sloan letter chart. Visual acuity 
test of Snellen chart is not required if it is implemented with FSS assessment), 
SF-36, VAS for pain, FACIT-fatigue, mRS, EQ-5D and T25W.

ZBI which is optional and will be performed for caregiver who signed informed 
consent to caregiver burden assessment.
PK-PD

Obtain PK sample

Obtain PD sample includes IL-6, sIL-6R and hsCRP and anti-AQP4 antibody.

Obtain plasmablasts sample.
Immunogenicity

Collect sample for anti-drug antibody.
CCSR-this sampling is optional and will require a separate signature on the 
informed consent

Blood samples for DNA analysis, 2 mL blood samples will be taken from the 
patients who consent to the procedure and to CCSR project prior to the first 
injection on Day 1 (Baseline).

Serum and plasma blood samples will be taken from the patients who consent 
to the procedure. 5 mL of serum blood and 4.5 mL for plasma blood.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
65/Protocol BN40900 (SA-309JG), Version 10
Day 15 (Week 2)

Administer study treatment injection (SC) after all other study-related procedures 
have been performed.

Physical exam

Record vital signs

Laboratory test: RBC, Hb, HCT, 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

Perform C-SSRS
PK-PD

Obtain PK sample

Obtain PD sample includes IL-6, sIL-6R and hsCRP and anti-AQP4 antibody.

Obtain plasmablasts sample.
Day 29 (Week 4)

Administer study treatment injection (SC) after all other study-related procedures 
have been performed.

Physical exam

Record vital signs

Perform pregnancy test

Laboratory test: RBC, Hb, HCT, 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

Perform C-SSRS
PK-PD

Obtain PK sample

Obtain PD sample includes IL-6, sIL-6R and hsCRP and anti-AQP4 antibody.

Obtain plasmablasts sample.
Immunogenicity

Collect sample for anti-drug antibody.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
66/Protocol BN40900 (SA-309JG), Version 10
CCSR- this sampling is optional and will require a separate signature on the 
informed consent

Serum and plasma blood samples will be taken from the patients who consent 
to the procedure. 5 mL of serum blood and 4.5 mL for plasma blood.
Day 36 (Week 5) and Day 43 (Week 6)
These visits are optional and will require a separate signature on the informed consent

Perform ECG-the copies of ECG chart should be collected for only patients who 
consent to additional PK sampling. ECG should be performed prior to blood draws.
PK

Obtain PK sample
Day 57 (Week 8)

Administer study treatment injection (SC) after all other study-related procedures 
have been performed.

Physical exam

Record vital signs 

Perform pregnancy test 

Laboratory test: RBC, Hb, HCT, 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

Perform C-SSRS
PK-PD

Obtain PK sample

Obtain PD sample includes IL-6, sIL-6R and hsCRP and anti-AQP4 antibody.

Obtain plasmablasts sample.
Immunogenicity

Collect sample for anti-drug antibody.
CCSR- this sampling is optional and will require a separate signature on the 
informed consent

Serum and plasma blood samples will be taken from the patients who consent 
to the procedure. 5 mL of serum blood and 4.5 mL for plasma blood.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
67/Protocol BN40900 (SA-309JG), Version 10
Day 85 (Week 12)

Administer study treatment injection (SC) after all other study-related procedures 
have been performed.

Physical exam

Record vital signs 

Perform pregnancy test 

Laboratory test: RBC, Hb, HCT, 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.

Hepatitis B viral DNA must be monitored in patients for whom a positive result for 
HBsAb is not clearly associated with vaccination against hepatitis B virus and HBV 
DNA is negative at screening or whom HBcAb is positive and HBV DNA is negative 
at screening.

Perform C-SSRS
Efficacy

Performing an MRI scan for exploratory evaluation is optional, will be
conducted at selected sites, and will require a separate signature on the 
informed consent (Window in days is within ±28 days).
PK-PD

Obtain PK sample

Obtain PD sample includes IL-6, sIL-6R and hsCRP and anti-AQP4 antibody.

Obtain plasmablasts sample.
Immunogenicity

Collect sample for anti-drug antibody.
CCSR- this sampling is optional and will require a separate signature on the 
informed consent

Serum and plasma blood samples will be taken from the patients who consent 
to the procedure. 5 mL of serum blood and 4.5 mL for plasma blood.
Day 113 (Week 16)

Administer study treatment injection (SC) after all other study-related procedures 
have been performed.

Physical exam


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
68/Protocol BN40900 (SA-309JG), Version 10

Record vital signs 

Perform pregnancy test 

Laboratory test RBC, Hb, HCT, 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

Perform C-SSRS
PK-PD

Obtain PK sample

Obtain PD sample includes IL-6, sIL-6R and hsCRP.
Immunogenicity

Collect sample for anti-drug antibody.
Day 141 (Week 20)

Administer study treatment injection (SC) after all other study-related procedures 
have been performed.

Physical exam

Record vital signs 

Perform pregnancy test 

Laboratory test RBC, Hb, HCT, 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

Perform C-SSRS
PK-PD

Obtain PK sample

Obtain PD sample includes IL-6, sIL-6R and hsCRP.
Immunogenicity

Collect sample for anti-drug antibody.
Day 169 (Week 24)

Administer study treatment injection (SC) after all other study-related procedures 
have been performed.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
69/Protocol BN40900 (SA-309JG), Version 10

Record body weight

Physical exam

Record vital signs

Perform ECG - the copies of ECG chart should be collected only for patients who 
consent to additional PK sampling. ECG should be performed prior to blood draws.

Perform pregnancy test 

Laboratory test RBC, Hb, HCT, 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

Hepatitis B viral DNA must be monitored in patients for whom a positive result for 
HBsAb is not clearly associated with vaccination against hepatitis B virus and HBV 
DNA is negative at screening or whom HBcAb is positive and HBV DNA is negative 
at screening.

Perform C-SSRS
Efficacy

Perform EDSS/FSS, Visual Function Testing (Visual function testing includes 
visual acuity tests of Snellen and Low-contrast Sloan letter chart. Visual acuity 
test of Snellen chart is not required if it is implemented with FSS assessment), 
SF-36, VAS for pain, FACIT-fatigue, mRS, EQ-5D and T25W.

Perform ZBI (Window in days is within ±28 days)

Performing an MRI scan for exploratory evaluation is optional, will be
conducted at selected sites, and will require a separate signature on the 
informed consent (Window in days is within ±28 days).
PK-PD

Obtain PK sample

Obtain PD sample includes IL-6, sIL-6R and hsCRP and anti-AQP4 antibody.

Obtain plasmablasts sample.
Immunogenicity

Collect sample for anti-drug antibody.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
70/Protocol BN40900 (SA-309JG), Version 10
CCSR- this sampling is optional and will require a separate signature on the 
informed consent

Serum and plasma blood samples will be taken from the patients who consent 
to the procedure. 5 mL of serum blood and 4.5 mL for plasma blood.
Day 197 (Week 28)

Administer study treatment injection (SC) after all other study-related procedures 
have been performed.

Physical exam

Record vital signs 

Perform pregnancy test 

Laboratory test RBC, Hb, HCT, 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

Perform C-SSRS
PK-PD

Obtain PK sample

Obtain PD sample includes IL-6, sIL-6R and hsCRP.
Immunogenicity

Collect sample for anti-drug antibody.
Day 225 (Week 32)

Administer study treatment injection (SC) after all other study-related procedures 
have been performed.

Physical exam

Record vital signs 

Perform pregnancy test 

Laboratory test RBC, Hb, HCT, 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

Perform C-SSRS


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
71/Protocol BN40900 (SA-309JG), Version 10
PK-PD

Obtain PK sample

Obtain PD sample includes IL-6, sIL-6R and hsCRP.
Immunogenicity

Collect sample for anti-drug antibody.
Day 253 (Week 36)

Administer study treatment injection (SC) after all other study-related procedures 
have been performed.

Physical exam

Record vital signs 

Perform pregnancy test 

Laboratory test RBC, Hb, HCT, 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

Hepatitis B viral DNA must be monitored in patients for whom a positive result for 
HBsAb is not clearly associated with vaccination against hepatitis B virus and HBV 
DNA is negative at screening or whom HBcAb is positive and HBV DNA is negative 
at screening.

Perform C-SSRS
PK-PD

Obtain PK sample

Obtain PD sample includes IL-6, sIL-6R and hsCRP.
Immunogenicity

Collect sample for anti-drug antibody.
Day 281 (Week 40)

Administer study treatment injection (SC) after all other study-related procedures 
have been performed.

Physical exam

Record vital signs 

Perform pregnancy test 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
72/Protocol BN40900 (SA-309JG), Version 10

Laboratory test: RBC, Hb, HCT, 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

Perform C-SSRS
PK-PD

Obtain PK sample

Obtain PD sample includes IL-6, sIL-6R and hsCRP.
Immunogenicity

Collect sample for anti-drug antibody.
Study Day 309 (Week 44)

Administer study treatment injection (SC) after all other study-related procedures 
have been performed.

Physical exam

Record vital signs 

Perform pregnancy test 

Laboratory test RBC, Hb, HCT, 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

Perform C-SSRS
PK-PD

Obtain PK sample

Obtain PD sample includes IL-6, sIL-6R and hsCRP.
Immunogenicity

Collect sample for anti-drug antibody.
Day 337 (Week 48)

Administer study treatment injection (SC) after all other study-related procedures 
have been performed.

Record body weight

Physical exam


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
73/Protocol BN40900 (SA-309JG), Version 10

Record vital signs 

Perform ECG-the copies of ECG chart should be collected for only patients who 
consent to additional PK sampling. ECG should be performed prior to blood draws.

Perform pregnancy test 

Laboratory test RBC, Hb, HCT, 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

Hepatitis B viral DNA must be monitored in patients for whom a positive result for 
HBsAb is not clearly associated with vaccination against hepatitis B virus and HBV 
DNA is negative at screening or whom HBcAb is positive and HBV DNA is negative 
at screening.

Perform C-SSRS
Efficacy

Perform EDSS/FSS, Visual Function Testing (Visual function testing includes 
visual acuity tests of Snellen and Low-contrast Sloan letter chart. Visual acuity 
test of Snellen chart is not required if it is implemented with FSS assessment), 
SF-36, VAS for pain, FACIT-fatigue, mRS, EQ-5D and T25W.

Perform ZBI (Window in days is within ±28 days)

Performing an MRI scan for exploratory evaluation is optional, will be
conducted at selected sites, and will require a separate signature on the 
informed consent (Window in days is within ±28 days).
PK-PD

Obtain PK sample

Obtain PD sample includes IL-6, sIL-6R and hsCRP and anti-AQP4 antibody.

Obtain plasmablasts sample.
Immunogenicity

Collect sample for anti-drug antibody.
CCSR- this sampling is optional and will require a separate signature on the 
informed consent

Serum and plasma blood samples will be taken from the patients who consent 
to the procedure. 5 mL of serum blood and 4.5 mL for plasma blood.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
74/Protocol BN40900 (SA-309JG), Version 10
After Day 337 (Week 48), the following assessments to be performed:
Every 4 Weeks  

Administer study treatment injection (SC) after all other study-related procedures 
have been performed.

Perform physical exam

Record vital signs 

Perform pregnancy test for females of child-bearing potential. Serum or urine β-hCG 
[sensitivity of at least 25 mIU/mL] will be performed.

Laboratory test: RBC, Hb, HCT, 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

Hepatitis B viral DNA must be monitored every 12 weeks in patients for whom a 
positive result for HBsAb is not clearly associated with vaccination against hepatitis 
B virus and HBV DNA is negative at screening or whom HBcAb is positive and HBV 
DNA is negative at screening.

Perform C-SSRS
Safety

Adverse events and concomitant medications will be monitored and recorded 
throughout the study
Efficacy

Relapse assessment will be monitored and recorded throughout the study.
PK-PD

Obtain PK sample

Obtain PD sample includes IL-6, sIL-6R and hsCRP.
Immunogenicity

Collect sample for anti-drug antibody
Every 24 Weeks

Administer study treatment injection (SC) after all other study-related procedures 
have been performed.

Record body weight.

Perform physical exam.

Record vital signs.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
75/Protocol BN40900 (SA-309JG), Version 10

ECG should be performed prior to blood draws.

Perform pregnancy test for females of child-bearing potential. Serum or urine β-hCG 
[sensitivity of at least 25 mIU/mL] will be performed.

Laboratory test RBC, Hb, HCT, 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.

Hepatitis B viral DNA must be monitored in patients for whom a positive result for 
HBsAb is not clearly associated with vaccination against hepatitis B virus and HBV 
DNA is negative at screening or whom HBcAb is positive and HBV DNA is negative 
at screening.

Perform C-SSRS
Safety

Adverse events and concomitant medications will be monitored and recorded 
throughout the study.
Efficacy

Relapse assessment will be monitored and recorded throughout the study.

EDSS/FSS.

Visual Function Testing (visual function testing includes visual acuity tests of 
Snellen and Low-contrast Sloan letter chart. Visual acuity test of Snellen chart 
is not required if it is implemented with FSS assessment), SF-36, VAS for pain, 
FACIT-fatigue, mRS, EQ-5D and T25W.

ZBI which is optional and will be performed (window in days is within ±28 days) 
for caregiver who signed informed consent to caregiver burden assessment.
PK-PD

Obtain PK sample.
–
Obtain PD sample includes IL-6, sIL-6R and hsCRP and anti-AQP4 
antibody.
–
Obtain plasmablasts sample.
Immunogenicity

Collect sample for anti-drug antibody


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
76/Protocol BN40900 (SA-309JG), Version 10
CCSR- this sampling is optional and will require a separate signature on the 
informed consent

Serum and plasma blood samples will be taken from the patients who consent 
to the procedure. 5 mL of serum blood and 4.5 mL for plasma blood.
During the double-blind period, when an extra visit at relapsing occurs, the 
following assessments are to be performed:

Perform physical exam

Record vital signs 

Laboratory test RBC, Hb, HCT, 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
Safety

Adverse events and concomitant medications will be monitored and recorded 
throughout the study
Efficacy

EDSS/FSS
PK-PD

Obtain PK sample

Obtain PD sample includes IL-6, sIL-6R and hsCRP and anti-AQP4 antibody.

Obtain plasmablasts sample.
CCSR- this sampling is optional and will require a separate signature on the 
informed consent

Serum and plasma blood samples will be taken from the patients who consent 
to the procedure. 5 mL of serum blood and 4.5 mL for plasma blood.
Withdrawal visit (WD) 
This visit should be performed for patients who withdraw from the study. Every effort 
should be made to conduct the visit at 12 weeks after the last dosing. Assessments to 
be performed at this visit are:

Record body weight

Perform physical exam

Record vital signs

ECG should be performed prior to blood draws.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
77/Protocol BN40900 (SA-309JG), Version 10

Perform Chest X-ray

Perform pregnancy test for females of child-bearing potential. Serum or urine β-hCG 
[sensitivity of at least 25 mIU/mL] will be performed.

Laboratory test RBC, Hb, HCT, 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

Hepatitis B viral DNA must be monitored in patients for whom a positive result for 
HBsAb is not clearly associated with vaccination against hepatitis B virus and HBV 
DNA is negative at screening or whom HBcAb is positive and HBV DNA is negative 
at screening.

Perform C-SSRS
Safety

AEs and concomitant medications will be monitored and recorded throughout 
the study
Efficacy

Relapse assessment will be monitored and recorded throughout the study.

EDSS/FSS

Visual Function Testing (visual function testing includes visual acuity tests of 
Snellen and Low-contrast Sloan letter chart. Visual acuity test of Snellen chart 
is not required if it is implemented with FSS assessment), SF-36, VAS for pain, 
FACIT-fatigue, mRS, EQ-5D and T25W.

ZBI which is optional and will be performed (window in days is within ±28 days) 
for caregiver who signed informed consent to caregiver burden assessment.
PK-PD

Obtain PK sample

Obtain PD sample includes IL-6, sIL-6R and hsCRP and anti-AQP4 antibody.

Obtain plasmablasts sample.
Immunogenicity

Collect sample for anti-drug antibody.


 
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd 
78/Protocol BN40900 (SA-309JG), Version 10 
CCSR- this sampling is optional and will require a separate signature on the 
informed consent 
• 
Serum and plasma blood samples will be taken from the patients who consent 
to the procedure. 5 mL of serum blood and 4.5 mL for plasma blood. 
 
Safety Follow-up (SFU) 
SFU will be conducted for patients who withdraw from the study in double-blind period 
due to clinical relapse and will last for 24 weeks from the last dosing. A telephone 
interview will be conducted by site personnel every 4 weeks from last dosing to identify 
any new or worsening neurological symptoms. The following assessments will be 
performed at these visits: 
Safety 
• 
Information on concomitant medication/therapy for NMO and NMOSD will be 
collected. 
 
Efficacy 
• 
Relapse assessment will be monitored and recorded throughout the study. 
  
Observation and Test Schedule in the Extension Period 
Week 0 
Patients who experienced a protocol-defined relapse which is adjudicated by CEC can 
visit the study site in the stable disease condition (Day 31 or later, where Day 1 is 
defined as the day of onset of a protocol-defined relapse which is adjudicated by CEC). 
Patients who completed the double-blind period can visit the study site after 4 weeks 
(± 7 days) from the last dosing in the double-blind period. The following procedures will 
be performed: 
• 
Administer satralizumab injection (SC) after all other study-related procedures have 
been performed. 
• 
Record body weight. 
• 
Perform physical exam. 
• 
Record vital signs.  
• 
Perform ECG prior to blood draws. 
• 
Perform pregnancy test for females of child-bearing potential. Serum or urine 
[sensitivity of at least 25 mIU/mL] β-hCG will be performed. 
• 
Laboratory test: RBC, Hb, HCT, 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. 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
79/Protocol BN40900 (SA-309JG), Version 10

Hepatitis B viral DNA must be monitored in patients for whom a positive result for 
HBsAb is not clearly associated with vaccination against hepatitis B virus and HBV 
DNA is negative at screening or whom HBsAb is positive and HBV DNA is negative 
at screening.

Perform C-SSRS
Safety

AEs and concomitant medications will be monitored and recorded throughout 
the study
Efficacy

Relapse assessment will be monitored and recorded throughout the study.

Perform EDSS/FSS

Visual Function Testing (visual function testing includes visual acuity tests of 
Snellen and Low-contrast Sloan letter chart. Visual acuity test of Snellen chart 
is not required if it is implemented with FSS assessment), SF-36, VAS for pain, 
FACIT-fatigue, mRS, EQ-5D and T25W.

ZBI which is optional and will be performed (window in days is within ±28 days) 
for caregiver who signed informed consent to caregiver burden assessment.

Performing an MRI scan for exploratory evaluation is optional, will be 
conducted at selected sites, and will require a separate signature on the 
informed consent (Window in days is within ±28 days). Only for patients who 
end the double-blind period by Week 48 of the double-blind period.
PK-PD

Obtain PK sample.

Obtain PD sample includes IL-6, sIL-6R and hsCRP and anti-AQP4 antibody.
Immunogenicity

Collect sample for anti-drug antibody.
Week 2

Administer satralizumab injection (SC) after all other study-related procedures have 
been performed.

Perform physical exam.

Vital signs.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
80/Protocol BN40900 (SA-309JG), Version 10

Laboratory test: RBC, Hb, HCT, 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.

Perform C-SSRS
Safety

AE and concomitant medications will be monitored and recorded throughout 
the study.
Efficacy

Relapse assessment will be monitored and recorded throughout the study.
From Week 0 to Week 48, the following procedures will be performed in the 
Extension Period:
Every 4 weeks

Administer satralizumab injection (SC) after all other study-related procedures have 
been performed.

Perform physical exam.

Record vital signs.

Perform pregnancy test for females of child-bearing potential. Serum or urine β-hCG 
[sensitivity of at least 25 mIU/mL] will be performed.

Laboratory test: RBC, Hb, HCT, 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.

Hepatitis B viral DNA must be monitored every 12 weeks in patients for whom a 
positive result for HBsAb is not clearly associated with vaccination against hepatitis 
B virus and HBV DNA is negative at screening or whom HBcAb is positive and HBV 
DNA is negative at screening.

Perform C-SSRS
Safety

AEs and concomitant medications will be monitored and recorded throughout 
the study.
Efficacy

Relapse assessment will be monitored and recorded throughout the study.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
81/Protocol BN40900 (SA-309JG), Version 10
PK-PD

Obtain PK sample.

Obtain PD sample includes IL-6, sIL-6R and hsCRP.
Immunogenicity

Collect sample for anti-drug antibody.
Every 24 Weeks

Administer satralizumab injection (SC) after all other study-related procedures have 
been performed.

Record body weight.

Perform physical exam.

Record vital signs.

ECG should be performed prior to blood draws.

Perform pregnancy test for females of child-bearing potential. Serum or urine 
[sensitivity of at least 25 mIU/mL] β-hCG will be performed.

Laboratory test: RBC, Hb, HCT, 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.

Hepatitis B viral DNA must be monitored in patients for whom a positive result for 
HBsAb is not clearly associated with vaccination against hepatitis B virus and HBV 
DNA is negative at screening or whom HBcAb is positive and HBV DNA is negative 
at screening.

Perform C-SSRS
Safety

AE and concomitant medications will be monitored and recorded throughout 
the study.
Efficacy

Relapse assessment will be monitored and recorded throughout the study.

Perform EDSS/FSS.

Visual Function Testing (visual function testing includes visual acuity tests of 
Snellen and Low-contrast Sloan letter chart. Visual acuity test of Snellen chart 
is not required if it is implemented with FSS assessment), SF-36, VAS for pain, 
FACIT-fatigue, mRS, EQ-5D and T25W.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
82/Protocol BN40900 (SA-309JG), Version 10

ZBI which is optional and will be performed (window in days is within ±28 days) 
for caregiver who signed informed consent to caregiver burden assessment.

Performing an MRI scan for exploratory evaluation is optional, will be 
conducted at selected sites, and will require a separate signature on the 
informed consent (Window in days is within ±28 days. Week 48 only.). Only for 
patients who end the double-blind period by Week 48 of the double-blind period.
PK-PD

Obtain PK sample

Obtain PD sample includes IL-6, sIL-6R and hsCRP and anti-AQP4 antibody.
Immunogenicity

Collect sample for anti-drug antibody
After Week 48, the following procedures will be performed in the Extension 
Period:
Every 4 weeks

Administer satralizumab injection (SC) after all other study-related procedures have 
been performed.

In accordance with local regulations, patients may have study drug administered 
outside of the study site for these visits.  In such cases, patients should be followed 
up through phone calls from the study site to monitor treatment compliance and 
perform safety and efficacy assessments as described below.
Safety

AEs and concomitant medications will be monitored and recorded throughout 
the study.
Efficacy

Relapse assessment will be monitored and recorded throughout the study.
Every 12 Weeks

Administer satralizumab injection (SC) after all other study-related procedures have 
been performed.

Perform physical exam.

Record vital signs. 

Perform pregnancy test for females of child-bearing potential. Serum or urine β-hCG 
[sensitivity of at least 25 mIU/mL] will be performed.

Laboratory test: RBC, Hb, HCT, 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 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
83/Protocol BN40900 (SA-309JG), Version 10
(CH50, C3, C4), uric acid, urinary glucose, urinary protein, urinary occult blood, 
urobilinogen.

Hepatitis B viral DNA must be monitored in patients for whom a positive result for 
HBsAb is not clearly associated with vaccination against hepatitis B virus and HBV 
DNA is negative at screening or whom HBcAb is positive and HBV DNA is negative 
at screening.

Perform C-SSRS
Safety

AEs and concomitant medications will be monitored and recorded throughout 
the study.
Efficacy

Relapse assessment will be monitored and recorded throughout the study.
Every 24 Weeks

Administer satralizumab injection (SC) after all other study-related procedures have 
been performed.

Record body weight.

Perform physical exam.

Record vital signs. 

ECG should be performed prior to blood draws.

Perform pregnancy test for females of child-bearing potential. Serum or urine 
[sensitivity of at least 25 mIU/mL] β-hCG will be performed.

Laboratory test: RBC, Hb, HCT, 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.

Hepatitis B viral DNA must be monitored in patients for whom a positive result for 
HBsAb is not clearly associated with vaccination against hepatitis B virus and HBV 
DNA is negative at screening or whom HBcAb is positive and HBV DNA is negative 
at screening.

Perform C-SSRS
Safety

AE and concomitant medications will be monitored and recorded throughout 
the study.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
84/Protocol BN40900 (SA-309JG), Version 10
Efficacy

Relapse assessment will be monitored and recorded throughout the study.

Perform EDSS/FSS.

Visual Function Testing (visual function testing includes visual acuity tests of 
Snellen and Low-contrast Sloan letter chart. Visual acuity test of Snellen chart 
is not required if it is implemented with FSS assessment), SF-36, VAS for pain, 
FACIT-fatigue, mRS, EQ-5D and T25W.

ZBI which is optional and will be performed (window in days is within ±28 days) 
for caregiver who signed informed consent to caregiver burden assessment.
PK-PD

Obtain PK sample
Immunogenicity

Collect sample for anti-drug antibody
During the Extension Period, when extra visits at relapsing occur, the 
following procedures will be performed:

Perform physical exam

Record Vital signs 

Laboratory test: RBC, Hb, HCT, 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
Safety

Adverse events and concomitant medications will be monitored and recorded 
throughout the study
Efficacy

Relapse assessment will be monitored and recorded throughout the study.

Perform EDSS/FSS
PK-PD

Obtain PK sample

Obtain PD sample includes IL-6, sIL-6R and hsCRP until Week 48 and 
anti-AQP4 antibody.
Immunogenicity

Collect sample for anti-drug antibody after Week 48.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
85/Protocol BN40900 (SA-309JG), Version 10
Last Observation Visit
This visit will be conducted 12 weeks after the last dose of satralizumab for patients who 
complete the extension period. The following procedures will be performed:

Record body weight.

Perform physical exam.

Record vital signs.

ECG should be performed prior to blood draws.

Perform chest X-ray.

Perform pregnancy test for females of child-bearing potential. Serum or urine 
[sensitivity of at least 25 mIU/mL] β-hCG will be performed.

Laboratory test: RBC, Hb, HCT, 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.

Hepatitis B viral DNA must be monitored in patients for whom a positive result for 
HBsAb is not clearly associated with vaccination against hepatitis B virus and HBV 
DNA is negative at screening or whom HBcAb is positive and HBV DNA is negative 
at screening.

Perform C-SSRS
Safety

AEs and concomitant medications will be monitored and recorded throughout 
the study.
Efficacy

Relapse assessment will be monitored and recorded throughout the study.

Perform EDSS/FSS

Visual Function Testing (visual function testing includes visual acuity tests of 
Snellen and Low-contrast Sloan letter chart. Visual acuity test of Snellen chart 
is not required if it is implemented with FSS assessment), SF-36, VAS for pain, 
FACIT-fatigue, mRS, EQ-5D and T25W.

ZBI which is optional and will be performed (window in days is within ±28 days) 
for caregiver who signed informed consent to caregiver burden assessment.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
86/Protocol BN40900 (SA-309JG), Version 10
PK-PD

Obtain PK sample

Obtain PD sample includes IL-6, sIL-6R and hsCRP
Immunogenicity

Collect sample for anti-drug antibody
Withdrawal Visit
For patients who withdraw from the study, every effort should be made to conduct the 
visit at 12 weeks after the last dose of satralizumab. The following assessments will be 
performed:

Record body weight.

Perform physical exam.

Record vital signs.

ECG should be performed prior to blood draws.

Perform chest X-ray.

Perform pregnancy test for females of child-bearing potential. Serum or urine 
[sensitivity of at least 25 mIU/mL] β-hCG will be performed.

Laboratory test: RBC, Hb, HCT, 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.

Hepatitis B viral DNA must be monitored in patients for whom a positive result for 
HBsAb is not clearly associated with vaccination against hepatitis B virus and HBV 
DNA is negative at screening or whom HBcAb is positive and HBV DNA is negative 
at screening.

Perform C-SSRS
Safety

AEs and concomitant medications will be monitored and recorded throughout 
the study
Efficacy

Relapse assessment will be monitored and recorded throughout the study.

Perform EDSS/FSS


 
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd 
87/Protocol BN40900 (SA-309JG), Version 10 
• 
Visual Function Testing (Visual function testing includes visual acuity tests of 
Snellen and Low-contrast Sloan letter chart. Visual acuity test of Snellen chart 
is not required if it is implemented with FSS assessment), SF-36, VAS for pain, 
FACIT-fatigue, mRS, EQ-5D and T25W. 
• 
ZBI which is optional and will be performed (window in days is within ±28 days) 
for caregiver who signed informed consent to caregiver burden assessment. 
 
PK-PD 
• 
Obtain PK sample 
• 
Obtain PD sample includes IL-6, sIL-6R and hsCRP 
 
Immunogenicity 
• 
Collect sample for anti-drug antibody 
 
4.6 
CHUGAI CLINICAL SAMPLE REPOSITORY (CCSR)  
The CCSR project is an independent and optional sub-study of the main study BN40900 
(SA-309JG). The CCSR for this study is run by Chugai Pharmaceutical Co., Ltd. on 
behalf of the Sponsor. 
Should a site opt to participate in the CCSR sub-study, their patients will be given the 
option to participate in CCSR project. 
For blood samples for DNA analysis, 2 mL blood samples will be taken from the patients 
who consent to the procedure and to CCSR project prior to the first injection on Day 1 
(Baseline). The blood samples will be stored by the Sponsor for up to 15 years after the 
end of the associated main study (database closure) at which time they will be destroyed. 
For the CCSR, serum and plasma samples will be taken from the patients who consent 
to the procedure. Blood for serum and plasma samples (each 5 mL for serum and 
4.5 mL for plasma) will be taken at the time points indicated in the Schedule of 
Assessments (see Appendix 1). The serum and plasma samples will be stored by the 
Sponsor for up to 5 years after the end of the associated main study. The samples will 
be used for analysis of proteins such as, but not limited to, cytokines and chemokines. 
These samples will be used only for purpose of retrospective CCSR research analysis to 
understand inter-individual variability in satralizumab efficacy, safety and 
pharmacokinetics as will be explained in the Informed Consent Form. The Informed 
Consent for an optional specimen donation will be incorporated as a specific section into 
the main Clinical Trial ICF. A second, separate, specific signature consenting to 
specimen donation will be required to document the study participant’s agreement to 
provide an optional specimen; if the participant declines, he/she will check a “no” box in 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
88/Protocol BN40900 (SA-309JG), Version 10
the appropriate section and not provided a second signature. The blood, serum and 
plasma sampling for CCSR will be contingent on a site’s Institutional Review Board (IRB) 
and/or Independent Ethics Committee (IEC) approval of sampling for the CCSR and the 
Informed Consent Form. If a site’s IRB and/or IEC does not approve the sampling, this 
section of CCSR project will not be applicable.
4.6.1
Schedule of Assessments and Procedures
4.6.1.1
Study Procedures
After written informed consent for the associated main clinical study has been obtained 
from a patient, the blood, serum and plasma sampling will be explained. The patient will 
be asked if they wish to participate in CCSR project, and written informed consent will be 
obtained specifically for CCSR project.
The blood, serum and plasma samples are scheduled to be collected at the time points 
detailed in the Schedule of Assessments (Appendix 1).
Dates of consent and sample collection should be recorded on the CCSR section of the 
study eCRF.
4.6.1.2
Sampling Procedures
Blood samples for DNA analysis: 
A 2 mL venous blood sample will be collected into a blood collection tube containing 
ethylenediaminetetraacetic acid as anti-coagulant. The blood will be transferred to a 
storage tube. Samples will then be stored at approximately -20°C. Details on sample 
handling procedures, sample storage, and shipment are described in the supplemental 
laboratory manual.
Serum samples:
A 5 mL venous blood sample will be collected into a blood collection tube. The blood will 
be placed to clot at room temperature (30 min, not more than 60 min after blood 
collection) and then be centrifuged for 10 min at 4°C at 1700 g. The serum will be 
collected and transferred to storage tubes. Details on sample handling procedures, 
sample storage and shipment are described in the laboratory manual.
Plasma samples:
A 4.5 mL venous blood sample will be collected into a blood collection tube containing 
sodium citrate as anti-coagulant. The blood will be centrifuged for 10 min at 4°C at 
1700 g. The plasma will be collected and transferred to storage tubes. Plasma 
separation should be carried out immediately after blood draw. If this is not possible, 
blood should be kept on an ice bath until centrifugation (not more than 30 minutes after 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
89/Protocol BN40900 (SA-309JG), Version 10
blood collection). Details on sample handling procedures, sample storage and shipment 
are described in the supplemental laboratory manual.
4.6.1.3
CCSR
These samples will be transferred to and stored in the CCSR on behalf of the Sponsor.
4.6.1.4
Biomarker Research Analysis Protocol 
When the schedules or contents of a biomarker analysis using CCSR samples are 
specified, “Biomarker Research Analysis Protocol” will also be prepared before the 
research will be performed. 
The samples and results of anti-AQP4 antibody may be used for development of a 
companion diagnostic for satralizumab in the future.
4.6.2
Sample Confidentiality and Sample Destruction
It is the intent of Sponsor to assure that pharmacogenomic and biomarker information 
obtained from patient blood, serum, and plasma samples remains confidential. The 
Sponsor already maintains rigorous confidentiality standards for clinical studies by 
“coding” (i.e., assigning a unique patient identification (ID) number at the Investigator site) 
all patients enrolled in the Sponsor’s clinical studies. This means patient names are 
never revealed to anyone at the Sponsor. Given the sensitive nature of 
pharmacogenomic data, the Sponsor has implemented a number of additional 
processes to assure patient confidentiality. All samples taken for blood samples for DNA 
analysis undergo a second level of “coding”. At the Sponsor, the new label with a new 
random number referred to as the double-coded ID is placed over the original label of 
the blood sample. Identified only by the double-code ID, the samples will be forwarded to 
storage and DNA analysis. 
Both the patient ID number and the double-coded ID number will co-exist as a table in a 
sample repository code manager. This allows patients to withdraw their sample from the 
blood samples for DNA analysis during their participation in the associated main clinical 
study if they change their mind after signing the ICF. 
The blood samples for DNA analysis and serum/blood samples for protein analysis will 
be stored by the Sponsor for up to 15 years and 5 years respectively after the end of the 
associated main study (database closure) at which time they will be destroyed.
4.6.3
Withdrawal of Patients from the CCSR Project
Patients who give consent to the CCSR project have the right to withdraw their consents 
from the CCSR project at any time for any reason. If a patient wishes to withdraw his/her 
consent from the CCSR project, the Investigator must inform the Sponsor in writing of 
the patient’s wishes using the CCSR Subject Withdrawal Form (Appendix 9). If a patient 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
90/Protocol BN40900 (SA-309JG), Version 10
wishes to withdraw his/her consent to the testing of his/her specimen(s) during their 
participation in the clinical study, the Investigator must enter the date of the withdrawal in 
the patients eCRF. Within the Sponsor, the request for sample withdrawal will be 
forwarded to the biomarker operation. A patient’s withdrawal from the main study does
not, by itself, constitute withdrawal from the CCSR project. Likewise, a patient’s 
withdrawal from the CCSR project does not constitute a withdrawal from the main study.
In the case of blood sample for DNA analysis, if a patient wishes to withdraw the consent 
to use the sample, then the sample must be destroyed. In the case of serum and plasma 
samples, if a patient wishes to withdraw the consent both to collect subsequent samples 
and to use the samples already collected, then the samples already collected must be 
destroyed. If a patient wishes to withdraw only the consent to collect subsequent 
samples, the Sponsor can use samples and the data from the samples already collected. 
If DNA, proteins, and other substances have already been analyzed at the time the 
Sponsor receives a CCSR Subject Withdrawal Form, the data from those analysis will 
not be destroyed. If the blood sample for DNA analysis, serum sample and plasma 
sample to be destroyed are at the Sponsor or central laboratory, the biomarker operation 
will issue confirmation of the withdrawal, which will be forwarded to the Investigator. If 
the blood samples for DNA analysis, serum sample and plasma sample to be destroyed 
are still at the Investigator site at the time a patient wishes to withdraw his/her sample, 
the Investigator must inform the Sponsor as before, destroy the sample and sign the 
CCSR Subject Withdrawal Form to confirm that this has been done. The Sponsor will 
forward confirmation of the destruction, recorded on the Subject Withdrawal Form, to the 
biomarker operation.
4.6.4
Benefits to Donors
Donors will not benefit personally from the biomarker research because the aim is to 
evaluate potential patient-selection and efficacy/safety markers and to generate or test 
hypotheses by analyzing the data and compiling the overall results. However, the 
findings may contribute to future medical treatment with satralizumab.
4.7
PATIENT, STUDY AND SITE DISCONTINUATION
4.7.1
Patient Discontinuation
The Investigator has the right to discontinue a patient from study treatment or withdraw a 
patient from the study at any time. In addition, patients have the right to voluntarily 
discontinue study treatment or withdraw from the study at any time for any reason. 
Reasons for discontinuation of study treatment or withdrawal from the study may include, 
but are not limited to, the following:

Patient withdrawal of consent at any time.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
91/Protocol BN40900 (SA-309JG), Version 10

Any medical condition that the Investigator or Sponsor/Medical Monitor determines 
may jeopardize the patient’s safety if he or she continues in the study.
Investigator or Sponsor/Medical Monitor determines it is in the best interest of the patient.
Additionally, the patient may be discontinued from the study for the following reasons:

Major protocol violation.

Administrative reasons.

Lost to follow-up.
If a patient wishes to discontinue from study treatment or withdraw from the study, the 
Investigator should conduct an interview with the patient using uniform procedures with 
scripted questions to evaluate potential relapse (e.g., any new symptoms of a potential 
relapse or adverse events) and minimize dropout or discontinuation from the study due 
to reasons such as misunderstanding of the study design.
The withdrawal visit will be performed as noted in Section 4.5.3.2 and Appendix 1.
4.7.1.1
Discontinuation of Study Treatment
In addition to the criteria listed above, reasons for withdrawal of the study treatment but 
which do not preclude the patient remaining in the study include, but are not limited to, if 
the patient:

Meets the discontinuation criteria in the risk mitigation and dose modification 
strategy (see Section 5.1).

Misses three consecutive doses of study drug on scheduled visits in the double-
blind period.

Experiences two relapses in the open-label extension period with a more severe 
intensity compared with the last relapse prior to baseline.
Investigator should consult with the Medical Monitor if these relapses meet this 
criterion.

Experiences malignancy or a severe allergic or anaphylactic reaction to 
satralizumab.

Pregnancy.

Unacceptable toxicity.
If the patient is unwilling to continue in the study, he/she will be asked to return to the 
clinic for a Withdrawal visit (see Section 4.5.2.3) and may undergo follow-up 
assessments (see Section 4.5.2.4). The primary reason for premature study treatment


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
92/Protocol BN40900 (SA-309JG), Version 10
discontinuation should be documented on the appropriate eCRF. Patients who 
discontinue study treatment prematurely will not be replaced.
4.7.1.2
Withdrawal from Study
Every effort should be made to obtain information on patients who withdraw from the 
study. The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF. Patients will not be followed for any reason after consent has been 
withdrawn. Patients who withdraw from the study will not be replaced.
4.7.2
Study and Site 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 or its designee will notify the Investigator if the study is placed on hold, or if 
the Sponsor decides to discontinue the study or development program.
The Sponsor has the right to replace a site at any time. Reasons for replacing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for GCP
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
5.1.1
Important Identified and Potential Risks of Satralizumab
On the basis of mechanism of action, key non-clinical and clinical safety findings, 
experience with similar molecules, an Integrated Summary of Safety Information is 
included in the current Investigator’s Brochure for satralizumab. Please refer to the 
current satralizumab Investigator's Brochure for an up-to-date summary of available 
safety information.
There have been no important identified or potential risks for satralizumab. The safety 
management plan for other potential risks and laboratory abnormalities associated with 
satralizumab, and risks for drugs in the same drug class are outlined below.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
93/Protocol BN40900 (SA-309JG), Version 10

Serious Infections

Neutropenia and Potential Risk of Infection 

Thrombocytopenia and Potential Risk of Bleeding

Liver Enzyme and Bilirubin Elevations and Potential Risk of Hepatotoxicity

Elevated Lipid Levels and Potential Risk of Cardiovascular/Cerebrovascular Events

Immunogenicity

Serious Hypersensitivity Reactions

CYP450 Enzyme Normalization

Complications of Diverticulitis

Malignancies

Demyelinating Disorders
In order to address the risks for the patients, the following safety precautions are 
included in the study design:

In addition to regular standard safety evaluations (laboratory measures, physical 
examinations, vital signs and ECG), a special focus will be placed on the above 
risks.

An IDMC will evaluate the safety of patients every six months during the double-
blind period of the study.

A patient ID card which includes information about the study, investigational drug 
and Investigator’s contact information will be provided to the patient. Patients should 
be instructed to show this card to healthcare professionals in case they contact any 
other hospital/clinic, etc. In addition, a Dear Doctor Letter which includes information 
about the study and investigational drug should be provided to healthcare 
professionals, in case patients contact any other hospital/clinic etc.
Recommendation for vigilance with regards to sign and symptoms of particular safety 
events are summarized in the following sections.
5.1.1.1
Serious infection
In a Phase I multiple dose study of satralizumab in patients with rheumatoid arthritis 
(SA-105JP), one case of serious infection, bronchopneumonia (1of 33 patients), was 
reported. Serious infection is an identified risk of tocilizumab. In the all-exposure 
population of tocilizumab, the most common serious infections included pneumonia, 
urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and 
bacterial arthritis. 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
94/Protocol BN40900 (SA-309JG), Version 10
Treatment with satralizumab 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. As a result, it may potentially 
make the infection more serious.
In the completed double-blind periods of the Phase 3 studies (BN40898 and BN40900), 
the rates of infections and serious infections in the satralizumab group were not higher 
than in the placebo group.
Patients with an active infection (excluding fungal infections of nail beds or caries 
dentium) within 4 weeks prior to baseline will be excluded from this study.
Patients with evidence of active TB (excluding patients receiving chemoprophylaxis for 
latent TB) will be excluded from this study.
Patients with chronic active hepatitis B or C will be excluded from this study.
Patients who received any live or live attenuated vaccine within 6 weeks prior to baseline 
will be excluded from this study.

Satralizumab should not be initiated or administered in patients with active infections.

Patients should be closely monitored for the development of signs and symptoms of 
infection, as signs and symptoms of acute inflammation may be lessened due to 
suppression of the acute phase reactants. 

Patients must be instructed to contact their physician immediately when any 
symptoms suggesting infection appear, in order to ensure rapid evaluation and 
appropriate treatment. 

If a patient develops 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 within 6 weeks prior to 
baseline and during the course of the study as clinical safety has not been
established.
5.1.1.2
Neutropenia and Potential Risk of Infection
Reversible neutropenia was reported in 1 of 33 patients with rheumatoid arthritis in the 
Phase I multiple dose study (SA-105JP).
In the completed double-blind period of the Phase 3 studies, decreases in neutrophil 
counts have occurred following treatment with satralizumab, which was not associated 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
95/Protocol BN40900 (SA-309JG), Version 10
with serious infections. The majority of neutrophil decreases were transient or 
intermittent.
Patients with a low neutrophil count <2 x103/uL will be excluded from this study.
Caution should be exercised in patients with a low neutrophil count and appropriate 
measures (such as interruption of satralizumab) should be considered if neutropenia 
persists.
Recommended dose interruption based on ANC results is shown in Table 2.
Table 2
Neutropenia Risk Mitigation
ANC (/uL)
Action
>1,000
Maintain dose
500 – 1,000

If neutropenia persists, satralizumab should be interrupted until ANC is 
above 1,000/uL.

If ANC is under 1,000/uL 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.
5.1.1.3
Thrombocytopenia and Potential Risk of Bleeding
Treatment-related reduction in platelet count has been observed in the Phase I multiple 
dose study with rheumatoid arthritis (SA-105JP), although these were within normal 
range. 
In the Phase 3 studies, decreases in platelet counts have been observed following 
treatment with satralizumab.
Treatment-related reduction in platelets was not associated with bleeding events in 
clinical trials.
Patients with a platelet count below 10 x104/μL will be excluded from this study.
Caution should be exercised in patients with a low platelet count and appropriate 
measures (such as interruption of satralizumab) should be considered if 
thrombocytopenia persists.
Recommended dose interruption based on PLT count is shown in Table 3.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
96/Protocol BN40900 (SA-309JG), Version 10
Table 3
Thrombocytopenia Risk Mitigation
Platelet count (/uL）
Action
>75,000
Maintain dose
50,000 – 75,000
If thrombocytopenia persists, satralizumab should be interrupted 
until platelet count is above 75,000/uL.
<50,000
Satralizumab should be discontinued.
5.1.1.4
Liver Enzyme and Bilirubin Elevations and Potential Risk of 
Hepatotoxicity
Reversible elevations of AST and total bilirubin were each observed in 2 healthy 
subjects and reversible elevation of ALT in 1 healthy subject out of 72 healthy subjects in 
the Phase 1 single ascending dose study (SA-001JP).
In the Phase 3 studies, mild and moderate elevations of liver transaminases have been 
observed with satralizumab treatment. Most elevations were 5 ULN and resolved 
while on treatment with satralizumab. Elevations of ALT or AST 3 ULN were not 
associated with increases in total bilirubin.
It has been reported that IL-6 appears to have a hepatoprotective effect on various forms 
of liver injury and promotes hepatocyte regeneration. Patients with elevated 
transaminases ALT or AST > 1.5x ULN will be excluded from this study. 
Liver function markers should be closely monitored when satralizumab is administered, 
especially concomitantly with hepatotoxic drugs or administered in patients with elevated 
transaminases.
Recommended dose interruption based on transaminases is shown in Table 4.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
97/Protocol BN40900 (SA-309JG), Version 10
Table 4
Hepatic Enzyme Risk Mitigation
ALPalkaline phosphatase; ALT alanine aminotransferase; AST aspartate aminotransferase; 
INRinternational normalized ratio; TBLtotal bilirubin; ULNupper limit of normal.
* ULN or patient’s baseline whichever is higher.
5.1.1.5
Elevated Lipid Levels and Potential Risk of 
Cardiovascular/Cerebrovascular Events
The slight increases in lipid levels (3 AEs of hyperlipidemia [mild] were observed in 3 out 
of 33 patients in Phase Ib [SA-105P]) or and no cardiovascular/cerebrovascular events 
have been observed in Phase 1 trials of satralizumab. 
Increases in total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides due to 
administration of tocilizumab have been observed. However, it is unknown whether 
these changes were associated with cardiovascular events.  
AST or ALT values
Action
>1 to 3x ULN*

Reduction (if necessary, interruption) of hepatotoxic drugs could be 
considered. 

For persistent increases in this range, satralizumab could be 
interrupted until AST and ALT is below ULN*.
>3 to 5x 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. If close monitoring is 
not possible, the drug should be discontinued.
Satralizumab should be interrupted until AST and ALT is below 3x ULN. 
If at least one of following associated, satralizumab should be 
discontinued.

Total bilirubin >2x ULN and/or

INR >1.5x ULN and/or

Appearance of fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness, fever, rash, and/or eosinophilia
>5x ULN
Laboratory tests (ALT, AST, ALP, and TBL) should be repeated within 
72 hours as soon as possible to confirm value. If continued, 
satralizumab should be discontinued immediately and gastroenterology 
expert should be contacted.
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 (SA237)—F. Hoffmann-La Roche Ltd
98/Protocol BN40900 (SA-309JG), Version 10
In the Phase 3 studies, elevations in total cholesterol and triglycerides were observed.
The elevations in lipid parameters did not require dose interruption.
Patients should be managed according to the guideline such as the National Cholesterol 
Education Program Adult Treatment Panel III or Japan Atherosclerosis Society guideline.
5.1.1.6
Immunogenicity
In a Phase 1 single-dose study (SA-001JP) of satralizumab in healthy Japanese and 
Caucasian adult male volunteers, ADA were detected in 39 of the 72 subjects who 
received satralizumab. Most of ADAs were characterized as neutralizing antibody. In a 
Phase 1 multiple dose study (SA-105JP) of satralizumab in patients with rheumatoid 
arthritis, ADA were detected in 2 of the 33 patients who received satralizumab. These 
ADAs were also characterized as neutralizing antibody, and in these 2 patients, 
elevation of serum level of satralizumab was not observed.
In the double-blind periods of the Phase 3 studies, ADAs were observed in 41% (Study 
BN40898) and 71% (Study BN40900) of patients receiving satralizumab. Exposure 
was lower in ADA positive patients; however, there was no impact of ADAs on safety 
and no clear impact on efficacy or pharmacodynamic markers indicative of target 
engagement.
5.1.1.7
Serious Hypersensitivity Reactions
Anaphylaxis and serious hypersensitivity reactions have not been reported in clinical 
trials with satralizumab treatment; however, anaphylaxis and hypersensitivity reactions 
are considered a potential risk with all biologic medications, including satralizumab. 
Patients with a history of a severe allergic reaction to a biologic agent are excluded from 
study participation.
The symptoms/signs of hypersensitivity include, but not limited to, blood pressure 
decrease, dyspnea, loss of consciousness, dizziness, queasiness, vomiting, itchiness, 
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.

Up to Week 48 in the OLE period of the study:
–
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 stay in the clinic/hospital at least 1 hour after study treatment 
administration in order to receive medication immediately if anaphylaxis occurs.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
99/Protocol BN40900 (SA-309JG), Version 10

Patients should be instructed to seek medical attention if they experience symptoms 
of hypersensitivity reaction outside of the clinic.

If an anaphylactic reaction or other serious hypersensitivity reaction occurs, 
satralizumab should be discontinued.

Administration of satralizumab prefilled syringes outside of the study site might be 
allowed (see Section 4.3.2.2) 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.
5.1.1.8
CYP450 Enzyme Normalization
Drug interaction studies have not been conducted with satralizumab. In patients with 
rheumatoid arthritis who were administered tocilizumab, increased expression of 
CYP3A4, CYP2C19 and CYP2D6 has been suggested. Reports have suggested that 
overproduction of IL-6 in patients with inflammatory response inhibits the expression of 
CYPs. Satralizumab administration may normalize CYP expression and the beneficial 
effects of concomitant drugs may decrease as the inflammatory reaction improves.

Patients taking medicinal products which are individually adjusted and are 
metabolized via CYP450 3A4, 1A2, 2C9 or 2C19 should be monitored as doses 
may need to be modified.
5.1.1.9
Complications of Diverticulitis
To date, gastrointestinal perforations have not been reported in clinical trials with 
satralizumab treatment.
Gastrointestinal perforations have been reported rarely in patients administered 
tocilizumab. Although it is unknown whether gastrointestinal perforations are associated 
with IL-6 inhibition, satralizumab may suppress the acute symptoms (abdominal pain, 
pyrexia, etc.) associated with diverticulitis, etc., causing delayed diagnosis and 
progression to perforation. 
In this study, patients who have a history of active diverticulitis may be precluded from 
participation.

Patients presenting with symptoms potentially indicative of complicated diverticulitis, 
such as abdominal pain, should be evaluated (X-ray, computerized tomography 
scan, etc.) promptly for early identification of gastrointestinal perforation and 
appropriate measures taken.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
100/Protocol BN40900 (SA-309JG), Version 10

Patients should be made aware of the symptomatology potentially indicative of 
complicated diverticular disease, and they should be instructed to alert their 
physician 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 inhibitor or H2 blocker should be 
considered
5.1.1.10
Malignancies
No increased risk of malignancies has been observed in clinical trials with satralizumab 
treatment.
Although malignancies have been reported in patients given tocilizumab, there have 
been no report to date that tocilizumab appreciably increases the occurrence of 
malignancies. 
All patients with history of malignancy within the last 5 years, including solid tumors, 
hematologic malignancies and in situ carcinoma (except basal cell and squamous cell 
carcinomas of the skin, or in situ carcinoma of the cervix uteri that have been completely 
excised and cured) will be excluded from this study. 
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)
5.1.1.11
Demyelinating Disorders
Demyelination-related diseases have not been reported in clinical trials with 
satralizumab treatment.
The impact of treatment with tocilizumab on demyelinating disorders is not known, but 
multiple sclerosis and chronic inflammatory demyelinating polyneuropathy were reported 
rarely in RA clinical studies. PML has not been reported. 
Patients with evidence of other demyelinating disease or PML will be excluded from this 
study.
If symptoms suggestive of a demyelination-related disease are observed, differential
diagnosis of the cause should be performed.
5.1.2
Other Information
Stevens-Johnson syndrome (SJS) has not been reported in clinical trials with 
satralizumab treatment.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
101/Protocol BN40900 (SA-309JG), Version 10
It is unknown whether SJS is associated with IL-6 inhibition, but SJS has been reported 
rarely in patients administered tocilizumab.
Patients with a history of SJS will be excluded from this study. Patients must be 
instructed to contact their physician immediately when any symptoms suggesting SJS 
appear, in order to assure early diagnosis and appropriate treatment. Satralizumab must 
not be administered in patients with SJS.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording AEs, including SAEs, AESIs 
and selected AEs (see Section 5.2.4); measurement of protocol-specified safety 
laboratory assessments; measurement of protocol-specified vital signs; and 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 GCP, an AE is any untoward medical occurrence in a 
clinical investigation subject administered a pharmaceutical product, regardless of 
causal attribution. An AE can therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.9

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 treatment

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., invasive screening 
procedures such as biopsies) 
New or worsening neurological symptoms considered NMO-related are not AEs. Clinical 
relapse will be recorded only on a pre-specified eCRF “NMO relapse” form. 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
102/Protocol BN40900 (SA-309JG), Version 10
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 5.3.5.10) 

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 treatment

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 NMO relapse, as long as the reason for hospitalization is to 
receive standard treatment with pulse IV corticosteroids and/or apheresis (including 
plasma exchange and plasmapheresis). 
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). 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
103/Protocol BN40900 (SA-309JG), Version 10
5.2.3
Non-serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Non-serious AESIs 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). Non-
serious AESIs for this study include the following: 

Cases of an elevated ALT or AST in combination with either an elevated bilirubin or 
clinical jaundice, as defined in Section 5.3.5.6.

Suspected transmission of an infectious agent by the study treatment. 
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 IV antibiotics, antifungals, antivirals

opportunistic infections that require treatments with oral antibiotics, antifungals, or 
antivirals 

injection-related reaction (IRR; an AE which occurs within 24 hours after study
treatment 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) are recorded 
on the Adverse Event pages of the 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 pages in the eCRF, the Investigator will 
make an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4).
5.3.1
Adverse Event Reporting Period
Investigators will seek information on 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 pages of the eCRF.
After informed consent has been obtained but prior to initiation of study treatment, only 
SAEs caused by a protocol-mandated intervention should be reported (e.g., SAEs 
related to invasive procedures of the protocol). These SAEs will be recorded in the Drug 
Safety database but not on the Adverse Event eCRF.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
104/Protocol BN40900 (SA-309JG), Version 10
After initiation of study treatment, all AEs, regardless of relationship to study treatment, 
will be reported on the eCRF until the Withdrawal Visit or Last Observation (12 weeks 
after the last dose of study treatment). After this period, Investigators should report any 
deaths, SAEs, or other AEs of concern that are believed to be related to prior treatment 
with study treatment (see Section 5.6).
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information. Example of non-directive questions includes 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 5
provides guidance for assessing AE severity.
Table 5
Adverse Event Severity Grading
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 SAE (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 or 
not an AE is considered to be related to the study treatment, indicating "yes" or "no" 
accordingly. The following guidance should be taken into consideration:

Temporal relationship of event onset to the initiation of study treatment

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study treatment, or reintroduction of study treatment (where 
applicable)

Known association of the event with the study treatment 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


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
105/Protocol BN40900 (SA-309JG), Version 10

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 page of the eCRF. Colloquialisms and abbreviations should be 
avoided.
Only one AE term should be recorded in the event field on the Adverse Event page of 
the eCRF.
5.3.5.1
Diagnosis versus Signs and Symptoms
Injection-Related Reactions
Injection-related reaction is defined as the event that occurs within 24 hours after study 
treatment 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 as not allergic reaction, it will be recorded on the Adverse 
Event page of the eCRF.
Other Adverse Events
For AEs other than injection-related reactions, a diagnosis (if known) should be recorded 
on the Adverse Event page of the 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 page of the eCRF. If a 
diagnosis is subsequently established, all previously reported AEs based on signs and 
symptoms should be nullified and replaced by one AE report based on the single 
diagnosis, with a starting date that corresponds to the starting date of the first symptom 
of the eventual diagnosis.
5.3.5.2
Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause, with the exception of severe or 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
106/Protocol BN40900 (SA-309JG), Version 10
serious secondary events. However, medically significant AEs occurring secondary to an 
initiating event that are separated in time should be recorded as independent events on 
the Adverse Event page of the 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 subsequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All AEs should be recorded separately on the Adverse Event page of the eCRF if it is 
unclear as to whether the events are associated.
5.3.5.3
Persistent or Recurrent Adverse Events
A persistent AE is one that extends continuously, without resolution, between patient 
evaluation time points. Such events should only be recorded once on the Adverse Event 
page of the eCRF. The initial severity of the event should be recorded, and the severity 
should be updated to reflect the most extreme severity any time the event worsens. If 
the event becomes serious, the Adverse Event page of the eCRF should be updated to 
reflect this.
A recurrent AE is one that resolves between patient evaluation timepoints and 
subsequently recurs. Each recurrence of an AE should be recorded separately on the 
Adverse Event page of the eCRF.
5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an AE. A laboratory test result should be 
reported as an AE if it meets any of the following criteria:

Accompanied by clinical symptoms

Results in a change in study treatment (e.g., treatment interruption, or treatment 
discontinuation)


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
107/Protocol BN40900 (SA-309JG), Version 10

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Clinically significant in the Investigator’s judgment 
It is the Investigator’s responsibility to review all laboratory findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an AE.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 times the ULN associated with cholecystitis), 
only the diagnosis (i.e., cholecystitis) should be recorded on the Adverse Event page of 
the eCRF.
If a clinically significant laboratory abnormality cannot be related to a disease or 
syndrome, the abnormality itself should be recorded on the Adverse Event page of the 
eCRF, along with a descriptor indicating if the test result is above or below the normal 
range (e.g., “elevated potassium” as opposed to “abnormal potassium”). If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the AE. 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 not be repeatedly recorded on the Adverse Event page of the eCRF, unless the 
etiology or severity changes. The initial severity of the event should be recorded, and the 
severity or seriousness should be updated any time the event worsens or improves.
5.3.5.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an AE. A vital sign result should be reported 
as an AE if it meets any of the following criteria:

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

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 AE.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
108/Protocol BN40900 (SA-309JG), Version 10
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 page of the eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event page of the eCRF, unless the 
etiology or severity changes. The initial severity of the event should be recorded, and the 
severity or seriousness should be updated any time the event worsens or improves.
5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3x ULN) in combination with either an elevated 
total bilirubin (2x ULN) or clinical jaundice in the absence of cholestasis or other causes 
of hyperbilirubinemia is considered to be an indicator of severe liver injury. Therefore, 
Investigators must report as an AE the occurrence of either of the following:

ALT or AST 3 ULN in combination with total bilirubin 2 ULN

ALT or AST 3 ULN in combination with clinical jaundice
Any other reason than study treatment induced liver injury should be checked, such as 
viral hepatitis A, B, or C, preexisting or acute liver disease, or another drug capable of 
causing the observed injury in case these have any clinical probability. The most 
appropriate diagnosis or (if a diagnosis cannot be established) the abnormal laboratory 
values should be recorded on the Adverse Event page of the eCRF (see Section 5.3.5.1) 
either as an SAE or a non-serious AESI (see Section 5.4.2) and must be reported to the 
Sponsor within 24 hours after learning of the event.
5.3.5.7
Deaths
All deaths that occur during the protocol-specified AE reporting period 
(see Section 5.3.1), regardless of relationship to study treatment, must be recorded on 
the Adverse Event page of the eCRF and immediately reported to the Sponsor (see 
Section 5.4.2). This includes death attributed to progression of NMO.
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 page of the eCRF. Generally, only one such event should 
be reported. The term “sudden death” should only be used for the occurrence of an 
abrupt and unexpected death due to e.g., presumed cardiac causes in a patient with or 
without preexisting heart disease, within 1 hour of the onset of acute symptoms or, in the 
case of an unwitnessed death, within 24 hours after the patient was last seen alive and 
stable. 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 page of the 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
109/Protocol BN40900 (SA-309JG), Version 10
eCRF. If the cause of death later becomes available (e.g., after autopsy), “unexplained 
death” should be replaced by the established cause of death.
If the death is attributed to progression of NMO "NMO progression” should be recorded 
on the Adverse Event page of the eCRF.
5.3.5.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present prior to baseline. Such conditions 
should be recorded on the General Medical History and Baseline Conditions eCRF.
A preexisting medical condition should be recorded as an AE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such 
events on the Adverse Event page of the eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”).
5.3.5.9
Lack of Efficacy or Worsening of NMO
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as AEs. These data will be captured as 
elements of the 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 using objective criteria. 
If there is any uncertainty as to whether an event is due to disease progression, it should 
be reported as an AE.
5.3.5.10
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.
The following hospitalization scenarios are not considered to be SAEs:

Hospitalization because of NMO relapse

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study treatment
administration)


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
110/Protocol BN40900 (SA-309JG), Version 10

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 suffered an AE.
5.3.5.11
Overdoses
Study treatment overdose is the accidental or intentional use of the drug in an amount 
higher than the dose being studied. An overdose or incorrect administration of study 
treatment is not an AE unless it results in untoward medical effects. 
Any study treatment overdose or incorrect administration of study treatment should be 
noted on the Study Drug Administration eCRF. 
All AEs associated with an overdose or incorrect administration of study treatment 
should be recorded on the Adverse Event page of the eCRF. If the associated AE fulfills 
serious criteria, the event should be reported as a SAE to the Sponsor within 24 hours 
after learning of the event (see Section 5.4.2).
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
The Investigator must report the following events to the Sponsor within 24 hours after 
learning of the event, regardless of relationship to study treatment:

Serious adverse events

Non-serious AESI

Pregnancies
The Investigator must report new significant follow-up information for these events to the 
Sponsor within 24 hours after becoming aware of the information. New significant 
information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for SAE reporting to the local 
health authority and IRB/IEC.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
111/Protocol BN40900 (SA-309JG), Version 10
5.4.1
Emergency Medical Contacts
The contact details for the Emergency Medical Contacts will be provided in the Study 
Manual and the Investigator (Site) File. Medical Monitor names, contact information, 
and country-specific toll free numbers will be included.
5.4.2
Reporting Requirements for Serious Adverse Events and Non-
serious Adverse Events of Special Interest 
For reports of SAEs and non-serious AESI, Investigators should record all case details 
that can be gathered within 24 hours on the paper SAE form and fax the completed SAE 
form to PAREXEL International Pharmacovigilance. Investigators should refer to the 
Study Manual and the Investigator (Site) File for the current contact information (fax and 
telephone numbers, and email addresses) for SAE and non-serious AESI reporting.
In the event of fax transmission failure of the SAE form, the site could alternatively e-mail 
the SAE form to the PAREXEL Pharmacovigilance department using the e-mail address 
provided.
Concurrently the Adverse Event eCRF should be completed immediately (see 
Section 5.3.1). 
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 last 
dose of study treatment. A paper pregnancy report form should be completed within 
24 hours and submitted via fax to the PAREXEL Pharmacovigilance department, using 
the fax numbers provided (see Section 5.4.2). Pregnancy should not be recorded on the 
Adverse Event page of the eCRF. The Investigator should discontinue study treatment
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 update the paper pregnancy report form when updated information on 
the course and outcome of the pregnancy become available.
In the event of the fax transmission failure of the pregnancy report form, the completed 
pregnancy report form could alternatively be sent by e-mail to PAREXEL
Pharmacovigilance department using the e-mail address provided.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
112/Protocol BN40900 (SA-309JG), Version 10
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the Investigator if their partner becomes pregnant during the study or within 
3 months after the last dose of study treatment. A paper pregnancy report form should 
be completed within 24 hours of learning of the pregnancy and submitted via fax to the 
PAREXEL Pharmacovigilance department, using the fax numbers provided (see 
Section 5.4.2). In the event of the fax transmission failure of the pregnancy report form, 
the completed pregnancy report form could alternatively be sent by e-mail to the 
PAREXEL Pharmacovigilance department using the e-mail address provided.
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 treatment. The pregnant 
partner will need to sign an ICF for Authorization for Use and Disclosure of Pregnancy 
Health Information to allow for follow-up on her pregnancy. Once the authorization has 
been signed, the Investigator will update the paper pregnancy report form when updated
information on the course and outcome of the pregnancy become 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
Any spontaneous abortion should be classified as an SAE (as the Sponsor considers 
spontaneous abortions to be medically significant events), recorded on the Adverse 
Event page of the eCRF, and reported to the Sponsor within 24 hours after learning of 
the event (see Section 5.4.2). 
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female or female partner of a 
male patient exposed to study treatment patient should be classified as an SAE, 
recorded both on the Adverse Event page of the eCRF and on the paper form, and 
reported to the Sponsor by faxing within 24 hours after learning of the event (see 
Section 5.4.2).
5.4.4
Reporting Requirements for Medical Device Complaints
In this study, PFS with NSD is considered a medical device. The Investigator must report 
all medical device complaints to the Sponsor or its designee. 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 or its designee (see IMP 
Deviation Form). 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
113/Protocol BN40900 (SA-309JG), Version 10
If the medical device results in an AE to the study patient, the event must be recorded on 
the eCRF (see Section 5.3.5). If the event is serious, SAE form must be completed 
immediately (i.e., no more than 24 hours after learning of the event), as outlined in 
Section 5.4.2. If the medical device results in an AE to an individual other than the study 
patient, the AE should be reported as a spontaneous AE to Sponsor Drug Safety via e-
mail (see IMP Deviation Form).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The Investigator should follow each AE 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 SAEs 
considered to be related to study treatment or study-related procedures until a final 
outcome can be reported.
During the study period, resolution of AEs (with dates) should be documented on the 
Adverse Event page of the eCRF and in the patient’s medical record to facilitate source 
data verification. If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event page of the eCRF. 
All pregnancies reported during the study should be followed until pregnancy outcome.
Follow reporting instructions provided in Section 5.4.3.1.
5.6
POST-STUDY ADVERSE EVENTS
At the last observation/withdrawal visit, the Investigator should instruct each patient to 
report to the Investigator any subsequent AEs that the patient’s personal physician 
believes could be related to prior study treatment or study procedures (e.g., infections or 
reactivation of previously acquired infective agents). 
The Investigator should notify the Sponsor of any death, SAE (e.g., development of 
cancer) and non-serious AESI of concern occurring at any time after the Withdrawal Visit 
or last observation if the event is believed to be related to prior study treatment or study 
procedures. The Sponsor should also be notified if the Investigator becomes aware of a 
congenital anomaly/birth defect in a subsequently conceived offspring of a patient that 
participated in this study.
The Investigator should report the event via a paper Serious Adverse Event form to the 
PAREXEL Pharmacovigilance department.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
114/Protocol BN40900 (SA-309JG), Version 10
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all SAEs and AESIs 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 AE cases, the Sponsor will assess the 
expectedness of these events through use of the reference safety information in the
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. 
Expedited reporting to Health Authorities will follow each country’s specific regulations. 
An IDMC will periodically monitor the incidence of AEs (not only expedited reporting to 
Health Authorities but also all AEs) during the double-blind period of the study. An 
aggregate report of any clinically relevant imbalances that do not favor the test product 
will be submitted to health authorities. 
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
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 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 will serve as the primary population for the analysis 
of efficacy, which consists of all randomized patients in the study. Patients will be 
analyzed as randomized for analysis purposes.
The Per-Protocol Set population (PPS) will include all patients in the ITT population who 
received at least 3 doses of study treatment, and without any major protocol deviations 
which are considered to have an impact on efficacy. Patients will be analyzed as treated 
for analysis purposes in the PPS.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
115/Protocol BN40900 (SA-309JG), Version 10
6.1.2
All-Patients-Treated Population
The All-Patients-Treated (All satralizumab) population will be defined as all enrolled 
patients who took at least one dose of active study treatment at any time.
6.1.3
Safety Analysis Populations
All safety variables will be analyzed based on the Safety Population (SAF). The SAF 
population will include all randomized patients who have received at least one dose of 
study treatment. 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 Set (PK-PPS) and immunogenicity (anti-drug
antibody) will include all patients in the SAF with at least 1 valid post-dose concentration 
result with a dosing record and sampling time. PD variables (IL-6, sIL-6R, hsCRP, anti-
AQP4 antibodies and plasmablast) will be analyzed using the SAF population. 
6.2
DETERMINATION OF SAMPLE SIZE
Approximately 90 patients need to be recruited and randomized in a 2:1 ratio to the two 
treatment groups (satralizumab and placebo). The sample size considerations are based 
on the following assumptions:

A two-sided log-rank test.

At least 80% power at the 5% significance level.

The hazard ratio of satralizumab over placebo for an initial 2 months from 
randomization is 1.0. The hazard ratio after an initial 2 months from randomization is 
0.25.

TFR in the placebo arm following an exponential distribution, with hazard rate for 
1 year h(t)1.1295.

A 2-year dropout rate of 10%.
Based on the assumptions, 44 TFR events are needed for the primary analysis. The 
90 patients enrolled over 33 months and followed for an additional 5 months will provide 
44 TFR events. The primary analysis will be performed once 44 TFR events have been 
observed or 1.5 years after the date of randomization of the last patient enrolled, 
whichever comes first. The Sponsor will conduct a blind review of the data including 
accumulation of events during the double-blind period and may take appropriate action 
such as to increase the number of patients or to extend the double-blind period based on 
this blind review.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
116/Protocol BN40900 (SA-309JG), Version 10
It has been assumed that the number of relapses will follow a Gamma-Poisson 
distribution and that the variance/mean ratio will be a constant value of √2. This 
distribution was assumed and the ratio was estimated using data from MS trials (Gold et 
al. 2012; Kappos et al. 2010) because there are no approved medications for NMO and 
no raw data from patients with this indication are available.
Because the mean ARR of NMO patients is estimated at 0.82 and eligibility criterion 2 
says patients at least 1 relapse in last 12 months prior to screening are selected, we 
calculate the zero-truncated mean of the Gamma-Poisson distribution with the mean of 
0.82 and the mean and variance ratio of √2, then the baseline ARR is estimated at 1.65. 
The post-treatment ARR in the placebo group in NMO patients with anti-AQP4 positive 
and negative is estimated as 1.5 and 1.0, respectively (Cree et al. 2015). Given that the 
proportion of patients who are negative for anti-AQP4 antibody at screening will be 
capped at 30% of the total number of patients in this study, post-treatment ARR is
estimated as 1.35.
Using the proportion of zero under supposed ARR distribution, we estimate the 
relapse-free rate at a year in placebo group at 32.3%. The relapse-free rate is assumed 
to follow the exponential distribution with a constant hazard, and then we set the hazard 
for 1 year of 1.1295 in placebo group.
According to tocilizumab case report in NMO patients, the pre- and post- baseline 
relapse counts were reduced from total 4 counts per 6 months to 1 count per 6 months. 
Then the pre- and post- baseline ratio of 0.25 is used as the estimation of the mean ARR 
ratio of tocilizumab compared with placebo. Under the assumption of ARR and relapse-
free rate distribution above, the mean ARR ratio is coincided with the hazard ratio. The 
primary rationale for the mechanism of anti-IL-6 blockade in NMO/NMOSD is the 
expected inhibition of the survival of plasmablast followed by a reduction in anti-AQP4 
antibody. Given that the reduction in anti-AQP4 antibody is required for prevention of 
relapse, and considering the half-life of immunoglobulin G, sufficient effectiveness might 
not be expected for an initial period of a few months even if IL-6 signaling is inhibited 
immediately. So we have set the hazard ratio of satralizumab over placebo at 1.0 for an 
initial 2 months from randomization and at 0.25 after an initial 2 months from 
randomization.
6.3
SUMMARY OF CONDUCT OF STUDY
The number of patients randomized will be tabulated by study site and treatment arm. 
Patient disposition (the number of patients randomized, treated, and completing each 
study period) will be tabulated by treatment group. Study discontinuation as well as 
reasons for discontinuations will be summarized. Eligibility criteria deviations and other 
major protocol deviations will be summarized.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
117/Protocol BN40900 (SA-309JG), Version 10
6.4
SUMMARY OF TREATMENT GROUP COMPARABILITY
Demographics (age, sex, race/ethnicity and concomitant medication) and baseline 
characteristics (hepatitis status, baseline annual relapse rate and number of previous 
episodes within one year before enrollment) of patents will be collected at screening or 
baseline visit before administration of first dose of study treatment.
In general, data will be summarized by treatment group and for all patients in the study 
(i.e., independent of treatment group). Descriptive statistics will be presented for 
continuous data with sample size, mean, standard deviation (SD), median, minimum, 
and maximum. Frequency table with percentage will be presented for discrete data. 
6.5
EFFICACY ANALYSES
All efficacy analyses will be based on the ITT population. Supportive evaluations will be 
performed using the PPS population for primary and key secondary endpoints.
6.5.1
Primary Efficacy Endpoint
The primary efficacy endpoint is TFR based on CEC evaluations (see Section 4.5.1.8). 
TFR is defined as the time from the date of the randomization until the first occurrence of 
relapse throughout the double-blind period. Time point of relapse onset is defined as 
time at which the patient experiences any new or worsening neurological NMO/NMOSD
representing clinical symptom(s). For patients who have not relapsed, the TFR will be 
censored on the date of end of the double-blind period (see the section “Length of Study” 
in PROTOCOL SYNOPSIS). Further details will be mentioned in the SAP. 
The primary analysis of the study 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 using strata of prior therapy for prevention of 
NMO/NMOSD attack (B-cell depleting therapy or immunosuppressants/others) and the 
most recent attack in the last one year prior to screening (first attack or relapse) will be 
used. If a patient was administered B-cell depleting therapies (e.g., anti-CD20 antibody 
[e.g., rituximab], anti-CD19 antibody) at least once in the year prior to baseline, the 
patient will be stratified into “B-cell depleting therapy group” and otherwise into the 
“immunosuppressants/others group” (e.g., oral corticosteroids, azathioprine, 
mycophenolate mofetil, cyclosporine, methotrexate, tacrolimus). 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 hazard ratio 
and 95% confidence intervals using a stratified (prior therapy for prevention of 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
118/Protocol BN40900 (SA-309JG), Version 10
NMO/NMOSD attack [B-cell depleting therapy or immunosuppressants/others] and the 
most recent attack in the last one year prior to screening [first attack or relapse]) Cox 
proportional-hazards model. Relapse-free rates and their 95% confidence intervals (CI),
in addition to the hazard ratio, will be used every 6 months to describe TFR distribution. 
6.5.2
Secondary Efficacy Endpoints
Key Secondary Efficacy Endpoints
The key secondary efficacy endpoints are change in VAS for pain and change in FACIT 
fatigue scale. In order to control the rate of false positive conclusions, the serial 
gatekeeping methodology (fixed-sequence test) will be employed to control for multiple 
(primary and key secondary) endpoints in this order.
Change in VAS score for Pain 
The VAS is a subjective measure of pain and it consists of a 100 mm line with two end-
points representing “no pain” and “pain as bad as it could be”. Patients are asked to rate 
their pain by placing a mark on the line corresponding to their current level of pain. The 
distance along the line from the ‘no pain’ marker is then measured with a ruler giving a 
pain score out of 10. 
The change in VAS for pain score from baseline to Week 24 in the double-blind period 
will be analyzed by analysis of covariance (ANCOVA) method with baseline observation 
carried forward (BOCF) imputation. The analysis will include the categorical effects for 
treatment, prior therapy for prevention of NMO/NMOSD attack and the most recent 
attack in the last one year prior to screening, as well as the continuous covariates of 
baseline VAS for pain score.
Change in FACIT Fatigue Score
FACIT fatigue scale includes 13 questions, which measure fatigue/asthenia for patients 
with chronic, life-threatening illnesses. For each question, a patient rates his / her 
condition for the past week on a 5-point Likert scale ranging from 0 (not at all) to 4 (very 
much). For the change in FACIT fatigue, descriptive statistics will be calculated for the 
change in FACIT fatigue by averaging the individual question scores.
The change in FACIT fatigue Scale score from baseline to Week 24 in the double-blind 
period will be analyzed by ANCOVA method with BOCF imputation. The analysis will 
include the categorical effects for treatment, prior therapy for prevention of
NMO/NMOSD attack and the most recent attack in the last one year prior to screening, 
as well as the continuous covariates of baseline FACIT fatigue score.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
119/Protocol BN40900 (SA-309JG), Version 10
Further Secondary Efficacy Endpoints
Change in Short Form Generic Health Survey (SF-36) Score
The scores will be presented and summarized for each of the 8 domains (vitality, 
physical functioning, bodily pain, general health, role-physical, role-emotional, social role 
functioning and mental health) and 2 summary components (physical and mental). The 
mean change in SF-36 domain scores will be analyzed from baseline to every 24 weeks 
after the baseline visit.
Change in EQ-5D Score
The EQ-5D 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. The EQ-
5D is therefore able to represent 243 (35) distinct health states. These states may then 
be converted into a single index value by using the time trade-off 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 to their baseline status. The 
mean change in EQ-5D score will be analyzed from baseline to every 24 weeks after the 
baseline visit.
Change in Timed 25-Foot Walk (T25W)
The T25W is the measurement to assess the walking ability. The time (in seconds) that it 
takes the patient to walk 25 feet is measured. The mean change of the amount of time 
will be analyzed from baseline to every 24 weeks after the baseline visit.
The Proportion of Relapse-free Patients
The proportion of patients who are relapse-free during the double-blinded period and the
entire study (double-blind and OLE periods combined) will be calculated for the two 
treatment groups. When both periods are analyzed together, patients are analyzed as 
randomized, even if patients randomized to placebo receive satralizumab in the OLE 
period.
The Kaplan-Meier estimates and corresponding 95% CIs for the proportion of patients 
who were relapse-free during the double-blind period are calculated for both treatment 
groups.
Relapse-free rates will be analyzed at every 24 weeks after baseline.
Annualized Relapse Rate (ARR)
The relapse episodes for each eligible patient will be recorded throughout the whole 
study. The ARR is calculated as the total number of relapses experienced divided by the 


 
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd 
120/Protocol BN40900 (SA-309JG), Version 10 
person-years at risk for each year of the study period. The 95% CI will be presented 
based on the Poisson distribution. 
For comparing the difference between two treatment arms, negative binomial regression 
model will be used with ARR as response variable; treatment group, prior therapy for 
prevention of NMO/NMOSD attack (B-cell depleting therapy or 
immunosuppressants/others), and the type of the most recent attack in the last one year 
prior to screening (first attack or relapse) as covariates.  
Change in Modified Rankin Scale Score 
The mRS is a 7-point disability scale that assesses the degree of disability in patients 
with neurological impairment. Possible scores range from 0 (no symptom at all) up to 
6 (death). The higher scores reflect increased disability. Descriptive statistics will be 
calculated for the change in mRS.  
The mean change in mRS score will be analyzed from baseline to every 24 weeks after 
the baseline visit. 
Change in Zarit Burden Interview Score 
The ZBI is the measurement to assess caregiver burden. The 22 items ask for the strain 
caregivers perceive. Responses range from 0 (never) to 4 (nearly always) with maximum 
score of 88. The higher the total score, the heavier the perceived burden. Descriptive 
statistics will be calculated for the change in ZBI.  
The mean change in ZBI score will be analyzed from baseline to every 24 weeks after 
the baseline visit. 
Change in Expanded Disability Status Scale (EDSS) Score 
The EDSS will be assessed on scheduled visits during entire study. The mean change in 
EDSS scores from baseline to every 24 weeks after the baseline visit will be analyzed. 
Time to EDSS worsening based on the definition for PDR is estimated with a cox 
regression with treatment group, prior therapy for prevention of NMO/NMOSD attack 
(B-cell depleting therapy or immunosuppressants/others), and the type of the most 
recent attack in the last year prior to screening (first attack or relapse) as covariates.  
The hazard ratio and 95% CI for the treatment groups is estimated in this model, the 
p-value is calculated based on the log rank test.  In addition, Kaplan-Meier estimate of 
event-free rates will be provided. 
These analyses are done for the double-blind period and the combined double-blind and 
OLE period.  When both periods are analyzed together, patients are analyzed as 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
121/Protocol BN40900 (SA-309JG), Version 10
randomized, even if patients randomized to placebo receive satralizumab in the OLE 
period.
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.
Change in low-contrast visual acuity (Low-contrast Sloan letter chart 
(LCSLC))
The LCSLC is the testing to evaluate the visual function and captures the minimum size 
at which individuals can perceive letters of a particular contrast level. The change in 
binocular visual acuity, as assessed by the number of letters read correctly from 
2 meters distance on 100% (high contrast, used to measure visual acuity as a descriptor 
of the study cohorts), 2.5% and 1.25% contrast level Sloan letter charts, will be analyzed 
from baseline to every 24 weeks after the baseline visit.
A mixed-effects model repeated measures (MMRM) analysis will be used for the change 
from baseline in EDSS, SF-36, VAS for pain, FACIT fatigue, T25W, mRS, ZBI and EQ-
5D scores, as well as visual function testing (including visual acuity tests of Snellen and 
low-contrast Sloan letter chart). The model will include treatment group, protocol-
specified visit, treatment-by-visit interaction as fixed effects; the baseline measurements 
as a covariate; and visit as a repeated measure. An unstructured covariance matrix will 
be assumed in the model.
If the unstructured covariance matrix does not converge, other covariance structure will 
be used. If treatment-by-visit interaction is not statistically significant, we still keep the full 
model.
If the normality assumption for the secondary efficacy variable does not hold, a 
generalized estimating equation or Generalized Linear Mixed-effect model analysis will 
be used. The assessment will be performed prior to un-blinding and details will be 
mentioned in the SAP.
Use of rescue medication
The use of rescue medication 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 
medication use. The use of rescue medication will be analyzed with a logistic 
regression model with treatment group, prior therapy for prevention of NMO/NMOSD 
attack (B-cell depleting therapy or immunosuppressants/others), and the type of the 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
122/Protocol BN40900 (SA-309JG), Version 10
most recent attack in the last year prior to screening (first attack or relapse) as 
covariates. The odds ratio, corresponding 95% CI, and p-value for the treatment group 
will be reported. This analysis is conducted for the double-blind period.
6.5.3
Further Analysis
6.5.3.1
Sensitivity Analysis for Primary Endpoint
Several sensitivity analyses are planned for the primary efficacy analysis of TFR to 
account for the potential impact of differences in definition of primary endpoint. In this 
analysis TFR will be defined as follows:

Clinical Relapse.

Treated Clinical Relapse.

Treated Clinical Relapse: Optic Neuritis.

Protocol-defined relapse based on CEC adjudication (regardless of assessment limit 
of seven days).
Further details will be mentioned in the SAP.
6.5.3.2
Sensitivity Analysis for Key Secondary Endpoint
Several sensitivity analyses are planned for the key secondary efficacy analysis of VAS 
for pain and FACIT fatigue to account for the potential impact of differences in handling 
of missing data. In this analysis the following analyses will be conducted: 

The change in VAS for pain score from baseline to Week 24 in the double-blind 
period will be analyzed by ANCOVA method with hot-deck imputation

The change in FACIT fatigue scale score from baseline to Week 24 in the 
double-blind period will be analyzed by ANCOVA method with hot-deck imputation
Further details will be mentioned in the SAP.
6.5.3.3
Subgroup Analysis
The subgroup summary tables will be presented by AQP4 antibody status at screening 
(positive/negative) in NMO and NMO/NMOSD. In case that satralizumab does not show 
the effectiveness in NMO patients who are AQP4 antibody negative at all, companion 
diagnostics co-development will be considered by using this data. Further details will be 
mentioned 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, IRRs, injection site reactions, patient withdrawals due to AEs, 
change in 12-lead ECGs, measurements of laboratory parameters, and vital signs 
(including body weight).


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
123/Protocol BN40900 (SA-309JG), Version 10
Summary tables for number and percentage of patients with adverse drug reactions 
which AEs related to study treatment will be tabulated.
Adverse events will be summarized by SOC and preferred term based on Medical 
Dictionary for Regulatory Activities (MedDRA) coding, and grade of severity. In addition, 
the incidence of AEs leading to withdrawal from treatment and SAEs will be tabulated.
Laboratory values (including hematology, blood chemistry, and urinalysis), frequencies 
of laboratory abnormalities, vital signs (temperature, SBP, DBP and pulse rate), physical 
examination 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 using descriptive statistics. 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 to their baseline
status. Numbers of patients who meet the marked abnormality criteria will also be 
presented.
6.7
PHARMACOKINETIC/PHARMACODYNAMICS ANALYSES
Descriptive statistics, such as geometric mean, geometric coefficient of variance (CV)
and the 95% CI for the geometric mean for the serum satralizumab concentration, as 
well as arithmetic mean, SD, median, minimum, and maximum on the measured serum 
satralizumab concentration, IL-6, sIL-6R, anti-AQP4 antibodies, and plasmablasts 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 pharmacodynamics (CRP, IL-6, sIL-6R, plasmablasts and anti-AQP4
antibodies) will be performed. These results will be described and reported in the clinical 
study report.
In addition, nonlinear mixed-effects modeling will be used to analyze the sparse 
sampling dose-concentration-time data of satralizumab. The data from this study will be 
pooled with data from SA-001JP study, SA-105JP study and BN40898 (SA-307JG)
study to develop a population PK model for satralizumab. A covariate analysis will be 
conducted to evaluate the effect of covariates on satralizumab exposure. Some 
covariates such as body weight, age and gender will be included in the covariate 
analysis. Population and individual estimates of primary PK parameters [e.g., clearance 
(CL/F), distribution volume (V/F)] and secondary PK parameters [e.g., area under the 
serum concentration-time curve (AUC), average trough serum concentration (Ctrough)] will 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
124/Protocol BN40900 (SA-309JG), Version 10
be computed and used to explore exposure response relationship on primary and key 
secondary as well as PD marker and safety.
Details of this mixed-effects modeling analysis, exploration of exposure-response and 
the results will be described and reported in a document separated from the clinical 
study report.
6.8
IMMUNOGENICITY
The percentage of patients who have positive or negative antibody results will be 
tabulated. PK/PD, efficacy parameter and safety will be summarized by anti-drug
antibody status.
6.9
HANDLING MISSING DATA
For TFR, patients who have not relapsed at the time of analysis, the TFR will be 
censored on the date of end of the double-blind period (see the section “Length of Study” 
in PROTOCOL SYNOPSIS). Further details will be mentioned in the SAP.
For key secondary endpoints, missing data at Week 24 in the double-blind period will be 
imputed by a BOCF and for the purpose to assess the robustness of the imputation 
method, we will also conduct hot-deck imputation as sensitivity analysis.
For secondary continuous endpoints, a MMRM analysis incorporating data in 
double-blind phase will be used to utilize data collected over time with consideration of 
the variance-covariance matrix of the repeated measures. This method allows a general 
unstructured variance-covariance matrix and will include data from patients with 
incomplete data from some scheduled time points.
For the FACIT fatigue questionnaire, if there are less than 7 responses recorded, then 
the total fatigue score will be considered missing. If there are 7 or more responses 
recorded, then the total fatigue score for that questionnaire will be calculated as the 
average of the non-missing scores multiplied by 13.
Detailed methods for handling of missing data will be mentioned in the SAP.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
A Contract Research Organization (CRO) will be responsible for the data management 
of this study, including quality checking of the data. Data entered manually will be 
collected via electronic data capture (EDC) using eCRFs. Sites will be responsible for 
data entry into the EDC system. In the event of discrepant data, the CRO will request 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
125/Protocol BN40900 (SA-309JG), Version 10
data clarification from the sites, which the sites will resolve electronically in the EDC 
system.
The Sponsor or its designee will perform oversight of the data management of this study. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data. Central laboratory data will be sent directly 
to the CRO, using the CRO'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 or its designee and records retention for 
the study data will be consistent with the Sponsor’s standard procedures.
Data from paper patient- or caregiver-completed questionnaires will be entered into the 
EDC system by site staff. 
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed using a Sponsor-designated EDC system. Sites will receive 
training and a have access to a manual for appropriate eCRF completion. eCRFs will be 
submitted electronically to the Sponsor or its designee 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 on a compact disc that must be kept with the study records. 
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification 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, 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
126/Protocol BN40900 (SA-309JG), Version 10
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, the Investigators and institutions must provide the 
Sponsor or its designee direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor or designee audits, and IRB/IEC review. The 
investigational site must also allow inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into an investigational 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, ICFs, laboratory test results, and medication inventory records, 
must be retained by the Principal Investigator for at least 15 years after completion or 
discontinuation of the study, or for the length of time required by relevant national or 
local health authorities, whichever is longer. After that period of time, the documents 
may be destroyed, subject to local regulations.
No records may be disposed of without the written approval of the Sponsor. Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
127/Protocol BN40900 (SA-309JG), Version 10
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for GCP and 
the principles of the Declaration of Helsinki, or the 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). 
8.2
INFORMED CONSENT
The Sponsor’s sample master ICF including CCSR, ICFs for ZBI and authorization for 
use and disclosure of pregnancy health information 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 ICF or any alternate consent forms proposed by the site (collectively, the 
“Consent Forms”) before IRB/IEC submission. The final IRB/IEC-approved Consent 
Forms must be provided to the Sponsor or its designee for health authority submission 
purposes according to local requirements.
The ICFs 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 ICFs 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/IEC-approved ICFs must be provided to the Sponsor 
for health authority submission purposes.
Patients must be re-consented to the most current version of the ICF (or to a significant 
new information/findings addendum in accordance with applicable laws and IRB/IEC 
policy) during their participation in the study. For any updated or revised ICFs, the case 
history or clinical records for each patient shall document the informed consent process 
and that written informed consent was obtained using the updated/revised ICFs for 
continued participation in the study.
A copy of each signed ICF must be provided to the patient or the patient’s legally 
authorized representative. All signed and dated ICFs 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.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
128/Protocol BN40900 (SA-309JG), Version 10
For sites in the United States, each ICF may also include patient authorization to allow 
use and disclosure of personal health information in compliance with the US Health 
Insurance Portability and Accountability Act of 1996 (HIPAA). 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/IEC by the Principal Investigator
and reviewed and approved by the IRB/IEC before the study is initiated. In addition, any 
patient recruitment materials must be approved by the IRB/IEC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/IEC 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 9.5).
In addition to the requirements for reporting all AEs to the Sponsor or its designee, 
Investigators must comply with requirements for SAE reporting to the local health 
authority and IRB/IEC. Investigators may receive written Investigational New Drug (IND) 
safety reports or other safety-related communications from the Sponsor or the CRO. 
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/IEC, and archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor or its designee 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 only be 
disclosed to third parties 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.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
129/Protocol BN40900 (SA-309JG), Version 10
Data generated by this study must be available for inspection upon request by 
representatives of the US FDA and other national and local health authorities, Sponsor 
or its designated monitors, auditors, representatives and collaborators, and the IRB/IEC 
for each study site, as appropriate.
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 (i.e., the last patient’s 
last visit).
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/IEC and governmental approval. In 
addition, at the end of the study, the Investigator will receive the patient data, which 
includes an audit trail containing a complete record of all changes to data.
9.2
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 or its designated monitors, 
representatives, and collaborators, and the IRBs/IECs to inspect facilities and records 
relevant to this study.
9.3
ADMINISTRATIVE STRUCTURE
This trial is co-sponsored by F. Hoffmann-La Roche Ltd and Chugai Pharmaceutical Co., 
Ltd. (in Taiwan and Japan). PAREXEL International LLC will provide clinical operations 
oversight, data management support, statistical analysis and medical monitoring. The 
eCRF data will be recorded via an EDC system. An IxRS will be used for study treatment
inventory, management and to randomize patients to study treatment. An IDMC will be 
set up to monitor the safety of the study.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
130/Protocol BN40900 (SA-309JG), Version 10
9.4
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
prior to submission per the Investigator’s Clinical Research Agreement. 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.
The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data. In this case, a coordinating Investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. Any formal publication of 
the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the Investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.5
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor. Investigators are 
responsible for promptly informing the IRB/IEC of any amendments to the protocol. 
Approval must be obtained from the IRB/IEC 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 Expert or 
contact information).


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
131/Protocol BN40900 (SA-309JG), Version 10
10.
REFERENCES
Araki M, Aranami T, MatsuokaT et al. Clinical improvement in a patient with 
neuromyelitis optica following therapy with the anti-IL-6 receptor monoclonal 
antibody tocilizumab. Mod Rheumatol 2013;23:827-31.
Araki M, Aranami T, Matsuoaka T et al. Clinical Efficacy of anti-IL-6 receptor antibody 
tocilizumab in three patients with neuromyelitis optica. ECTRIMS 2012b (Poster 
presentation).
Ayzenberg I, Kleiter I, Schroder A et al. Interleukin 6 receptor blockade in patients with 
neuromyelitis optica nonresponsive to anti-CD20 therapy. JAMA Neurol 
2013;70:394-7.
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.
Cohen JA, Barkhof F, Comi G et al. Oral fingolimod or intramuscular interferon for 
relapsing multiple sclerosis. New Engl J Med 2010;362:402-15.
Cree BA, Bennett JL, Sheehan M et al. Placebo-controlled study in neuromyelitis optica-
Ethical and design considerations. Multi Scler 2015 published online.
Fischer JS, Rudick RA, Cutter GR et al. The multiple sclerosis functional composite 
measure (MSFC): an integrated approach to MS clinical outcome assessment. 
National MS Society Clinical Outcomes Assessment Task Force.Mult Scler 
1999;5:244-50.
Frey N, Grange S, Woodworth T. Population pharmacokinetic analysis of tocilizumab in 
patients with rheumatoid arthritis. J Clin Pharmacol 2010;50:754-66.
Giovannoni G, Comi G, Cook S et al. A placebo-controlled trial of oral cladribine for 
relapsing multiple sclerosis. New Engl J Med 2010;362:416-26.
Gold R, Kappos L, Arnold DL et al. Placebo-controlled phase 3 study of oral BG-12 for 
relapsing multiple sclerosis. N Engl J Med 2012;367:1098-107.
Hinson SR, Romero MF, Popescu BF et al. Molecular outcomes of neuromyelitis optica 
(NMO)-IgG binding to aquaporin-4 in astrocytes. Proc Natl Acad Sci USA 
2012;109:1245-50.
Jarius S, Ruprecht K, Wildemann B et al. Contrasting disease patterns in seropositive 
and seronegative neuromyelitis optica: A multicentre study of 175 patients. J 
Neuroinflammation 2012;9:14.
Kappos L, Radue EW, O'Connor P et al. A placebo-controlled trial of oral fingolimod in 
relapsing multiple sclerosis. N Engl J Med 2010;362:387-401.
Kieseier BC, Stuve O, Dehmel T et al. Disease amelioration with tocilizumab in a 
treatment-resistant patient with neuromyelitis optica: implicationfor cellular immune 
responses. JAMA Neurol 2013;70:390-3.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
132/Protocol BN40900 (SA-309JG), Version 10
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.
Marignier R, Bernard-Valnet R, Giraudon P et al. Aquaporin-4 antibody-negative 
neuromyelitis optica: Distinct assay sensitivity-dependent entity. Neurology 
2013;80:2194-200.
O’Connor P, Wolinsky J, Confacreux C et al. Randomized trial of oral teriflunomide for 
relapsing multiple sclerosis. New Engl J Med 2011;365:1293-303.
Oh J, Levy M. Neuromyelitis optica: an antibody-mediated disorder of the central 
nervous system. Neurol Res Int 2012 published online.
Takahashi T, Fujihara K, Nakashima I et al. Anti-aquaporin-4 antibody is involved in the 
pathogenesis of NMO: a study on antibody titre. Brain 2007;130:1235-43.
Webster K, Cella D, Yost K. The functional assessment of chronic illness therapy (FACIT) 
measurement system: properties, applications, and interpretation. Health Qual Life 
Outcomes 2003;1:79.
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.
Wingerchuk DM, Lennon VA, Pittock SJ et al. Revised diagnostic criteria for 
neuromyelitis optica. Neurology 2006;66:1485-9.
Wingerchuk DM, Lennon VA, Lucchinetti CF et al. The spectrum of neuromyelitis optica. 
Lancet Neurol 2007;6:805-15. 
Zarit SH, Reever KE, Bach-Peterson J. Relatives of the impaired elderly: correlates of 
feelings of burden. Gerontologist 1980;20:649-55.






Appendix 1: Schedule of Activities (cont.)
Table 6:  Observation and Test Schedule in the Double-Blind Period (cont.)
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
135/Protocol BN40900 (SA-309JG), Version 10
d) This visit/sampling is optional and will require a separate signature on the informed consent.
e) Only EDSS is conducted
f) MRI for exploratory evaluation is optional and conducted at selected sites, and will require a separate signature on the informed consent
h) For females of child-bearing potential. Serum β-hCG must be performed at screening. During the study, serum or urine [sensitivity of at least 
25 mIU/mL] β-hCG will be performed.
i) 
Brain MRI for screening is required for excluding PML. If PML cannot be excluded by MRI, JC virus in the cerebrospinal fluid (CSF) will be 
measured.
j) 
Body temperature, systolic and diastolic blood pressure and pulse rate are measured just before dosing and 15 min (±5 min) and 60 min (±5
min) after dosing in case of study treatment injection visit.
k) TB test (e.g., tuberculin test and/or Quantiferontest) should be conducted according as local guidance.
l) 
For patients who consent to additional PK sampling, triplicate digital ECG recordings will be obtained with approximately 2 - 5 minutes 
between each ECG recording and the copies of ECG chart should be collected.
m) Visual function testing includes visual acuity tests of Snellen and Low-contrast Sloan letter chart. Visual acuity test of Snellen chart is not 
required if it is implemented with FSS assessment.
n) 
For all patients who consent to the study, ECG should be performed prior to blood draws.
o) 
Window in days is within ±28 days.
p) ZBI is optional and will be performed in selected countries for caregiver who signed informed consent to caregiver burden assessment.
q) Hepatitis B viral DNA must be measured in patients for whom a positive result for HBsAb is not clearly associated with vaccination against 
hepatitis B virus or whom HBcAb is positive at screening. 
r) Hepatitis B viral DNA must be monitored in patients for whom a positive result for HBsAb is not clearly associated with vaccination against 
hepatitis B virus and HBV DNA is negative at screening or whom HBcAb is positive and HBV DNA is negative at screening.
s) Anti-AQP4 antibody at screening will be measured only by ELISA as an exploratory biomarker. Other points will be measured by cell-based 
assay and/or ELISA as a PD marker.
t) C-SSRS at baseline scale should be used.
u) C-SSRS since last visit scale should be used.
v) Informed consent must be obtained prior to first screening assessment, but if informed consent is obtained before the 28-day screening 
period (i.e., before Day -27), all screening assessments must be completed within 28 days prior to baseline (i.e., from Day -27 to 0).
BL Baseline, CCSR Chugai Clinical Sample Repository.






Appendix 1: Schedule of Activities (cont.)
Table 6:  Observation and Test Schedule in the Double-Blind Period (cont.)
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
138/Protocol BN40900 (SA-309JG), Version 10
m) Body temperature, systolic and diastolic blood pressure and pulse rate are measured just before dosing and 15 min (±5 min) and 60 min (±5 
min) after dosing in case of study treatment injection visit.
n) Hepatitis B viral DNA must be monitored in patients for whom a positive result for HBsAb is not clearly associated with vaccination against 
hepatitis B virus and HBV DNA is negative at screening or whom HBcAb is positive and HBV DNA is negative at screening.
o) Every 12 weeks.
p) C-SSRS since last visit scale should be used.
q) In the event that the study drug is not administered within the scheduled visit window and is subsequently administered outside the visit 
window. Minimum dosing interval should be 14 days.
DOW dose outside the visit window, SFU Safety follow-up, WDWithdrawal visit, CCSR Chugai Clinical Sample Repository.






Appendix 1: Schedule of Activities (cont.)
Table 7:  Observation and Test Schedule in the Extension Period (Week 0 – Week 48) (cont.)
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
141/Protocol BN40900 (SA-309JG), Version 10
o) In the event that the study drug is not administered within the scheduled visit window and is subsequently administered outside the visit 
window. Minimum dosing interval should be 14 days.
p) 
MRI for exploratory evaluation is optional and conducted at selected sites, and will require a separate signature on the informed consent. 
Only for patients who end the double-blind period by Week 48 of the double-blind period.
q) 
Week 48 only.
DOW dose outside the visit window, WDWithdrawal visit.




Appendix 1: Schedule of Activities (cont.)
Table 8:  Observation and Test Schedule in the Extension Period (After Week 48) (cont.)
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
143/Protocol BN40900 (SA-309JG), Version 10
a) RBC, Hb, HCT, 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 
emergency situations 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 5.3.5.
b) IL-6, sIL-6R, hsCRP
c) For females of child-bearing potential. Serum or urine [sensitivity of at least 25 mIU/mL] β-hCG will be performed.
d) Last observation will be conducted 12 weeks after the last dose of satralizumab for patients who complete the extension period.
e) For patients who withdraw from the study. Every effort should be made to conduct the visit at 12 weeks after the last dose of satralizumab.
f) Window in days is within ±28 days.
g) Visual function testing includes visual acuity tests of Snellen and Low-contrast Sloan letter chart. Visual acuity test of Snellen chart is not 
required if it is implemented with FSS assessment.
h) For all patients who consent to the study, ECG should be performed prior to blood draws.
i) 
ZBI is optional and will be performed in selected countries for caregiver who signed informed consent to caregiver burden assessment.
j) 
Body temperature, systolic and diastolic blood pressure and pulse rate are measured just before dosing and 15 min (±5 min) and 60 min (±5 
min) after dosing in case of study treatment injection visit.
k) 
Hepatitis B viral DNA must be monitored in patients for whom a positive result for HBsAb is not clearly associated with vaccination against 
hepatitis B virus and HBV DNA is negative at screening or whom HBcAb is positive and HBV DNA is negative at screening.
l) 
C-SSRS since last visit scale should be used.
m) In the event that the study drug is not administered within the scheduled visit window and is subsequently administered outside the visit 
window. Minimum dosing interval should be 14 days.
n) In the OLE period after Week 48, 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, or home administration by a mobile nurse) will be allowed in emergency situations such as the SARS-CoV-2 
(COVID-19) pandemic.


Appendix 1: Schedule of Activities (cont.) 
Table 8:  Observation and Test Schedule in the Extension Period (After Week 48) (cont.) 
  
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd 
144/Protocol BN40900 (SA-309JG), Version 10 
o)  If patients cannot physically attend a visit at the study site in emergency situations 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. 
p)  Following the implementation of Protocol Version 10 and in accordance with local regulations, administration of satralizumab outside of 
the study site can be implemented.  Patients will be followed up by study site personnel through phone calls to monitor compliance and 
perform safety assessments. 
DOW = dose outside the visit window, WD = Withdrawal visit. 


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
145/Protocol BN40900 (SA-309JG), Version 10
Appendix 2
EDSS/FSS Assessment Form

0.0 - Normal neurological exam (all grade 0 in all Functional System (FS) scores*). 

1.0 - No disability, minimal signs in one FS* (i.e., grade 1). 

1.5 - No disability, minimal signs in more than one FS* (more than 1 FS grade 1). 

2.0 - Minimal disability in one FS (one FS grade 2, others 0 or 1). 

2.5 - Minimal disability in two FS (two FS grade 2, others 0 or 1). 

3.0 - Moderate disability in one FS (one FS grade 3, others 0 or 1) or mild disability in three 
or four FS (three or four FS grade 2, others 0 or 1) though fully ambulatory.  

3.5 - Fully ambulatory but with moderate disability in one FS (one grade 3) and one or two 
FS grade 2; or two FS grade 3 (others 0 or 1) or five grade 2 (others 0 or 1). 

4.0 - Fully ambulatory without aid, self-sufficient, up and about some 12 hours a day despite 
relatively severe disability consisting of one FS grade 4 (others 0 or 1), or combination of 
lesser grades exceeding limits of previous steps; able to walk without aid or rest some 500 
meters. 

4.5 - Fully ambulatory without aid, up and about much of the day, able to work a full day, 
may otherwise have some limitation of full activity or require minimal assistance; 
characterized by relatively severe disability usually consisting of one FS grade 4 (others or 1) 
or combinations of lesser grades exceeding limits of previous steps; able to walk without aid 
or rest some 300 meters. 

5.0 - Ambulatory without aid or rest for about 200 meters; disability severe enough to impair 
full daily activities (e.g., to work a full day without special provisions); (Usual FS equivalents 
are one grade 5 alone, others 0 or 1; or combinations of lesser grades usually exceeding 
specifications for step 4.0). 

5.5 - Ambulatory without aid for about 100 meters; disability severe enough to preclude full 
daily activities; (Usual FS equivalents are one grade 5 alone, others 0 or 1; or combination of 
lesser grades usually exceeding those for step 4.0). 

6.0 - Intermittent or unilateral constant assistance (cane, crutch, brace) required to walk 
about 100 meters with or without resting; (Usual FS equivalents are combinations with more 
than two FS grade 3+). 

6.5 - Constant bilateral assistance (canes, crutches, braces) required to walk about 
20 meters without resting; (Usual FS equivalents are combinations with more than two FS 
grade 3+). 

7.0 - Unable to walk beyond approximately 5 meters even with aid, essentially restricted to 
wheelchair; wheels self in standard wheelchair and transfers alone; up and about in 
wheelchair some 12 hours a day; (Usual FS equivalents are combinations with more than 
one FS grade 4+; very rarely pyramidal grade 5 alone). 


Appendix 2: EDSS/FSS Assessment Form (cont.)
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
146/Protocol BN40900 (SA-309JG), Version 10

7.5 - Unable to take more than a few steps; restricted to wheelchair; may need aid in 
transfer; wheels self but cannot carry on in standard wheelchair a full day; May require 
motorized wheelchair; (Usual FS equivalents are combinations with more than one FS grade 
4+). 

8.0 - Essentially restricted to bed or chair or perambulated in wheelchair, but may be out of 
bed itself much of the day; retains many self-care functions; generally has effective use of 
arms; (Usual FS equivalents are combinations, generally grade 4+ in several systems). 

8.5 - Essentially restricted to bed much of day; has some effective use of arm(s); retains 
some self-care functions; (Usual FS equivalents are combinations, generally 4+ in several 
systems). 

9.0 - Helpless bed patient; can communicate and eat; (Usual FS equivalents are 
combinations, mostly grade 4+). 

9.5 - Totally helpless bed patient; unable to communicate effectively or eat/swallow; (Usual 
FS equivalents are combinations, almost all grade 4+). 

10.0 - Death due to NMO. 
*Excludes cerebral function grade 1. 
Note 1: EDSS steps 1.0 to 4.5 refer to patients who are fully ambulatory and the precise step 
number is defined by the Functional System score(s).  EDSS steps 5.0 to 9.5 are defined 
by the impairment to ambulation and usual equivalents in Functional Systems scores are 
provided. 
Note 2: EDSS should not change by 1.0 step unless there is a change in the same direction of 
at least one step in at least one FS. 
Sources: Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability 
status scale (EDSS). Neurology. 1983 Nov;33(11):1444-52. 
Haber A, LaRocca NG. eds. Minimal Record of Disability for multiple sclerosis.  New 
York: National Multiple Sclerosis Society; 1985. 


Appendix 2: EDSS/FSS Assessment Form (cont.)
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
147/Protocol BN40900 (SA-309JG), Version 10


Appendix 2: EDSS/FSS Assessment Form (cont.)
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
148/Protocol BN40900 (SA-309JG), Version 10


Appendix 2: EDSS/FSS Assessment Form (cont.)
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
149/Protocol BN40900 (SA-309JG), Version 10
The actual forms will be provided to the sites and should be used for assessment.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
150/Protocol BN40900 (SA-309JG), Version 10
Appendix 3
SF-36 Questionnaire
This survey asks for your views about your health. This information will help keep track 
of how you feel and how well you are able to do your usual activities. Thank you for 
completing this survey! For each of the following questions, please tick the one box that 
best describes your answer.
1.
In general, would you say your health is:
2.
Compared to one year ago, how would you rate your health in general now? 
3.
The following questions are about activities you might do during a typical day. 
Does your health now limit you in these activities? If so, how much?
4.
During the past 4 weeks, how much of the time have you had any of the following 
problems with your work or other regular daily activities as a result of your physical 
health 
5.
During the past 4 weeks, how much of the time have you had any of the following 
problems with your work or other regular daily activities as a result of any emotional 
problems (such as feeling depressed or anxious)? 
6.
During the past 4 weeks, to what extent has your physical health or emotional 
problems interfered with your normal social activities with family, friends, neighbors
or groups?
7.
How much bodily pain have you had during the past 4 weeks? 
8.
During the past 4 weeks, how much did pain interfere with your normal work 
(including both work outside the home and housework)? 
9.
These questions are about how you feel and how things have been with you during 
the past 4 weeks. For each question, please give the one answer that comes 
closest to the way you have been feeling. How much of the time during the past 4 
weeks… 
10. During the past 4 weeks, how much of the time has your physical health or 
emotional problems interfered with your social activities (like visiting with friends, 
relatives, etc.)? 
11. How TRUE or FALSE is each of the following statements for you?
The actual forms will be provided to the sites and should be used for assessment.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
151/Protocol BN40900 (SA-309JG), Version 10
Appendix 4
Visual Analogue Scale for Pain
The actual forms will be provided to the sites and should be used for assessment.




Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
153/Protocol BN40900 (SA-309JG), Version 10
Appendix 6
Modified Rankin Scale
The actual forms will be provided to the sites and should be used for assessment.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
154/Protocol BN40900 (SA-309JG), Version 10
Appendix 7
Zarit Burden Interview
INSTRUCTIONS: The following is a list of statements, which reflect how people sometimes feel 
when taking care of another person.  After each statement, indicate how often you feel that way; 
never, rarely, sometimes, quite frequently, or nearly always.  There are no right or wrong 
answers.
1.
Do you feel that your relative asks for more help than he/she needs?
0.  Never
1.  Rarely
2.  Sometimes
3.  Quite Frequently
4.  Nearly Always
2.
Do you feel that because of the time you spend with your relative that you don’t have 
enough time for yourself?
0.  Never
1.  Rarely
2.  Sometimes
3.  Quite Frequently
4.  Nearly Always
3.
Do you feel stressed between caring for your relative and trying to meet other 
responsibilities for your family or work?
0.  Never
1.  Rarely
2.  Sometimes
3.  Quite Frequently
4.  Nearly Always
4.
Do you feel embarrassed over your relative’s behavior?
0.  Never
1.  Rarely
2.  Sometimes
3.  Quite Frequently
4.  Nearly Always
5.
Do you feel angry when you are around your relative?
0.  Never
1.  Rarely
2.  Sometimes
3.  Quite Frequently
4.  Nearly Always
6.
Do you feel that your relative currently affects your relationship with other family 
members or friends in a negative way?
0.  Never
1.  Rarely
2.  Sometimes
3.  Quite Frequently
4.  Nearly Always
7.
Are you afraid what the future holds for your relative?
0.  Never
1.  Rarely
2.  Sometimes
3.  Quite Frequently
4.  Nearly Always
8.
Do you feel your relative is dependent upon you?
0.  Never
1.  Rarely
2.  Sometimes
3.  Quite Frequently
4.  Nearly Always
9.
Do you feel strained when you are around your relative?
0.  Never
1.  Rarely
2.  Sometimes
3.  Quite Frequently
4.  Nearly Always
10. Do you feel your health has suffered because of your involvement with your relative?
0.  Never
1.  Rarely
2.  Sometimes
3.  Quite Frequently
4.  Nearly Always
11.
Do you feel that you don’t have as much privacy as you would like, because of your 
relative?
0.  Never
1.  Rarely
2.  Sometimes
3.  Quite Frequently
4.  Nearly Always
12.
Do you feel that your social life has suffered because you are caring for your relative?
0.  Never
1.  Rarely
2.  Sometimes
3.  Quite Frequently
4.  Nearly Always


Appendix 7: Zarit Burden Interview (cont.)
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
155/Protocol BN40900 (SA-309JG), Version 10
13.
Do you feel uncomfortable about having friends over, because of your relative?
0.  Never
1.  Rarely
2.  Sometimes
3.  Quite Frequently
4.  Nearly Always
14.
Do you feel that your relative seems to expect you to take care of him/her, as if you were 
the only one he/she could depend on?
0.  Never
1.  Rarely
2.  Sometimes
3.  Quite Frequently
4.  Nearly Always
15.
Do you feel that you don’t have enough money to care for your relative, in addition to the 
rest of your expenses?
0.  Never
1.  Rarely
2.  Sometimes
3.  Quite Frequently
4.  Nearly Always
16.
Do you feel that you will be unable to take care of your relative much longer?
0.  Never
1.  Rarely
2.  Sometimes
3.  Quite Frequently
4.  Nearly Always
17.
Do you feel you have lost control of your life since your relative’s illness?
0.  Never
1.  Rarely
2.  Sometimes
3.  Quite Frequently
4.  Nearly Always
18.
Do you wish you could just leave the care of your relative to someone else?
0.  Never
1.  Rarely
2.  Sometimes
3.  Quite Frequently
4.  Nearly Always
19.
Do you feel uncertain about what to do about your relative?
0.  Never
1.  Rarely
2.  Sometimes
3.  Quite Frequently
4.  Nearly Always
20.
Do you feel you should be doing more for your relative?
0.  Never
1.  Rarely
2.  Sometimes
3.  Quite Frequently
4.  Nearly Always
21. Do you feel you could do a better job in caring for your relative?
0.  Never
1.  Rarely
2.  Sometimes
3.  Quite Frequently
4.  Nearly Always
22.
Overall, how burdened do you feel in caring for your relative?
0.  Not at all
1.  A little
2.  Moderately
3.  Quite a bit
4.  Extremely
Copyright 1983, 1990, Steven H. Zarit and Judy M. Zarit
The actual forms will be provided to the sites and should be used for assessment.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
156/Protocol BN40900 (SA-309JG), Version 10
Appendix 8
EuroQol-5D (EQ-5D)


Appendix 8: EuroQol-5D (EQ-5D) (cont.)
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
157/Protocol BN40900 (SA-309JG), Version 10


Appendix 8: EuroQol-5D (EQ-5D) (cont.)
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
158/Protocol BN40900 (SA-309JG), Version 10
The actual forms will be provided to the sites and should be used for assessment.






Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
161/Protocol BN40900 (SA-309JG), Version 10
Appendix 10
C-SSRS at Baseline


Appendix 10:  C-SSRS at Baseline (cont.)
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
162/Protocol BN40900 (SA-309JG), Version 10


Appendix 10:  C-SSRS at Baseline (cont.)
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
163/Protocol BN40900 (SA-309JG), Version 10
The actual forms will be provided to the sites and should be used for assessment.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
164/Protocol BN40900 (SA-309JG), Version 10
Appendix 11
C-SSRS since Last Visit


Appendix 11:  C-SSRS since Last Visit (cont.)
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
165/Protocol BN40900 (SA-309JG), Version 10


Appendix 11:  C-SSRS since Last Visit (cont.)
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
166/Protocol BN40900 (SA-309JG), Version 10
The actual forms will be provided to the sites and should be used for assessment.


Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
167/Protocol BN40900 (SA-309JG), Version 10
Appendix 12
Instruction for Tuberculosis (TB) Screening and Treatment
Interpretation of TB screening results
Immunosuppressant biologic treatments have been shown to increase the risk of 
tuberculosis (TB) infection or to cause conversion from latent to active TB in some 
circumstances. Because of this, patients must be screened for active or latent TB prior to 
entry to this study.
Definitions
Active TB is a disease caused by Mycobacterium tuberculosis in any part of the body 
and that is in an active state as determined by either a smear or culture taken from any 
source which tests positive for TB or if there is radiographic evidence of TB. Individuals 
with active TB are symptomatic, depending upon the location of the disease (most 
commonly in the lungs but also possibly in the brain, kidneys, spine or elsewhere) and 
can spread the infection to others. 
Latent TB is said to exist when an individual is infected with Mycobacterium tuberculosis, 
as evidenced by a positive Tuberculin Skin Test (TST) or Interferon Gamma Release 
Assay (IGRA - such as Quantiferon-TB Gold) but is asymptomatic and has no evidence 
of active infection on screening pathology or radiographic tests. Such individuals do not 
pass the disease to others. Such individuals must be treated with appropriate anti-
mycobacterial therapy for at least 3 weeks prior to initiating study treatment 
administration in this study.
TB screening 
TB screening must be performed prior to initiation of study drug treatment. TB screening 
should be conducted per local guidance (or the table described below if none exist). For 
reference, the US CDC notes on TB testing may be found at 
http://www.cdc.gov/TB/TOPIC/testing/default.htm.

As part of recording the patient's medical history, the patient will be asked if they 
have had either active or latent TB in the past and whether they have received a 
BCG vaccination. They will also be asked if they have been in contact with any 
individuals known to have active TB.

TB test (e.g., TST [PPD, Purified Protein Derivative] and/or IGRA [e.g., Quantiferon-
TB Gold]) is required at screening. 

A chest X-ray is required at screening and is recommended to be performed and 
reported by a qualified radiologist. 


Appendix 12:  Instruction for Tuberculosis (TB) Screening and Treatment (cont.)
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
168/Protocol BN40900 (SA-309JG), Version 10
Note:
1.
The TST may be positive if the patient has had a BCG vaccination or has been 
infected with TB in the past; IGRA results may also be positive in some cases of 
past infection.
2.
Positive results of the TST and IGRA test may be reduced by immune suppression.
3.
Local guidance may vary depending upon the sensitivity of strains of Mycobacterium 
tuberculosis present locally.
In case of any doubt as to the diagnosis of latent TB, it is advised that a local physician 
with expertise in the treatment of TB or the Medical Monitor is consulted.
A combination of the medical history, the results of the TST test, the IGRA test, chest X-
ray and any other investigations deemed appropriate by the Investigator based on 
clinical signs and symptoms indicative of TB infection elsewhere in the body will be used 
by the Investigator to determine study eligibility at screening for this study as follows:
TST or IGRA 
result
Chest X-ray
Interpretation/Action
Evidence of 
current, 
active TB
Evidence of
old TB 
a)
Positive TST or 
IGRA
Positive
Positive or 
negative
Active TB present. Ineligible for entry 
to study. 
b)
Positive TST
Negative
Positive or 
negative
Could be either i) prior BCG vaccine, 
ii) past history of TB, iii) latent TB or 
iv) extra-pulmonary active TB. 
Perform IGRA test to exclude i) then 
follow instructions in section c) below.
c)
Positive IGRA
Negative
Positive or 
negative
Possible latent TB or extra-pulmonary 
TB present. Exclude extra-pulmonary 
TB using further investigations 
appropriate to any sign/symptoms. 
Once extra-pulmonary TB has been 
excluded patient is only eligible for 
study entry after at least 3 weeks of 
prophylactic anti-mycobacterial 
therapy prior to initiating study 
treatment administration and if 
committed to completing this course 
of treatment.
d)
Negative TST 
or IGRA
Positive
Positive or 
negative
Likely anomalous TST/IGRA result. 
Repeat TST/IGRA test if in doubt. 
Ineligible for entry to study. 


Appendix 12:  Instruction for Tuberculosis (TB) Screening and Treatment (cont.)
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd
169/Protocol BN40900 (SA-309JG), Version 10
TST or IGRA 
result
Chest X-ray
Interpretation/Action
Evidence of 
current, 
active TB
Evidence of
old TB 
e)
Negative TST 
or IGRA
Negative
Positive
Prophylactic anti-mycobacterial 
therapy should be considered, 
according to local guidelines (if such 
exist) because there may be a false 
negative TST or IGRA if the patient 
has been on prior 
immunosuppressants. Such 
prophylactic therapy is not 
compulsory but is at the Investigator's 
discretion. The patient may be eligible 
for study treatment with or without 
prophylactic anti-mycobacterial 
treatment.
(If in doubt about TST/IGRA result, 
repeat tests.)
f)
Negative TST 
or IGRA
Negative
Negative
Eligible for study entry.
g)
Indeterminate 
TST or IGRA
Positive
Positive or 
negative
Likely anomalous TST/IGRA result. 
Repeat TST/IGRA test if in doubt. 
Ineligible for entry to study.
h)
Indeterminate 
TST or IGRA
Negative
Positive or 
negative
Possible anomalous TST/IGRA result 
or latent TB. Repeat IGRA test. If 
result still indeterminate, and there 
are no signs/symptoms of extra-
pulmonary, follow instructions in 
section e) or f) above.
If result of repeat IGRA negative, 
follow instructions in section e) or f) 
above.
TB Treatment 
If the patient is positive for latent TB, then the patient must be treated with appropriate 
anti-mycobacterial therapy for at least 3 weeks prior to initiating study treatment 
administration. Treatment regimens should be followed by the local guidance. If no local 
guidance exists for treatment of immunocompromised individuals, then the US CDC 
must be followed (http://www.cdc.gov/TB/publications/LTBI/default.htm).
In case of any doubt as to the appropriate course of anti-mycobacterial therapy of latent 
TB, it is advised that a local physician with expertise in the treatment of TB or the 
Medical Monitor is consulted.


Appendix 12:  Instruction for Tuberculosis (TB) Screening and Treatment (cont.) 
  
Satralizumab (SA237)—F. Hoffmann-La Roche Ltd 
170/Protocol BN40900 (SA-309JG), Version 10 
Management of signs/symptoms of TB during the study 
If new signs/symptoms of TB infection develop during the study, perform diagnostic tests 
as above. If TB infection is diagnosed, interrupt study treatment and consult the Medical 
Monitor. Report TB infection as a "Selected Adverse Event" (see protocol Section 5.2.4). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
 
Official Title:    
 
A multicenter, randomized, double-blind, placebo-controlled, phase 3 
study to evaluate the efficacy and safety, of SA237 as monotherapy in 
patients with neuromyelitis optica (NMO) and neuromyelitis optica 
spectrum disorder (NMOSD) 
NCT Number: NCT02073279 
Document Date: SAP Version 7: 26-Nov-18 
 
 
 


TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
Page 1 of 60 
 
 
 
Chugai Pharmaceutical Co. Ltd. 
SA-309JG 
A multicenter, randomized, double-blind, placebo-controlled, phase 3 study to evaluate 
the efficacy and safety, of SA237 as monotherapy in patients with neuromyelitis optica 
(NMO) and neuromyelitis optica spectrum disorder (NMOSD) 
Statistical Analysis Plan 
PAREXEL Project Number: 214545 
Version 7.0 
Date: 26NOV2018 
 
 
 










Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 6 of 60 
LIST OF ABBREVIATIONS 
AE(s) 
Adverse event(s) 
ANCOVA 
Analysis of covariance 
ATC 
Anatomical Therapeutic and Chemical 
AQP4 
Aquaporin-4 
ARR 
Annualized relapse rate 
BOCF 
Baseline observation carried forward 
CEC 
Clinical Endpoint Committee 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV 
Coefficient of Variation 
eCRF  
Electronic Case Report form 
ECG  
Electrocardiogram 
EDSS 
Expanded Disability Status Scale 
FACIT 
Functional Assessment Of Chronic Illness Therapy 
FPI 
First patient in 
GEE 
Generalized Estimating Equation 
ITT 
Intent-to-treat 
LLOQ 
Lower Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect model repeated measures 
mRS 
Modified Rankin Scale 
NMO 
Neuromyelitis optica 
NMOSD 
NMO spectrum disorder 
PD 
Pharmacodynamics 
PK  
Pharmacokinetics 
PK-PPS 
Pharmacokinetic Per-Protocol Set 
PPS 
Per-Protocol Set 
PT 
Preferred term 
Q4W 
Every 4 Weeks 
SAE(s)  
Serious adverse event(s) 
SAP 
Statistical analysis plan  
SC 
Subcutaneously 
SD  
Standard deviation 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 7 of 60 
SF-36 
Short Form Generic Health Survey 
SF-MPQ 
Short Form McGill Pain Questionnaire 
SFU 
Safety Follow-Up 
SOC 
System organ class 
SAF 
Safety Set 
TFR 
Time to first relapse 
VAS 
Visual Analogue Scale 
WHO-DD 
World Health Organization Drug Dictionary 
ZBI 
Zarit Burden Interview 
 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 8 of 60 
1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) provides details of the summaries and analyses to be 
performed to report the results of the study. It should be read in conjunction with 
following documents: 
• 
Study Protocol, Version 8.2AB, 25th October 2018 
• 
Electronic Case Report Form (eCRF), Version 10.0, 22nd December 2017  
2 
STUDY OBJECTIVES 
The objective of this study is to evaluate the efficacy and safety of SA237 monotherapy in 
patients with neuromyelitis optica (NMO) and neuromyelitis optica spectrum disorder 
(NMOSD). 
3 
INVESTIGATIONAL PLAN 
3.1 Overall Study Design and Plan 
This is a multicenter randomized, double-blind, placebo-controlled parallel assignment 
study followed by an open-label extension (OLE) period. Patients will be randomized to 
two groups (2:1, Group A or B) and will receive subcutaneous (SC) SA237 (Group A) or 
placebo (Group B) at Weeks 0, 2, 4, and every 4 weeks (Q4W) thereafter. The 
randomization will be stratified by prior therapy for prevention of NMO/NMOSD attack 
(B-cell depleting therapy or immunosuppressants/others) and the most recent attack in the 
last one year prior to screening (first attack or relapse). If a patient was administered B-cell 
depleting therapies (e.g. anti-CD20 antibody [e.g. rituximab], anti-CD19 antibody) at least 
once in the year prior to baseline, the patient will be stratified into “B-cell depleting therapy 
group” and otherwise into the “immunosuppressants/others group” (e.g. oral 
corticosteroids, azathioprine, mycophenolate mofetil, cyclosporine, methotrexate, 
tacrolimus). 
Patients who experience a protocol-defined relapse which is adjudicated by the Clinical 
Endpoint Committee (CEC) in the double-blind period or complete the double-blind period 
can enter the open-label extension period. The double-blind period of the study ends when 
the total number of CEC-confirmed protocol-defined relapses is 44. At the end of the 
double-blind period, the clinical cut-off date for the primary analysis will be on the day of 
the onset of the protocol defined 44th relapse (adjudicated by the CEC) or 1.5 years after 
the date of randomization of the last patient enrolled, whichever comes first. In the 
extension period, patients can receive open-label treatment with 120 mg SA237 SC at 
Weeks 0, 2, 4, and every 4 weeks (Q4W) thereafter, until commercial availability of SA237 
or Sponsor’s decision to discontinue the development program.  
For patients who experience a relapse in the double-blind period, appropriate rescue 
therapy for relapse will be administered. For patients who experienced  a relapse which is 
adjudicated by the CEC as  a protocol-defined relapse, SA237 should start under stable 
disease conditions (i.e. Day 31 or later, where Day 1 is defined as the day of onset of a 
protocol-defined relapse confirmed by CEC). For patients who completed the double-blind 




Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 10 of 60 
score, change in visual acuity (Snellen chart) score, and change in low-contrast visual 
acuity (Low-contrast Sloan letter chart [LCSLC]) score. 
3.2.2 Safety Variables 
The safety variables include incidence and severity of adverse events (AEs), adverse events 
of special interest (AESIs), SAEs, injection related reactions (IRRs), injection site reactions 
(ISRs), patient withdrawals due to AEs, vital signs (temperature, systolic blood pressure 
[SBP] and diastolic blood pressure [DBP] and pulse rate), physical examinations, clinical 
laboratory tests (hematology, chemistry, and urinalysis), 12-lead ECG, body weight, and 
suicidality (Columbia-Suicide Severity Rating Scale [C-SSRS]). 
 
4 
STATISTICAL METHODS 
4.1 Data Quality Assurance 
All tables, figures and data listings to be included in the report will be independently 
checked for consistency, integrity and in accordance with standard PAREXEL procedures. 
 
4.2 General Presentation Considerations  
The analyses periods are defined as follows:  
• Study duration of double blind period for efficacy analysis 
- 
Study duration of double-blind period starts on the day of the randomization. 
The double-blind period ends on the earliest day of 1) clinical cutoff date 
(CCOD), 2) the day before the first treatment in the extension period, 3) the 
end of the study, or 4) last contact for patients lost to follow up. 
 
• Double blind period for safety analysis  
- 
Double blind period starts on the day of first dose of study drug.  The 
double-blind period ends on the same day as the efficacy analysis.    
 
• Study duration of SA237 exposure for safety analysis (for All SA237 analysis)  
- 
Study duration of SA237 exposure starts on the day of first dose of SA237. 
Study duration of SA237 exposure ends on the earliest day of 1) CCOD, 2) 
the end of the study, or 3) last contact for patients lost to follow up. 
 
The definition of summaries by visit is as follows: 
• Summaries by visit for double blind period  
- 
Baseline is defined as the latest data before or on the date prior to first 
administration with either placebo or SA237. Summarized visits except for 
baseline are defined as follows. Irregular visits such as unscheduled visit 
between week X, dose outside the visit window (DOW), extra visit at 
relapsing, and the end of the study are out of scope. Week X visits are 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 11 of 60 
directly used for categories of time. In other words, time window is not 
applied. If there are the same visits data, one representative assessment 
nearest to the scheduled visit day will be summarized. 
 
• Summaries by visit for All SA237 analysis  
- 
Baseline is defined as the latest data before or on the date prior to first 
administration of SA237. Summarized visits except for baseline are defined 
as follows. Irregular visits such as unscheduled visit between week X, dose 
outside the visit window (DOW), extra visit at relapsing, and the end of the 
study are out of scope. Time window is applied as if visit schedules continue 
in the double-blind period. Middle of each specified day of visit will be used 
for the range of time window of each visit. One representative assessment 
nearest to the specified day of visit in time window of each visit will be 
summarized. 
Continuous data will be summarized in terms of the mean, standard deviation (SD), 
median, minimum, maximum and number of observations, unless otherwise stated. The 
minimum and maximum will be reported to the same number of decimal places as the raw 
data recorded in the database. The mean, median and SD will be reported to one more 
decimal place than the raw data recorded in the database. In general, the maximum number 
of decimal places reported shall be four for any summary statistics.  
For categorical parameters, the number and percentages of subjects in each category will 
be presented at the relevant time point. The denominator for percentage will be based on 
the number of subjects appropriate for the purpose of analysis. Unless otherwise noted, 
percentages will be presented to one decimal place. Percentages will not be presented for 
zero counts and 100% will be presented as an integer. The denominator for all percentages 
will be the number of subjects in that treatment group within the population of interest, 
unless otherwise noted. Missing category will only be displayed when there are missing 
data. 
For pharmacokinetic endpoints, concentrations will be analyzed using all reported decimal 
places, and displayed to the same number of decimal places as recorded in the database. If 
any samples are collected outside of the protocol defined time window (Appendix 1 in the 
protocol), the relevant values will be excluded for the calculation of descriptive statistics. 
Furthermore, if the samples are collected more than 6 weeks after the last study drug 
administration, the relevant values will be excluded for the calculation of descriptive 
statistics considering the half-life of IgG.  Descriptive statistics will include number of the 
subjects, geometric mean, geometric coefficient of variation (CV) and the 95% confidence 
interval for the geometric mean of the concentrations, as well as arithmetic mean, SD, 
median, minimum, and maximum of SA237 concentrations will be calculated by visit and 
per defined time window post-dose according to the Pharmacokinetics Per-Protocol Set 
(PK-PPS). The CV will be presented with 1 decimal place. For the calculation of 
descriptive statistics, a serum concentration below limit of quantification will be 
substituted by half of lower limit of quantification (i.e. LLOQ/2).  If more than half of the 
measured values are BLQ at any blood sampling time point, the statistics will not be 
tabulated for that time point and will be shown as “N.C.”. 
 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 12 of 60 
For immunogenicity, below rules will be applied to neutralizing antibodies:   
• Except baseline measurement, neutralizing antibodies will be assessed only if anti- 
SA237 antibody results are positive.  
• If SA237 concentration is over 1 ug/mL, the data of the neutralizing antibodies will 
be excluded for the calculation of descriptive statistics. High concentrations of 
SA237 could lead to false negative results in the neutralizing antibody analysis  
Changes from baseline in categorical data will be summarized using shift tables where 
appropriate. 
P-values greater than or equal to 0.001, in general, will be presented to three decimal 
places. . P-values less than 0.001 will be presented as “<0.001”. 
Confidence intervals will be presented to one more decimal place than the raw data. 
The Confidence Interval for hazard ratio will be calculated based on the Wald type and the 
relapse rate Confidence Interval will be provided using Kaplan Meier method with a 
LOGLOG transformation.  
All report outputs will be produced using SAS® version 9.2 or a later version in a secure 
and validated environment.  
 
4.3 Handling of Missing dates  
Medications with a missing start date, whose stop date is either unknown or after the date 
of the first dose of study drug, will be considered concomitant. Medications with a missing 
start date, whose stop date is prior to the date of the first dose of study drug, will be 
considered as prior medications. 
Where the adverse events start dates of year part are missing then the value will not be 
imputed. For the partial missing situation (month or day missing), the value will be 
imputed for the analysis purpose. 
Missing pattern 
Start Date / Pre-Dosing  
End Date / Post-Dosing 
completely missing 
leave missing 
missing year 
leave missing 
missing month 
set to ‘JAN’ 
set to ‘DEC’ 
missing day 
set to ‘01’ 
set to last day of the month 
missing month and day set to ‘01JAN’  
set to ‘31DEC’ 
missing time 
(concomitant 
medication) 
set to ‘00:00:00’ 
missing hours: 0 
missing minutes: 0 
missing seconds: 0 
set to ‘23:59:59’ 
missing hours: 23 
missing minutes: 59 
missing seconds: 59 
missing time 
(adverse event) 
set to ‘23:59:59’ 
missing hours: 23 
missing minutes: 59 
missing seconds: 59 
These rules apply to AE and concomitant medication. For AE, beginning/end date of AE, 
first date of study treatment and date of death are considered to avoid inconsistency. 




Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 14 of 60 
received at least 3 doses of study drug, and without any major protocol deviations which 
are considered to have an impact on efficacy. Subjects will be analyzed as treated for 
analysis purposes in the PPS. 
The Safety Set (SAF) population will include all randomized subjects who have received 
at least one dose of active study drug or placebo. Subject will be included in the treatment 
group corresponding to the trial treatment they actually received for the analysis of safety 
data using the SAF population, i.e. patients who received at least one dose of SA237 will 
be assigned to the SA237 treatment arm, irrespective of randomized arm. 
The All-Subjects-Treated (All SA237) population will be defined as all enrolled subjects 
who took at least one dose of active study drug at any time.  Date of the first active study 
drug administration will be defined as Day 1 for All SA237 analysis (i.e. Day 1 of subjects 
randomized to the placebo group is redefined on the day of first dose of SA237 when 
entering extension period. 
The Pharmacokinetics Per-Protocol Set (PK-PPS) and immunogenicity (anti-SA237 
antibody) will include all subjects in the SAF with at least 1 valid post-dose concentration 
result with a dosing record and sampling time. Pharmacodynamics variables will be 
analyzed using the SAF population. 
The following summary and listing will be provided based on all randomized subjects: 
• A summary of analysis populations, including the number and percentage of subjects in 
the defined analysis sets by treatment group and overall. 
• A by-subject listing of analysis population (ITT, PPS, SAF, All SA237 and PK-PPS) 
information will be provided. 
This listing should include: subject number, inclusion/exclusion flag for each population 
and reason for exclusion from each population. 
 
4.6 Demographic and Baseline Characteristics 
Summary tables and listing will be provided as follows for ITT, PPS, PK-PPS and SAF. 
Demographics and baseline characteristics will be summarized as collected at screening or 
baseline visit before administration of first dose of study drug and will include:  
 
• gender,  
• race (American Indian/Alaska Native, Asian [Japanese], Asian [Non-Japanese], 
Black/African American, Native Hawaiian/other Pacific Islander, White and Other),  
• geographic region (Asia, Europe/other),  
• age (years), Age category( <65, >= 65 years)  
• ethnicity,  
• height,  
• 
body weight (the first and the third quartiles of body weight will be presented),  
• body mass index (BMI, kg/m2), BMI category (<18.5, ≥18.5 to <25, ≥25 to <30, and 
≥30 kg/m2), 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 15 of 60 
• Prior therapy for prevention of NMO/NMOSD attack (B-cell depleting therapy or 
immunosuppressants/others), 
• Most recent attack in the last one year prior (first attack or relapse) ,  
• AQP4 status at screening (positive, negative), and  
• Diagnosis (NMO, NMOSD) by treatment group and overall. 
The following listing will be provided. 
• 
A by-subject listing of demographic data. 
Age will be calculated as the number of complete years between a subject's birth date and 
the date of the first informed consent. 
 
4.7 Medical History 
Medical history will be classified according to the terminology of the latest version of the 
Medical Dictionary for Regulatory Activities (MedDRA). 
Medical conditions are categorized as past or baseline as follows: 
• 
Past diseases: Medical conditions which are specified as start date is before Day 1 Visit 
date with no ongoing status or the stop date is prior to Day 1 Visit date. 
• 
Baseline diseases: Medical conditions which are specified as start date is before Day 1 
Visit date with ongoing status or with the stop date on or after Day 1 Visit date. 
The following summaries will be provided by treatment group and overall, based on the 
SAF. 
• 
A summary table of past diseases will be provided by system organ class (SOC) and 
preferred term (PT), by treatment group and overall. 
• 
A summary table of baseline diseases will be presented by SOC and PT, by treatment 
group and overall. 
• 
A by-subject listing of medical history data will be provided. 
4.8 Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization 
Drug Dictionary (WHO-DD). 
Medication start and stop dates will be compared to the date of the first dose of randomized 
study drug and thus the medications will be classified as Prior and / or Concomitant. 
Medications that start and stop prior to the date of first dose of study drug will be classified 
as Prior medications. Medications taken on or after (including ongoing) the first dose of 
study drug will be classified as Concomitant medication. If a medication starts before the 
date of first dose of study medication and stops on or after the date of first dose of study 
medication then the medication will be classified as both Prior and Concomitant 
medication.  NMO/NMOSD pain drugs will be reported as collected on the CRF. 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 16 of 60 
• 
A summary table of Prior Medications (other treatments than NMO/NMOSD) will be 
provided by anatomical therapeutic chemical (ATC) and PT. 
• 
A summary table of Concomitant Medications (other treatments than NMO/NMOSD) 
will be provided by ATC and PT. 
• 
A summary table of Prior NMO/NMOSD drugs for relapse prevention will be provided 
by ATC and PT. 
• 
A summary table of Concomitant NMO/NMOSD drugs for relapse prevention will be 
provided by ATC and PT. 
• 
A summary table of Prior NMO/NMOSD drugs for relapse/rescue therapy will be 
provided by ATC and PT. 
• 
A summary table of Concomitant NMO/NMOSD drugs for relapse/rescue therapy will 
be provided by ATC and PT. 
• 
A summary table of Prior NMO/NMOSD pain drugs will be provided by ATC and PT. 
• 
A summary table of Concomitant NMO/NMOSD pain drugs will be provided by ATC 
and PT. 
• 
A summary table of Prior other NMO/NMOSD drugs will be provided by ATC and PT. 
• 
A summary table of Concomitant other NMO/NMOSD drugs will be provided by ATC 
and PT. 
• 
A by-subject listing of Prior medication data will be provided for NMO/NMOSD  
• 
A by-subject listing of Concomitant medication for NMO/NMOSD. 
4.9 Treatment Compliance 
Overall compliance will be assessed for each subject. Compliance will be computed by 
determining the number of SC injections relative to the number of SC injections that should 
have been administered. The compliance will only be evaluated during the double-blind 
period.  For subjects who experience a protocol-defined relapse which is confirmed by 
CEC or discontinued from study treatment early, the number of planned and actual SC 
injections will be counted based on the visits before the discontinuation. Treatment 
compliance will be summarized in terms of compliance based on the Safety population. 
Compliance will be calculated using the following formula: 
Compliance 
(%) 
= 
Number of SC injections during the double-blind period 
x 100 
Number of planned SC injections during the double-
blind period 
The following summaries and listings will be provided: 
• A summary table of compliance will be presented by treatment group, and overall. The 
number and percentage of treatment compliance will also be presented by categorized 
compliance as: <80%, 80%-100%, >100%. 








Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 20 of 60 
An8 
4 
- 
___________  = 
__________ 
An12 
4 
- 
___________  = 
__________ 
An14 
4 
- 
___________  = 
__________ 
An15 
4 
- 
___________  = 
__________ 
An16 
4 
- 
___________  = 
__________ 
 
 
 
 
 
 
 
Sum individual item scores:_____ 
 
 
Multiply by 13: ________ 
 
 
Divide by number of items answered:________=FACIT 
score 
4.10.1.9 
EDSS Scoring 
The EDSS is an ordinal clinical rating scale ranging from 0 (normal neurological exam) to 
10 (death due to NMO) in 0.5 unit increments that represent higher levels of disability. The 
EDSS scoring will be based on the score recorded on CRF. 
4.10.1.10 
mRS Scoring 
The mRS is a 7-point disability scale that assesses the degree of disability in patients with 
neurological impairment. Possible scores range from 0 (no symptom at all) up to 6 (death). 
The higher scores reflect increased disability. The mRS scoring will be based on the score 
recorded on CRF. 
4.10.1.11 
ZBI Scoring 
The ZBI is the measurement to assess caregiver burden. The 22 items ask for the strain 
caregivers perceive. Responses range from 0 (never) to 4 (nearly always) with maximum 
score of 88. The higher the total score, the heavier the perceived burden. The ZBI scoring 
will be based on the score recorded on CRF. For summary tables, only questionnaire with 
responses to 17 or more out of 22 questions (>= 75% valid response) are used.  
The ZBI can be scored if 17 or more items are completed. Interpretation approach can be 
used if at least 75% of the items have been completed: 
- 
Sum the items that were answered. 
- 
Divide the sum by the number of items that were answered to yield the mean 
response per item. 
- 
Multiply the mean response per item by 22 (the total items in the scale). 
 
4.10.1.12 
Visual acuity function (Snellen chart) 
Visual acuity will be measured by a Snellen 20-foot wall chart. The test will be performed 
monocularly and subjects may use their habitual distance glasses or contact lenses. If visual 
acuity is less than 20/200, these data will be recorded on CRF as below: 
・ If the subject can count fingers, this is recorded as “20/300” (CF). 
・ If the subject can see finger movements, this is recorded as “20/400” (HM). 
・ If the subject can perceive the flashlight, this is recorded as “20/500” (LP). 
・ If the subject cannot perceive the flashlight, this is recorded as “20/600” (NLP). 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 21 of 60 
In order to calculate change from baseline, visual acuity scores will be converted to 
logMAR visual acuity scoring. Transformation of scores will be conducted based on the 
following table (Table 5-2). If the record of visual acuity score (Snellen chart) is worse 
than 20/200 (i.e. CF, HM, LP or NLP in this study), the score will be converted to 
logMAR 1.85, logMAR 2.00, logMAR 2.70 and logMAR 3.00, respectively. If a score 
which is not in the table is recorded, it would be adjusted to the following lower score 
(e.g. 20/27 will be converted to 20/30). 
Table 5-2: logMAR visual acuity scoring 
Snellen chart 
LogMAR 
20/10 
-0.30 
20/12.5 
-0.20 
20/15 
-0.12 
20/16 
-0.10 
20/20 
0.00 
20/25 
0.10 
20/30 
0.18 
20/32 
0.20 
20/40 
0.30 
20/50 
0.40 
20/60 
0.48 
20/63 
0.50 
20/70 
0.54 
20/80 
0.60 
20/100 
0.70 
20/114 
0.76 
20/125 
0.80 
20/150 
0.88 
20/160 
0.90 
20/200 
1.00 
CF 
1.85 
HM 
2.00 
LP 
2.70 
NLP 
3.00 
 
4.10.2 Primary Efficacy Variable 
The primary efficacy analyses will be based on the ITT population. Supportive evaluations 
will be performed using the PPS population. 
The primary efficacy endpoint is TFR based on protocol-defined relapses confirmed by the 
CEC with EDSS/FSS assessment performed by the examining assessor within 7 days after 
relapse symptoms were reported to the site by the subject. TFR is defined as the time from 
the date of the randomization until the first occurrence of relapse throughout the 
double-blind period. Time point of relapse onset is defined as time at which the subject 






Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 24 of 60 
• 
A figure of Kaplan-Meier estimate of TFR (protocol-defined relapse based on CEC 
adjudication, regardless of assessment limit of 7 days) will be presented by treatment 
group. 
• 
A figure of Kaplan-Meier estimate of TFR (protocol-defined relapse) censored by 
affecting medications will be presented by treatment group. 
• 
Analysis of TFR (protocol-defined relapse) will be performed using a weighted 
stratified log-rank test and the parameters of the weight function are set to be rho=0 
and gamma=1. 
• 
Analysis of TFR (clinical relapse) will be performed using stratified log-rank test. 
• 
Analysis of TFR (treated clinical relapse) will be performed using stratified log-rank 
test. 
• 
Analysis of TFR (treated clinical relapse: optic neuritis) will be performed using 
stratified log-rank test. 
• 
Analysis of TFR (protocol-defined relapse based on CEC adjudication (regardless of 
assessment limit of 7 days)) will be performed using stratified log-rank test. 
• 
Analysis of TFR (protocol-defined relapse) censored by affecting medications will be 
performed using stratified log-rank test. 
• 
Analysis of TFR (clinical relapse) will be performed using the stratified Cox regression. 
• 
Analysis of TFR (treated clinical relapse) will be performed using the stratified Cox 
regression. 
• 
Analysis of TFR (treated clinical relapse: optic neuritis) will be performed using the 
stratified Cox regression. 
• 
 Analysis of TFR (protocol-defined relapse based on CEC adjudication (regardless of 
assessment limit of 7 days)) will be performed using the stratified Cox regression. 
• 
Analysis of TFR (protocol-defined relapse) censored by affecting medications will be 
performed using stratified Cox regression. 
• 
A by-subject listing of TFR, which also includes clinical relapse, treated clinical 
relapses and treated clinical relapse: optic neuritis, will be provided. 
 
4.10.3 Secondary Efficacy Variables 
The key secondary efficacy endpoints are change from baseline in VAS for pain score and 
the FACIT fatigue scale score to week 24. All efficacy analyses will be based on the ITT 
population and the double-blind period.  
4.10.3.1 
Key Secondary Endpoints 
• 
Analysis of change in VAS for pain score from baseline to week 24 using ANCOVA 
(BOCF). 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 25 of 60 
• 
Analysis of change in FACIT fatigue scale score from baseline to week 24 using 
ANCOVA (BOCF). 
The ANCOVA will include treatment group as fixed effect; the baseline measurements and 
stratification variables as covariates. 
The missing data will be imputed by baseline observation carried forward (BOCF) method. 
 
Additionally, sensitivity analyses using different imputation methods (random hot deck, 
imputation using OLE baseline/withdrawal visits) and MMRM using all collected data 
during the double-blind period will be performed as follows:  
 
Random hot deck:  
Random hot deck imputation method using a regression based approach will be conducted. 
In this imputation method, missing values will be replaced with values from a similar 
responding unit.  
 
Imputation using OLE baseline/ withdrawal visits:  
VAS for Pain and fatigue are assessed at OLE baseline visit for patients entering  into OLE 
and the withdrawal visit for patients discontinuing from treatment. Missing values for 
patients that do not have a Week 24 assessment, but for which a pain /fatigue assessments 
is available between study days 85 and 252 from an OLE baseline or withdrawal visit, will 
be replaced with these values. The remaining missing values will be imputed using BOCF.  
 
• 
Analysis of change in VAS for pain score from baseline to week 24 using ANCOVA 
by random hot deck imputation method. 
• 
Analysis of change in FACIT fatigue scale score from baseline to week 24 using 
ANCOVA by random hot deck imputation method. 
• 
Analysis of change in VAS for pain score from baseline to week 24 using ANCOVA 
with imputation using OLE baseline/ withdrawal visits 
• 
Analysis of change in FACIT fatigue scale score from baseline to week 24 using 
ANCOVA with imputation using OLE baseline/ withdrawal visits 
The following summary tables and analyses including all available visits in the double-
blind period will also be provided as exploratory analyses: 
• 
A summary table of change in VAS for pain score from baseline to every 24 weeks. 
• 
A summary table of change in FACIT fatigue scale score from baseline to every 24 
weeks. 
• 
Analysis of change in VAS for pain score from baseline to every 24 weeks using 
MMRM analysis. 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 26 of 60 
• 
Analysis of change in FACIT fatigue scale score from baseline to every 24 weeks using 
MMRM analysis. 
The MMRM will include treatment group, protocol-specified visit, treatment-by-visit 
interaction as fixed effects; the baseline measurements and stratification variables as 
covariates; and visit as a repeated measure. The unstructured covariance matrix will be 
assumed in the model. 
If the unstructured covariance matrix does not converge, the length of the observation 
interval will  be limited (e.g. to Week 96) and/or other covariance structure will be used. If 
treatment-by-visit interaction is not statistically significant, the full model will be kept.  
If the normality assumption for the key secondary variable does not hold, GEE or 
Generalized Linear Mixed-effect model analysis will be used. The assessment will be 
performed prior to unblinding. 
 
4.10.3.2 
Other Secondary Endpoints 
The following summary tables, figures and analysis will be provided for the ITT: 
• 
A summary table of change in SF-36 domain scores from baseline to every 24 weeks. 
• 
A summary table of change in SF-36 summary score (physical and mental) from 
baseline to every 24 weeks. 
• 
A summary table of change in EQ-5D scores from baseline to every 24 weeks. 
• 
A summary table of change in T25W from baseline to every 24 weeks.  
• 
A summary table of the proportion of relapse-free patients. 
• 
A summary table of ARR. 
The ARR is calculated as the total number of relapses experienced divided by the 
person-years at risk. The 95% CI will be presented based on the Poisson distribution. 
ARR based on the person-years at risk on the total study period will also be provided. 
In order to account for different study treatment exposure durations among subjects, 
log-transformed exposure time will be included in the model as an “offset” variable for 
appropriate computation of ARR. 
• 
A summary table of ARR for patients with clinical relapse. 
• 
A summary table of ARR for patients with treated clinical relapse. 
• 
Analysis of ARR will be performed using negative binomial regression model 
(protocol-defined relapse). 
For comparing the difference between 2 treatment arms, relapse number will be the 
response variable; treatment group, prior therapy for prevention of NMO/NMOSD 
attack (B-cell depleting therapy or immunosuppressants/others) and the most recent 
attack in the last one year prior to baseline (first attack or relapse) as covariates. Log-
transformed exposure time will be included in the model as an “offset” variable. 
• 
A summary table of change in mRS scores from baseline to every 24 weeks. 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 27 of 60 
• 
A summary table of change in ZBI scores from baseline to every 24 weeks. 
• 
A summary table of change in EDSS scores from baseline to every 24 weeks. 
• 
A summary table of change in visual acuity (Snellen chart) scores from baseline to 
every 24 weeks. 
• 
A summary table of change in low-contrast visual acuity (Low-contrast Sloan letter 
chart [LCSLC]) scores from baseline to every 24 weeks. 
• 
Analysis of change in SF-36 domain scores from baseline to every 24 weeks using 
MMRM analysis. 
• 
Analysis of change in SF-36 components (physical and mental) from baseline to every 
24 weeks using MMRM analysis. 
• 
Analysis of change in EQ-5D scores from baseline to every 24 weeks using MMRM 
analysis. 
• 
Analysis of change in T25W scores from baseline to every 24 weeks using MMRM 
analysis. 
• 
Analysis of change in mRS scores from baseline to every 24 weeks using MMRM 
analysis. 
• 
Analysis of change in ZBI scores from baseline to every 24 weeks using MMRM 
analysis. 
• 
Analysis of change in EDSS scores from baseline to every 24 weeks using MMRM 
analysis. 
• 
Analysis of change in visual function (Snellen chart) scores from baseline to every 24 
weeks using MMRM analysis. 
• 
Analysis of change in low-contrast visual acuity (Low-contrast Sloan letter chart 
[LCSLC]) scores from baseline to every 24 weeks using MMRM analysis. 
The MMRM will include treatment group, protocol-specified visit, treatment-by-visit 
interaction as fixed effects; the baseline measurements and stratification factors as a 
covariate; and visit as a repeated measure. The unstructured covariance matrix will be 
assumed in the model. 
If the unstructured covariance matrix does not converge, the length of the observation 
interval will be limited (e.g. to Week 96) and/or compound symmetric structure will be 
used. If treatment-by-visit interaction is not statistically significant, the full model will be 
kept. 
If the normality assumption for other secondary variables does not hold, GEE or 
Generalized Linear Mixed-effect model analysis will be used. The assessment will be 
performed prior to unblinding. 
 
4.11 Safety Evaluation 




Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 29 of 60 
 
4.11.4 Deaths, Serious Adverse Events, and Other Significant Adverse Events 
SAE will be provided by treatment group. SAE will be provided by subgroups The 
following summary tables of SAEs will be provided: 
• 
A summary of incidence of serious AEs (SAEs) by SOC and PT. 
• 
A summary of incidence of SAEs leading to discontinuation by SOC and PT. 
• 
A by-subject listing for all deaths. 
4.11.5 C-SSRS 
The following will be presented for C-SSRS:  
• 
A summary of C-SSRS.  
• 
A by-subject listing of C-SSRS. 
Scores reported in the “Baseline” and ”Prior to study” pages of  the CRF will be handled 
as baseline score. Scores reported in “Since Last Visit” and “Since Study Start” page of 
CRF will be summarized by visit when the data is recorded. 
4.11.6  Adverse event of special interest (AESI) 
AESI are defined in the protocol as follows and collected in the eCRF using a specific 
question.  
• Cases of an elevated ALT or AST in combination with either an elevated bilirubin or 
clinical jaundice. 
• Suspected transmission of an infectious agent by the study treatment. 
The following listings will be provided: 
• A by-subject listing of all AESI. 
 
4.11.5 Selected Adverse Events 
Selected adverse events are  
• non serious infections that require treatments with IV antibiotic, antifungal, antiviral 
• opportunistic infections defined as per basket with PO antibiotic, antifungal, antiviral 
injection-related reaction (IRR; an AE which occurs within 24 hours after study 
treatment injection except where the event is not considered an allergic reaction. 
The following summary tables and listings will be provided:  
• A by-subject listing for non-serious infection (SOC: Infections and infestations) 
medicated by IV treatment antibiotic, antifungal, antiviral. 






Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 32 of 60 
Absolute 
differential 
count 
(neutrophils, 
eosinophils, 
lymphocytes, 
monocytes, 
basophils, other 
cells) 
Total bilirubin 
Fibrinogen 
Total serum protein 
Albumin 
ALT 
AST 
Alkaline 
phosphatase 
Gamma-glutamyl 
transpeptidase (γ-
GTP) 
Lactate 
dehydrogenase 
(LDH) 
Total cholesterol 
Low density 
lipoprotein 
cholesterol (LDL) 
High density 
lipoprotein 
Cholesterol (HDL) 
Triglycerides 
Creatine kinase 
(CK) 
Uric acid 
  
4.11.11 AST and ALT:  
AST and ALT will be categorized into four group (>3-5 xULN, 6-10 xULN, 11-20 xULN 
and 21- xULN) based on maximum post-baseline levels within baseline and post-baseline 
respectively for each test by maximum post-baseline levels for total bilirubin and alkaline 
phosphatase (total bilirubin <= 2xULN, total bilirubin > 2xULN, total bilirubin > 2xULN 
and alkaline phosphatase < 2xULN, total bilirubin > 2xULN and alkaline phosphatase <= 
5xULN). The denominator is the number of subjects with any valid assessment at baseline 
and post-baseline respectively. Subjects with AST or ALT results fulfilling criteria for 
more than one category are counted only once, in the category indicating the highest 
elevation level within baseline and post-baseline. 
• Summary of AST and ALT Results. 
4.11.12 Electrocardiograms 
For quantitative ECG measurements (heart rate, PR interval, QRS duration, QT interval, 
and corrected QT intervals using Bazett and Fridericia correction methods), values during 
the double-blind period will be presented by treatment group for all visits.  
The Bazett corrected QT (QTcB) will be calculated as 
QTcB=QT/RR0.5, where RR = 60/HR. 
The Fridericia corrected QT (QTcF) will be calculated as 
QTcF=QT/RR0.33, where RR = 60/HR. 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 33 of 60 
The following summaries and listings will be provided for the SAF and all SA237: 
• 
A summary of 12-lead by treatment group at each specified visit. 
• 
The number and percentage of subjects with a QTc (using Bazett and Fridericia 
corrected) of 450ms, >450 to 480ms, >480 to 500ms, and >500ms will be 
summarized by treatment group at each specified visit. 
• 
The number and percentage of subjects with a QTc (using Bazett and Fridericia 
corrected) of an increase from baseline of >0 to 30ms, >30 to 60ms, and >60ms will 
be summarized by treatment group at each specified visit. 
• 
The number and percentage of subjects with PR interval values 120ms, >120 to 
220ms, and >220ms, and the number and percentage of subjects with QRS interval 
values 60ms, >60 to 120ms, and >120ms will be presented by treatment group at 
each specified visit. 
• 
A summary of incidence of treatment-emergent abnormality 12-lead ECG findings 
after start of study drug by treatment group. 
• 
A by-subject listing of abnormal 12-lead ECG data will be provided. 
4.11.13 Vital Signs, Physical Findings and Other Observations Related to Safety 
Noninvasive pulse rate, temperature, systolic blood pressure (SBP) and diastolic blood 
pressure (DBP) will be measured at visits with the subject in a sitting position after at least 
10 minutes at rest, according to the tabular schedule of study procedures in the protocol. 
Summary statistics of the actual measurement and their changes from baseline will be 
presented by treatment group at each specified visit. 
In addition, summary statistics for the actual value and change from baseline will be 
presented by treatment group for all visits during the double-blind period. 
Abnormal vital sign criteria as follows: 
- 
diastolic blood pressure [DBP]: <50,  >100 mmHg 
- 
systolic blood pressure [SBP]: <90, >160 mmHg 
- 
pulse rate [PR]: <60, >100 bpm 
- 
Temperature: <36.0, >38.0 
The following summaries and listings will be provided: 
• 
A summary of pulse rates temperature, blood pressure and change from baseline by 
treatment group and visit. 
• 
The number and percentage of subjects with abnormal vital signs during double-blind 
period by treatment group. 
• 
A by-subject listing of vital signs. 
 
4.12 Pharmacokinetics and Pharmacodynamics 




Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 35 of 60 
• 
A by-subject listing of anti-AQP4 antibody (positive/negative and titer) 
• 
Plasmablast (Plasmablasts/CD19+(%), Plasmablasts/CD45+(%), and Plasmablast 
(cells/uL)), and CD19+ cells (CD19+/CD45+(%) and CD 19+ (cells/uL)) 
• 
A by-subject spaghetti plot of concentration for SA237 in serum by subgroup (age 
category, Japanese/non-Japanese, relapse/no-relapse, ADA status) using linear scale 
and overall using linear and semi log scale. 
• 
A by-subject spaghetti plot of the absolute value and the change from baseline for 
concentration of IL-6, sIL-6R, and hsCRP by treatment group using linear and semi log 
scale. 
• 
A by-subject spaghetti plot of the absolute value for concentration of IL-6, sIL-6R, and 
hsCRP by subgroup (age category, Japanese/non-Japanese, relapse/no-relapse, ADA 
status) in each of treatment group using linear scale 
• 
A by-subject spaghetti plot of the absolute value for concentration of IL-6, sIL-6R, and 
hsCRP by treatment group in each subgroup (relapse/no-relapse, ADA status) using 
linear scale 
• 
A by-subject spaghetti plot of the absolute value and the change from baseline for titer 
of anti-AQP4 antibody, Plasmablast (Plasmablasts/CD19+ (%), Plasmablasts/CD45+ 
(%), and Plasmablasts (cells/uL)), and CD19+ cells (CD19+/CD45+ (%), and CD19+ 
(cells/uL)) by treatment group using linear and semi-log scale 
• 
A by-subject spaghetti plot of the absolute value for titer of anti-AQP4 antibody, 
Plasmablast (Plasmablasts/CD19+ (%), Plasmablasts/CD45+ (%), and Plasmablasts 
(cells/uL)), and CD19+ cells (CD19+/CD45+ (%), and CD19+ (cells/uL)) by subgroup 
(NMO/NMOSD and AQP4 Status, relapse/no-relapse) in each of treatment group using 
linear scale. 
• 
A by-subject spaghetti plot of the absolute value for titer of anti-AQP4 antibody, 
Plasmablast (Plasmablasts/CD19+ (%), Plasmablasts/CD45+ (%), and Plasmablasts 
(cells/uL)), and CD19+ cells (CD19+/CD45+ (%), and CD19+ (cells/uL)) by treatment 
group in each subgroup (NMO/NMOSD and AQP4 Status, relapse/no-relapse) using 
linear scale. 
• 
An Arithmetic mean ± SD plot of concentration for SA237 in serum by subgroup (age 
category, Japanese/non-Japanese, relapse/no-relapse, ADA status) using linear scale 
and overall using linear and semi log scale. 
• 
An Arithmetic mean ± SD plot of the absolute value and the change from baseline for 
concentration of IL-6, sIL-6R, and hsCRP by treatment group using linear and semi-
log scale. 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 36 of 60 
• 
An Arithmetic mean ± SD plot of the absolute value for concentration of IL-6, sIL-
6R, and hsCRP by subgroup (age category, Japanese/non-Japanese, relapse/no-relapse, 
ADA status) in each of treatment group using linear scale. 
• 
An Arithmetic mean ± SD plot of the absolute value for concentration of IL-6, sIL-
6R, and hsCRP by treatment group in each subgroup (age category, Japanese/non-
Japanese, relapse/no-relapse, ADA status) using linear scale 
• 
An Arithmetic mean ± SD plot of the absolute value for titer of anti-AQP4 antibody, 
Plasmablast (Plasmablasts/CD19+ (%), Plasmablasts/CD45+ (%), Plasmablasts 
(cells/uL)), and CD19+ cells (CD19+/CD45+ (%) and CD19+ (cells/uL)) by treatment 
group using linear and semi-log scale 
• 
An Arithmetic mean ± SD plot of the absolute value for titer of anti-AQP4 antibody, 
Plasmablast (Plasmablasts/CD19+ (%), Plasmablasts/CD45+ (%), Plasmablasts 
(cells/uL)), and CD19+ cells (CD19+/CD45+ (%) and CD19+ (cells/uL)) by subgroup 
(NMO/NMOSD and AQP4 Status, relapse/no-relapse) in each of treatment group using 
linear scale 
• 
An Arithmetic mean ± SD plot of the absolute value for titer of anti-AQP4 antibody, 
Plasmablast (Plasmablasts/CD19+ (%), Plasmablasts/CD45+ (%), Plasmablasts 
(cells/uL)), and CD19+ cells (CD19+/CD45+ (%) and CD19+ (cells/uL)) by treatment 
group in each subgroup (NMO/NMOSD and AQP4 Status, relapse/no-relapse) using 
linear scale. 
• 
A by-subject listing of actual doses, date and time of sampling, visit, relative day, and 
the accession number.  
• 
Scatter plot of anti-AQP4 antibody titer versus plasmablast (Plasmablasts/CD19+ 
Plasmablasts/CD45+ (%), Plasmablasts (cells/uL)) will be presented at Weeks 0, 2 and 
4, 8, 12, 24, and Q24W. When the data of anti-AQP4 antibody is negative, put “1” as 
a titer for negative samples and replace to “BLQ”. 
• 
Scatter plots of serum SA237 concentration versus body weight at weeks 2, 4, Q4W 
respectively. 
 
4.13 Immunogenicity 
ADA subgroup using confirmatory sample status are defined as below. 
➢ ADA negative subjects: subjects without positive ADA during study. If sample at 
baseline is missing and no sample after the baseline is positive, the subject is defined 
as” ADA negative subjects”. 
➢ ADA unaffected subjects: subjects who have pre-existing ADA (POSITIVE at 
baseline) that was NOT boosted to a higher level after the post dose. “NOT boosted 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 37 of 60 
to a higher level” means that ADA titer after the baseline is <fourfold than the ADA 
titer at baseline. 
➢ Treatment-boosted ADA subjects: subjects who have pre-existing ADA that was 
boosted to a higher level at least one time point after baseline “Boosted to a higher 
level” means as follow 
1) ADA titer after the baseline is greater fourfold than the ADA titer at baseline  
➢ Treatment-induced ADA subjects: subjects who have positive ADA not at baseline 
but after the baseline. If sample at baseline is missing and at least one sample after the 
baseline is positive, the subject is defined as” Treatment-induced ADA subjects” 
The immunogenicity will be analyzed using the SAF population. 
• 
The numbers and proportions of subjects with positive ADA at baseline will be 
presented by treatment group and overall. 
• 
The numbers and proportions of ADA negative subjects, ADA unaffected subjects, 
treatment-boosted ADA subjects, and treatment-induced ADA subjects will be 
summarized. The numbers and proportions of transient ADA and persistent ADA will 
be summarized in the treatment-induced ADA subjects. 
Transient ADA: 1) Treatment-induced ADA detected only at one sampling time point 
(excluding the last sampling time point) during the study or 2) treatment-induced ADA 
detected at two or more sampling time points during the study, where the period between 
first and last ADA-positive sampling time points is less than 16 weeks, and the subject’s 
last sampling time point is ADA-negative. 
Persistent ADA: 1) Treatment-induced ADA detected at two or more sampling time points 
during the study, where the period between first and last ADA-positive sampling time 
points is 16 weeks or longer or 2) where the period between first and last ADA-positive 
sampling time points is less than 16 weeks, and the subject’s last sampling time point is 
ADA-positive or 3) treatment-induced ADA detected only at the last sampling time point.  
➢ The numbers and proportions of patients with positive/negative anti-SA237 
antibodies and neutralizing antibodies will be presented at Week 0 and Q4W in 
SA237 group by visit. 
➢  
A by-subject listing of anti-SA237 antibody (confirmatory judgment 
(positive/negative), titer, ratio of peak titer/baseline titer, and ADA subgroup), 
neutralizing judgment (positive/negative)), and adverse events in the subject 
having anti-SA237 antibody at least once at any point in time. 
4.14 Determination of Sample Size 
Approximately 90 patients need to be recruited and randomized in a 2:1 ratio to the two 
treatment groups (SA237 and placebo). The sample size considerations are based on the 
following assumptions: 
• 
A two-sided log-rank test. 




Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 39 of 60 
 
 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 40 of 60 
5 
Changes in the Conduct of the Study or Planned Analysis 
5.1 Amendment from Ver 1.0 to 2.0 
The primary purpose of this SAP amendment is to revise the context to align with the 
statistical section in the amended protocol. 
For TFR, the condition of handling missing data has been added. For patients with protocol-
defined relapse based on CEC evaluation, but not performed EDSS/FSS assessment within 
seven days after the patient reports the symptoms to the site, the TFR will be censored on 
the date of relapse onset. The sensitivity analysis of protocol-defined relapse based on CEC 
adjudication has also been added. 
5.2 Amendment from Ver 2.0 to 3.0 
The primary purpose of this SAP amendment is to follow the FDA comments: 
For primary endpoint, analysis method has changed to the log-rank based permutation test 
from stratified log-rank test. For key secondary endpoints of VAS and FACIT, ANCOVA 
has been added for change from baseline at 24 weeks. For primary and key secondary 
endpoints, SAS code has been added. 
5.3 Amendment from Ver 3.0 to 4.0 
The primary purpose of this SAP amendment is to revise the context to align with the 
amended protocol version 5.0 dated 5 Nov 2015. For TFR, the definition of censoring has 
been revised. 
5.4 Amendment from Ver 4.0 to 5.0 
The primary purpose of this SAP amendment is to revise the context to align with the 
amended protocol version 6.0 dated 1 March 2016. The assumption for determination of 
sample size has been revised. For key secondary endpoints, sensitivity analysis has been 
added. 
5.5 Amendment from Ver 5.0 to 6.0 
The primary purpose of this SAP amendment is to follow the FDA comments: 
FDA Response dated 28th March 2017 for type C meeting Question 7: 
We agree that an asymptotic log-rank test instead of a permutation based log-rank test 
can be used as the primary analysis method. You may keep the permutation based log-
rank test as a secondary analysis method. 
Another purpose is to revise the context to align with the amended protocol version 7.0 
dated 13th July 2017. The following changes are made in this Statistical Analysis Plan 
(SAP) from the previous version of SAP due to the amendment to the protocol.  
• For primary endpoint, analysis method has changed to stratified log-rank test from 
the log-rank based permutation test.  


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 41 of 60 
• Only treatment-emergent adverse events are collected in this study. Previously the 
SAP contained summaries of adverse events and treatment-emergent adverse 
events, the latter were removed to avoid redundancy.    
• Detailed description on the identification of the following adverse event were 
added:  serious infections, opportunistic infections, anaphylaxis, injection related 
reactions and injection site reactions.   
• Detailed description of the following efficacy evaluation is added: EQ-5D Scoring 
and Visual acuity function.  
• Detailed description of the immunogenicity and immunogenicity analyses were 
added.  
• The analysis of relapse-free subjects using logistic regression will not be 
conducted because of a lot of early events.   
• Clarify the definition of baseline ARR.  
• Resolve inconsistencies mainly for scope of analysis in SAP. 
5.6 Amendment from Ver 6.0 to 6.1 
The primary purpose of this SAP amendment is to update the amended protocol version 
8.0 dated 18th June 2018.  
 
5.7 Amendment from Ver 6.1 to 7.0 
The primary purpose of this SAP amendment is to include additional sensitivity analyses 
for the primary and key secondary endpoints:  
• Sensitivity analysis for primary endpoint TFR (protocol-defined relapse) using 
stratified weighted log-rank test with Fleming-Harrington weight function was 
added.  
• Sensitivity analysis for change from baseline in pain and fatigue was added, 
including additional information from the withdrawal and OLE baseline visits.  
• Minor updates throughout the document to increase clarity and consistency.  
 
 
 




Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 43 of 60 
7 
APPENDIX 
7.1 SAS code for primary and key secondary analysis 
Primary analysis for TFR 
 
proc lifetest data = xxx; 
class TREAT; 
time TIME*CENS (1); 
strata PRIORTHERAPY ATTACK / group = TREAT; 
run; 
 
Notation: 
TREAT: treatment group (SA237 or Placebo), 
TIME: time to first relapse, 
CENS: censoring variable, 
PRIORTHERAPY: prior therapy for prevention of NMO/NMOSD attack (B-cell 
depleting therapy or immunosuppressants/others), 
ATTACK: the most recent attack in the last one year prior to screening (first attack or 
relapse). 
 
Sensitivity analysis for primary analysis 
 
proc lifetest data = xxx; 
class TREAT; 
time TIME*CENS (1); 
strata PRIORTHERAPY ATTACK / group = TREAT test=fleming(0,1); 
run; 
 
 
Secondary analysis for pain and fatigue  
 
proc mixed data = xxx; 
class TREAT; 
model CFBL = BL TREAT PRIORTHERAPY ATTACK; 
lsmeans TREAT / pdiff cl 
run; 
 
Notation: 
TREAT: treatment group (SA237 or Placebo), 
CFBL: change from baseline value of VAS or FACIT, 
BL: baseline value of VAS or FACIT, 
PRIORTHERAPY: prior therapy for prevention of NMO/NMOSD attack (B-cell 
depleting therapy or immunosuppressants/others), 
ATTACK: the most recent attack in the last one year prior to screening (first attack or 
relapse)


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 44 of 60 
 
7.2 EQ-5D Scoring Algorithm: 
This program computes the U.S. preference-weighted index score using self-reported EQ-5D data.  
It is presumed that the data set includes the following 5 variables: 
Dimension               Variable Name     Range 
Mobility                       MO                  1-3 
Self-care                      SC                  1-3 
Usual activities             UA                  1-3 
Pain/discomfort            PD                  1-3 
Anxiety/depression       AD                  1-3 
Where a 1 indicates no problems, a 2 indicates moderate problems, and a 3 indicates severe problems. 
To get U.S. EQ-5D index scores, paste data to the first 5 columns and read values from the last column. 
The index score will not be generated when responses are missing for 1 or more of the 5 dimensions.  
If there are more than 5,000 respondents, apply the algorithms for all the variables except the first 5 to more lines.  
MO 
SC 
UA 
PD 
AD 
m1 
s1 
u1 
p1 
a1 
m2 
s2 
u2 
p2 
a2 
d1 
i2 
i22 
i3 
i32 
pred 
full health 
EQ-5D 
index(US_D1) 
  
3 
3 
3 
3 
3 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
4 
0 
0 
4 
16 
-0.1090707 
-0.109 
-0.1090707 
 
3 
3 
2 
3 
3 
0 
0 
1 
0 
0 
1 
1 
0 
1 
1 
4 
0 
0 
3 
9 
-0.0996728 
-0.100 
-0.0996728 
 
3 
3 
1 
3 
3 
0 
0 
0 
0 
0 
1 
1 
0 
1 
1 
3 
0 
0 
3 
9 
-0.0995382 
-0.100 
-0.0995382 
 
3 
3 
3 
3 
2 
0 
0 
0 
0 
1 
1 
1 
1 
1 
0 
4 
0 
0 
3 
9 
-0.0402381 
-0.040 
-0.0402381 
 
3 
2 
3 
3 
3 
0 
1 
0 
0 
0 
1 
0 
1 
1 
1 
4 
0 
0 
3 
9 
-0.0383556 
-0.038 
-0.0383556 
 
3 
3 
3 
3 
1 
0 
0 
0 
0 
0 
1 
1 
1 
1 
0 
3 
0 
0 
3 
9 
-0.02361 
-0.024 
-0.02361 
 
3 
3 
2 
3 
2 
0 
0 
1 
0 
1 
1 
1 
0 
1 
0 
4 
1 
1 
2 
4 
-0.0119344 
-0.012 
-0.0119344 
 
3 
2 
2 
3 
3 
0 
1 
1 
0 
0 
1 
0 
0 
1 
1 
4 
1 
1 
2 
4 
-0.0100519 
-0.010 
-0.0100519 
 
3 
1 
3 
3 
3 
0 
0 
0 
0 
0 
1 
0 
1 
1 
1 
3 
0 
0 
3 
9 
-0.002608 
-0.003 
-0.002608 
 
3 
3 
1 
3 
2 
0 
0 
0 
0 
1 
1 
1 
0 
1 
0 
3 
0 
0 
2 
4 
-0.001113 
-0.001 
-0.001113 
 
3 
2 
1 
3 
3 
0 
1 
0 
0 
0 
1 
0 
0 
1 
1 
3 
0 
0 
2 
4 
0.0007695 
0.001 
0.0007695 
 
3 
3 
2 
3 
1 
0 
0 
1 
0 
0 
1 
1 
0 
1 
0 
3 
0 
0 
2 
4 
0.0153805 
0.015 
0.0153805 
 
3 
3 
1 
3 
1 
0 
0 
0 
0 
0 
1 
1 
0 
1 
0 
2 
0 
0 
2 
4 
0.0155151 
0.016 
0.0155151 
 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 45 of 60 
3 
3 
3 
2 
3 
0 
0 
0 
1 
0 
1 
1 
1 
0 
1 
4 
0 
0 
3 
9 
0.0300077 
0.030 
0.0300077 
 
3 
1 
2 
3 
3 
0 
0 
1 
0 
0 
1 
0 
0 
1 
1 
3 
0 
0 
2 
4 
0.0363825 
0.036 
0.0363825 
 
3 
1 
1 
3 
3 
0 
0 
0 
0 
0 
1 
0 
0 
1 
1 
2 
0 
0 
2 
4 
0.0365171 
0.037 
0.0365171 
 
3 
2 
3 
3 
2 
0 
1 
0 
0 
1 
1 
0 
1 
1 
0 
4 
1 
1 
2 
4 
0.0493828 
0.049 
0.0493828 
 
3 
3 
2 
2 
3 
0 
0 
1 
1 
0 
1 
1 
0 
0 
1 
4 
1 
1 
2 
4 
0.0583114 
0.058 
0.0583114 
 
3 
3 
3 
1 
3 
0 
0 
0 
0 
0 
1 
1 
1 
0 
1 
3 
0 
0 
3 
9 
0.0633035 
0.063 
0.0633035 
 
3 
3 
1 
2 
3 
0 
0 
0 
1 
0 
1 
1 
0 
0 
1 
3 
0 
0 
2 
4 
0.0691328 
0.069 
0.0691328 
 
3 
2 
3 
3 
1 
0 
1 
0 
0 
0 
1 
0 
1 
1 
0 
3 
0 
0 
2 
4 
0.0766977 
0.077 
0.0766977 
 
2 
3 
3 
3 
3 
1 
0 
0 
0 
0 
0 
1 
1 
1 
1 
4 
0 
0 
3 
9 
0.0774663 
0.077 
0.0774663 
 
1 
3 
3 
3 
3 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
3 
0 
0 
3 
9 
0.0838874 
0.084 
0.0838874 
 
3 
2 
2 
3 
2 
0 
1 
1 
0 
1 
1 
0 
0 
1 
0 
4 
2 
4 
1 
1 
0.0859055 
0.086 
0.0859055 
 
3 
1 
3 
3 
2 
0 
0 
0 
0 
1 
1 
0 
1 
1 
0 
3 
0 
0 
2 
4 
0.0958172 
0.096 
0.0958172 
 
3 
3 
2 
1 
3 
0 
0 
1 
0 
0 
1 
1 
0 
0 
1 
3 
0 
0 
2 
4 
0.102294 
0.102 
0.102294 
 
3 
3 
1 
1 
3 
0 
0 
0 
0 
0 
1 
1 
0 
0 
1 
2 
0 
0 
2 
4 
0.1024286 
0.102 
0.1024286 
 
2 
3 
2 
3 
3 
1 
0 
1 
0 
0 
0 
1 
0 
1 
1 
4 
1 
1 
2 
4 
0.10577 
0.106 
0.10577 
 
3 
1 
3 
3 
1 
0 
0 
0 
0 
0 
1 
0 
1 
1 
0 
2 
0 
0 
2 
4 
0.1124453 
0.112 
0.1124453 
 
2 
3 
1 
3 
3 
1 
0 
0 
0 
0 
0 
1 
0 
1 
1 
3 
0 
0 
2 
4 
0.1165914 
0.117 
0.1165914 
 
3 
3 
3 
2 
2 
0 
0 
0 
1 
1 
1 
1 
1 
0 
0 
4 
1 
1 
2 
4 
0.1177461 
0.118 
0.1177461 
 
3 
2 
1 
3 
2 
0 
1 
0 
0 
1 
1 
0 
0 
1 
0 
3 
1 
1 
1 
1 
0.1181005 
0.118 
0.1181005 
 
3 
2 
3 
2 
3 
0 
1 
0 
1 
0 
1 
0 
1 
0 
1 
4 
1 
1 
2 
4 
0.1196286 
0.120 
0.1196286 
 
1 
3 
2 
3 
3 
0 
0 
1 
0 
0 
0 
1 
0 
1 
1 
3 
0 
0 
2 
4 
0.1228779 
0.123 
0.1228779 
 
1 
3 
1 
3 
3 
0 
0 
0 
0 
0 
0 
1 
0 
1 
1 
2 
0 
0 
2 
4 
0.1230125 
0.123 
0.1230125 
 
3 
2 
2 
3 
1 
0 
1 
1 
0 
0 
1 
0 
0 
1 
0 
3 
1 
1 
1 
1 
0.134594 
0.135 
0.134594 
 
3 
3 
3 
2 
1 
0 
0 
0 
1 
0 
1 
1 
1 
0 
0 
3 
0 
0 
2 
4 
0.145061 
0.145 
0.145061 
 
3 
2 
1 
3 
1 
0 
1 
0 
0 
0 
1 
0 
0 
1 
0 
2 
0 
0 
1 
1 
0.1454154 
0.145 
0.1454154 
 
3 
1 
2 
3 
2 
0 
0 
1 
0 
1 
1 
0 
0 
1 
0 
3 
1 
1 
1 
1 
0.1537135 
0.154 
0.1537135 
 
3 
3 
2 
2 
2 
0 
0 
1 
1 
1 
1 
1 
0 
0 
0 
4 
2 
4 
1 
1 
0.1542688 
0.154 
0.1542688 
 
3 
2 
2 
2 
3 
0 
1 
1 
1 
0 
1 
0 
0 
0 
1 
4 
2 
4 
1 
1 
0.1561513 
0.156 
0.1561513 
 
3 
3 
3 
1 
2 
0 
0 
0 
0 
1 
1 
1 
1 
0 
0 
3 
0 
0 
2 
4 
0.1617287 
0.162 
0.1617287 
 
3 
2 
3 
1 
3 
0 
1 
0 
0 
0 
1 
0 
1 
0 
1 
3 
0 
0 
2 
4 
0.1636112 
0.164 
0.1636112 
 
3 
1 
1 
3 
2 
0 
0 
0 
0 
1 
1 
0 
0 
1 
0 
2 
0 
0 
1 
1 
0.1645349 
0.165 
0.1645349 
 
2 
3 
3 
3 
2 
1 
0 
0 
0 
1 
0 
1 
1 
1 
0 
4 
1 
1 
2 
4 
0.1652047 
0.165 
0.1652047 
 
3 
1 
3 
2 
3 
0 
0 
0 
1 
0 
1 
0 
1 
0 
1 
3 
0 
0 
2 
4 
0.166063 
0.166 
0.166063 
 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 46 of 60 
2 
2 
3 
3 
3 
1 
1 
0 
0 
0 
0 
0 
1 
1 
1 
4 
1 
1 
2 
4 
0.1670872 
0.167 
0.1670872 
 
3 
3 
3 
1 
1 
0 
0 
0 
0 
0 
1 
1 
1 
0 
0 
2 
0 
0 
2 
4 
0.1783568 
0.178 
0.1783568 
 
3 
1 
2 
3 
1 
0 
0 
1 
0 
0 
1 
0 
0 
1 
0 
2 
0 
0 
1 
1 
0.1810284 
0.181 
0.1810284 
 
3 
1 
1 
3 
1 
0 
0 
0 
0 
0 
1 
0 
0 
1 
0 
1 
0 
0 
1 
1 
0.181163 
0.181 
0.181163 
 
1 
3 
3 
3 
2 
0 
0 
0 
0 
1 
0 
1 
1 
1 
0 
3 
0 
0 
2 
4 
0.1823126 
0.182 
0.1823126 
 
1 
2 
3 
3 
3 
0 
1 
0 
0 
0 
0 
0 
1 
1 
1 
3 
0 
0 
2 
4 
0.1841951 
0.184 
0.1841951 
 
3 
3 
1 
2 
2 
0 
0 
0 
1 
1 
1 
1 
0 
0 
0 
3 
1 
1 
1 
1 
0.1864638 
0.186 
0.1864638 
 
3 
2 
1 
2 
3 
0 
1 
0 
1 
0 
1 
0 
0 
0 
1 
3 
1 
1 
1 
1 
0.1883463 
0.188 
0.1883463 
 
2 
3 
3 
3 
1 
1 
0 
0 
0 
0 
0 
1 
1 
1 
0 
3 
0 
0 
2 
4 
0.1925196 
0.193 
0.1925196 
 
1 
3 
3 
3 
1 
0 
0 
0 
0 
0 
0 
1 
1 
1 
0 
2 
0 
0 
2 
4 
0.1989407 
0.199 
0.1989407 
 
3 
1 
3 
1 
3 
0 
0 
0 
0 
0 
1 
0 
1 
0 
1 
2 
0 
0 
2 
4 
0.1993588 
0.199 
0.1993588 
 
2 
3 
2 
3 
2 
1 
0 
1 
0 
1 
0 
1 
0 
1 
0 
4 
2 
4 
1 
1 
0.2017274 
0.202 
0.2017274 
 
3 
3 
2 
2 
1 
0 
0 
1 
1 
0 
1 
1 
0 
0 
0 
3 
1 
1 
1 
1 
0.2029573 
0.203 
0.2029573 
 
2 
2 
2 
3 
3 
1 
1 
1 
0 
0 
0 
0 
0 
1 
1 
4 
2 
4 
1 
1 
0.2036099 
0.204 
0.2036099 
 
2 
1 
3 
3 
3 
1 
0 
0 
0 
0 
0 
0 
1 
1 
1 
3 
0 
0 
2 
4 
0.2135216 
0.214 
0.2135216 
 
3 
3 
1 
2 
1 
0 
0 
0 
1 
0 
1 
1 
0 
0 
0 
2 
0 
0 
1 
1 
0.2137787 
0.214 
0.2137787 
 
3 
2 
3 
2 
2 
0 
1 
0 
1 
1 
1 
0 
1 
0 
0 
4 
2 
4 
1 
1 
0.215586 
0.216 
0.215586 
 
3 
3 
2 
1 
2 
0 
0 
1 
0 
1 
1 
1 
0 
0 
0 
3 
1 
1 
1 
1 
0.219625 
0.220 
0.219625 
 
1 
1 
3 
3 
3 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
2 
0 
0 
2 
4 
0.2199427 
0.220 
0.2199427 
 
3 
2 
2 
1 
3 
0 
1 
1 
0 
0 
1 
0 
0 
0 
1 
3 
1 
1 
1 
1 
0.2215075 
0.222 
0.2215075 
 
3 
1 
2 
2 
3 
0 
0 
1 
1 
0 
1 
0 
0 
0 
1 
3 
1 
1 
1 
1 
0.2239593 
0.224 
0.2239593 
 
3 
3 
1 
1 
2 
0 
0 
0 
0 
1 
1 
1 
0 
0 
0 
2 
0 
0 
1 
1 
0.2304464 
0.230 
0.2304464 
 
3 
2 
1 
1 
3 
0 
1 
0 
0 
0 
1 
0 
0 
0 
1 
2 
0 
0 
1 
1 
0.2323289 
0.232 
0.2323289 
 
2 
3 
1 
3 
2 
1 
0 
0 
0 
1 
0 
1 
0 
1 
0 
3 
1 
1 
1 
1 
0.2339224 
0.234 
0.2339224 
 
3 
1 
1 
2 
3 
0 
0 
0 
1 
0 
1 
0 
0 
0 
1 
2 
0 
0 
1 
1 
0.2347807 
0.235 
0.2347807 
 
2 
3 
3 
2 
3 
1 
0 
0 
1 
0 
0 
1 
1 
0 
1 
4 
1 
1 
2 
4 
0.2354505 
0.235 
0.2354505 
 
2 
2 
1 
3 
3 
1 
1 
0 
0 
0 
0 
0 
0 
1 
1 
3 
1 
1 
1 
1 
0.2358049 
0.236 
0.2358049 
 
1 
3 
2 
3 
2 
0 
0 
1 
0 
1 
0 
1 
0 
1 
0 
3 
1 
1 
1 
1 
0.2402089 
0.240 
0.2402089 
 
1 
2 
2 
3 
3 
0 
1 
1 
0 
0 
0 
0 
0 
1 
1 
3 
1 
1 
1 
1 
0.2420914 
0.242 
0.2420914 
 
3 
3 
2 
1 
1 
0 
0 
1 
0 
0 
1 
1 
0 
0 
0 
2 
0 
0 
1 
1 
0.2469399 
0.247 
0.2469399 
 
3 
3 
1 
1 
1 
0 
0 
0 
0 
0 
1 
1 
0 
0 
0 
1 
0 
0 
1 
1 
0.2470745 
0.247 
0.2470745 
 
2 
3 
2 
3 
1 
1 
0 
1 
0 
0 
0 
1 
0 
1 
0 
3 
1 
1 
1 
1 
0.2504159 
0.250 
0.2504159 
 
1 
3 
1 
3 
2 
0 
0 
0 
0 
1 
0 
1 
0 
1 
0 
2 
0 
0 
1 
1 
0.2510303 
0.251 
0.2510303 
 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 47 of 60 
1 
3 
3 
2 
3 
0 
0 
0 
1 
0 
0 
1 
1 
0 
1 
3 
0 
0 
2 
4 
0.2525584 
0.253 
0.2525584 
 
1 
2 
1 
3 
3 
0 
1 
0 
0 
0 
0 
0 
0 
1 
1 
2 
0 
0 
1 
1 
0.2529128 
0.253 
0.2529128 
 
3 
2 
2 
2 
2 
0 
1 
1 
1 
1 
1 
0 
0 
0 
0 
4 
3 
9 
0 
0 
0.2603277 
0.260 
0.2603277 
 
2 
3 
1 
3 
1 
1 
0 
0 
0 
0 
0 
1 
0 
1 
0 
2 
0 
0 
1 
1 
0.2612373 
0.261 
0.2612373 
 
2 
2 
3 
3 
2 
1 
1 
0 
0 
1 
0 
0 
1 
1 
0 
4 
2 
4 
1 
1 
0.2630446 
0.263 
0.2630446 
 
3 
2 
3 
2 
1 
0 
1 
0 
1 
0 
1 
0 
1 
0 
0 
3 
1 
1 
1 
1 
0.2642745 
0.264 
0.2642745 
 
1 
3 
2 
3 
1 
0 
0 
1 
0 
0 
0 
1 
0 
1 
0 
2 
0 
0 
1 
1 
0.2675238 
0.268 
0.2675238 
 
1 
3 
1 
3 
1 
0 
0 
0 
0 
0 
0 
1 
0 
1 
0 
1 
0 
0 
1 
1 
0.2676584 
0.268 
0.2676584 
 
3 
1 
2 
1 
3 
0 
0 
1 
0 
0 
1 
0 
0 
0 
1 
2 
0 
0 
1 
1 
0.2679419 
0.268 
0.2679419 
 
3 
1 
1 
1 
3 
0 
0 
0 
0 
0 
1 
0 
0 
0 
1 
1 
0 
0 
1 
1 
0.2680765 
0.268 
0.2680765 
 
2 
1 
2 
3 
3 
1 
0 
1 
0 
0 
0 
0 
0 
1 
1 
3 
1 
1 
1 
1 
0.2714179 
0.271 
0.2714179 
 
2 
3 
2 
2 
3 
1 
0 
1 
1 
0 
0 
1 
0 
0 
1 
4 
2 
4 
1 
1 
0.2719732 
0.272 
0.2719732 
 
2 
3 
3 
1 
3 
1 
0 
0 
0 
0 
0 
1 
1 
0 
1 
3 
0 
0 
2 
4 
0.2794331 
0.279 
0.2794331 
 
3 
2 
3 
1 
2 
0 
1 
0 
0 
1 
1 
0 
1 
0 
0 
3 
1 
1 
1 
1 
0.2809422 
0.281 
0.2809422 
 
2 
1 
1 
3 
3 
1 
0 
0 
0 
0 
0 
0 
0 
1 
1 
2 
0 
0 
1 
1 
0.2822393 
0.282 
0.2822393 
 
3 
1 
3 
2 
2 
0 
0 
0 
1 
1 
1 
0 
1 
0 
0 
3 
1 
1 
1 
1 
0.283394 
0.283 
0.283394 
 
1 
3 
3 
1 
3 
0 
0 
0 
0 
0 
0 
1 
1 
0 
1 
2 
0 
0 
2 
4 
0.2858542 
0.286 
0.2858542 
 
1 
1 
2 
3 
3 
0 
0 
1 
0 
0 
0 
0 
0 
1 
1 
2 
0 
0 
1 
1 
0.2885258 
0.289 
0.2885258 
 
1 
1 
1 
3 
3 
0 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
0 
0 
1 
1 
0.2886604 
0.289 
0.2886604 
 
1 
2 
3 
3 
2 
0 
1 
0 
0 
1 
0 
0 
1 
1 
0 
3 
1 
1 
1 
1 
0.3015261 
0.302 
0.3015261 
 
2 
3 
1 
2 
3 
1 
0 
0 
1 
0 
0 
1 
0 
0 
1 
3 
1 
1 
1 
1 
0.3041682 
0.304 
0.3041682 
 
2 
2 
2 
3 
2 
1 
1 
1 
0 
1 
0 
0 
0 
1 
0 
4 
3 
9 
0 
0 
0.3077863 
0.308 
0.3077863 
 
3 
2 
3 
1 
1 
0 
1 
0 
0 
0 
1 
0 
1 
0 
0 
2 
0 
0 
1 
1 
0.3082571 
0.308 
0.3082571 
 
1 
3 
2 
2 
3 
0 
0 
1 
1 
0 
0 
1 
0 
0 
1 
3 
1 
1 
1 
1 
0.3104547 
0.310 
0.3104547 
 
3 
1 
3 
2 
1 
0 
0 
0 
1 
0 
1 
0 
1 
0 
0 
2 
0 
0 
1 
1 
0.3107089 
0.311 
0.3107089 
 
2 
2 
3 
3 
1 
1 
1 
0 
0 
0 
0 
0 
1 
1 
0 
3 
1 
1 
1 
1 
0.3117331 
0.312 
0.3117331 
 
3 
2 
1 
2 
2 
0 
1 
0 
1 
1 
1 
0 
0 
0 
0 
3 
2 
4 
0 
0 
0.3138963 
0.314 
0.3138963 
 
1 
3 
1 
2 
3 
0 
0 
0 
1 
0 
0 
1 
0 
0 
1 
2 
0 
0 
1 
1 
0.3212761 
0.321 
0.3212761 
 
3 
1 
3 
1 
2 
0 
0 
0 
0 
1 
1 
0 
1 
0 
0 
2 
0 
0 
1 
1 
0.3273766 
0.327 
0.3273766 
 
1 
2 
3 
3 
1 
0 
1 
0 
0 
0 
0 
0 
1 
1 
0 
2 
0 
0 
1 
1 
0.328841 
0.329 
0.328841 
 
3 
2 
2 
2 
1 
0 
1 
1 
1 
0 
1 
0 
0 
0 
0 
3 
2 
4 
0 
0 
0.3303898 
0.330 
0.3303898 
 
2 
1 
3 
3 
2 
1 
0 
0 
0 
1 
0 
0 
1 
1 
0 
3 
1 
1 
1 
1 
0.3308526 
0.331 
0.3308526 
 
2 
3 
3 
2 
2 
1 
0 
0 
1 
1 
0 
1 
1 
0 
0 
4 
2 
4 
1 
1 
0.3314079 
0.331 
0.3314079 
 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 48 of 60 
2 
2 
3 
2 
3 
1 
1 
0 
1 
0 
0 
0 
1 
0 
1 
4 
2 
4 
1 
1 
0.3332904 
0.333 
0.3332904 
 
2 
3 
2 
1 
3 
1 
0 
1 
0 
0 
0 
1 
0 
0 
1 
3 
1 
1 
1 
1 
0.3373294 
0.337 
0.3373294 
 
3 
1 
3 
1 
1 
0 
0 
0 
0 
0 
1 
0 
1 
0 
0 
1 
0 
0 
1 
1 
0.3440047 
0.344 
0.3440047 
 
3 
2 
2 
1 
2 
0 
1 
1 
0 
1 
1 
0 
0 
0 
0 
3 
2 
4 
0 
0 
0.3470575 
0.347 
0.3470575 
 
1 
1 
3 
3 
2 
0 
0 
0 
0 
1 
0 
0 
1 
1 
0 
2 
0 
0 
1 
1 
0.3479605 
0.348 
0.3479605 
 
2 
3 
1 
1 
3 
1 
0 
0 
0 
0 
0 
1 
0 
0 
1 
2 
0 
0 
1 
1 
0.3481508 
0.348 
0.3481508 
 
3 
1 
2 
2 
2 
0 
0 
1 
1 
1 
1 
0 
0 
0 
0 
3 
2 
4 
0 
0 
0.3495093 
0.350 
0.3495093 
 
1 
3 
2 
1 
3 
0 
0 
1 
0 
0 
0 
1 
0 
0 
1 
2 
0 
0 
1 
1 
0.3544373 
0.354 
0.3544373 
 
1 
3 
1 
1 
3 
0 
0 
0 
0 
0 
0 
1 
0 
0 
1 
1 
0 
0 
1 
1 
0.3545719 
0.355 
0.3545719 
 
2 
1 
3 
3 
1 
1 
0 
0 
0 
0 
0 
0 
1 
1 
0 
2 
0 
0 
1 
1 
0.3581675 
0.358 
0.3581675 
 
2 
2 
1 
3 
2 
1 
1 
0 
0 
1 
0 
0 
0 
1 
0 
3 
2 
4 
0 
0 
0.3613549 
0.361 
0.3613549 
 
3 
2 
1 
2 
1 
0 
1 
0 
1 
0 
1 
0 
0 
0 
0 
2 
1 
1 
0 
0 
0.3625848 
0.363 
0.3625848 
 
1 
1 
3 
3 
1 
0 
0 
0 
0 
0 
0 
0 
1 
1 
0 
1 
0 
0 
1 
1 
0.3645886 
0.365 
0.3645886 
 
1 
2 
2 
3 
2 
0 
1 
1 
0 
1 
0 
0 
0 
1 
0 
3 
2 
4 
0 
0 
0.3676414 
0.368 
0.3676414 
 
1 
3 
3 
2 
2 
0 
0 
0 
1 
1 
0 
1 
1 
0 
0 
3 
1 
1 
1 
1 
0.3698894 
0.370 
0.3698894 
 
1 
2 
3 
2 
3 
0 
1 
0 
1 
0 
0 
0 
1 
0 
1 
3 
1 
1 
1 
1 
0.3717719 
0.372 
0.3717719 
 
2 
3 
2 
2 
2 
1 
0 
1 
1 
1 
0 
1 
0 
0 
0 
4 
3 
9 
0 
0 
0.3761496 
0.376 
0.3761496 
 
2 
2 
2 
3 
1 
1 
1 
1 
0 
0 
0 
0 
0 
1 
0 
3 
2 
4 
0 
0 
0.3778484 
0.378 
0.3778484 
 
2 
2 
2 
2 
3 
1 
1 
1 
1 
0 
0 
0 
0 
0 
1 
4 
3 
9 
0 
0 
0.3780321 
0.378 
0.3780321 
 
3 
2 
1 
1 
2 
0 
1 
0 
0 
1 
1 
0 
0 
0 
0 
2 
1 
1 
0 
0 
0.3792525 
0.379 
0.3792525 
 
2 
3 
3 
2 
1 
1 
0 
0 
1 
0 
0 
1 
1 
0 
0 
3 
1 
1 
1 
1 
0.3800964 
0.380 
0.3800964 
 
3 
1 
1 
2 
2 
0 
0 
0 
1 
1 
1 
0 
0 
0 
0 
2 
1 
1 
0 
0 
0.3817043 
0.382 
0.3817043 
 
3 
2 
2 
1 
1 
0 
1 
1 
0 
0 
1 
0 
0 
0 
0 
2 
1 
1 
0 
0 
0.395746 
0.396 
0.395746 
 
2 
3 
3 
1 
2 
1 
0 
0 
0 
1 
0 
1 
1 
0 
0 
3 
1 
1 
1 
1 
0.3967641 
0.397 
0.3967641 
 
2 
1 
2 
3 
2 
1 
0 
1 
0 
1 
0 
0 
0 
1 
0 
3 
2 
4 
0 
0 
0.3969679 
0.397 
0.3969679 
 
1 
3 
3 
2 
1 
0 
0 
0 
1 
0 
0 
1 
1 
0 
0 
2 
0 
0 
1 
1 
0.3972043 
0.397 
0.3972043 
 
3 
1 
2 
2 
1 
0 
0 
1 
1 
0 
1 
0 
0 
0 
0 
2 
1 
1 
0 
0 
0.3981978 
0.398 
0.3981978 
 
2 
2 
3 
1 
3 
1 
1 
0 
0 
0 
0 
0 
1 
0 
1 
3 
1 
1 
1 
1 
0.3986466 
0.399 
0.3986466 
 
1 
2 
1 
3 
2 
0 
1 
0 
0 
1 
0 
0 
0 
1 
0 
2 
1 
1 
0 
0 
0.3998364 
0.400 
0.3998364 
 
2 
1 
3 
2 
3 
1 
0 
0 
1 
0 
0 
0 
1 
0 
1 
3 
1 
1 
1 
1 
0.4010984 
0.401 
0.4010984 
 
3 
2 
1 
1 
1 
0 
1 
0 
0 
0 
1 
0 
0 
0 
0 
1 
0 
0 
0 
0 
0.4065674 
0.407 
0.4065674 
 
3 
1 
1 
2 
1 
0 
0 
0 
1 
0 
1 
0 
0 
0 
0 
1 
0 
0 
0 
0 
0.4090192 
0.409 
0.4090192 
 
2 
2 
1 
3 
1 
1 
1 
0 
0 
0 
0 
0 
0 
1 
0 
2 
1 
1 
0 
0 
0.4100434 
0.410 
0.4100434 
 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 49 of 60 
1 
3 
3 
1 
2 
0 
0 
0 
0 
1 
0 
1 
1 
0 
0 
2 
0 
0 
1 
1 
0.413872 
0.414 
0.413872 
 
3 
1 
2 
1 
2 
0 
0 
1 
0 
1 
1 
0 
0 
0 
0 
2 
1 
1 
0 
0 
0.4148655 
0.415 
0.4148655 
 
1 
2 
3 
1 
3 
0 
1 
0 
0 
0 
0 
0 
1 
0 
1 
2 
0 
0 
1 
1 
0.4157545 
0.416 
0.4157545 
 
1 
2 
2 
3 
1 
0 
1 
1 
0 
0 
0 
0 
0 
1 
0 
2 
1 
1 
0 
0 
0.4163299 
0.416 
0.4163299 
 
1 
1 
3 
2 
3 
0 
0 
0 
1 
0 
0 
0 
1 
0 
1 
2 
0 
0 
1 
1 
0.4182063 
0.418 
0.4182063 
 
2 
3 
3 
1 
1 
1 
0 
0 
0 
0 
0 
1 
1 
0 
0 
2 
0 
0 
1 
1 
0.424079 
0.424 
0.424079 
 
3 
1 
1 
1 
2 
0 
0 
0 
0 
1 
1 
0 
0 
0 
0 
1 
0 
0 
0 
0 
0.4256869 
0.426 
0.4256869 
 
1 
2 
1 
3 
1 
0 
1 
0 
0 
0 
0 
0 
0 
1 
0 
1 
0 
0 
0 
0 
0.4271513 
0.427 
0.4271513 
 
2 
1 
1 
3 
2 
1 
0 
0 
0 
1 
0 
0 
0 
1 
0 
2 
1 
1 
0 
0 
0.4291629 
0.429 
0.4291629 
 
2 
3 
1 
2 
2 
1 
0 
0 
1 
1 
0 
1 
0 
0 
0 
3 
2 
4 
0 
0 
0.4297182 
0.430 
0.4297182 
 
1 
3 
3 
1 
1 
0 
0 
0 
0 
0 
0 
1 
1 
0 
0 
1 
0 
0 
1 
1 
0.4305001 
0.431 
0.4305001 
 
2 
2 
1 
2 
3 
1 
1 
0 
1 
0 
0 
0 
0 
0 
1 
3 
2 
4 
0 
0 
0.4316007 
0.432 
0.4316007 
 
1 
1 
2 
3 
2 
0 
0 
1 
0 
1 
0 
0 
0 
1 
0 
2 
1 
1 
0 
0 
0.4354494 
0.435 
0.4354494 
 
1 
3 
2 
2 
2 
0 
0 
1 
1 
1 
0 
1 
0 
0 
0 
3 
2 
4 
0 
0 
0.4360047 
0.436 
0.4360047 
 
2 
2 
3 
2 
2 
1 
1 
0 
1 
1 
0 
0 
1 
0 
0 
4 
3 
9 
0 
0 
0.4374668 
0.437 
0.4374668 
 
1 
2 
2 
2 
3 
0 
1 
1 
1 
0 
0 
0 
0 
0 
1 
3 
2 
4 
0 
0 
0.4378872 
0.438 
0.4378872 
 
3 
1 
2 
1 
1 
0 
0 
1 
0 
0 
1 
0 
0 
0 
0 
1 
0 
0 
0 
0 
0.4421804 
0.442 
0.4421804 
 
3 
1 
1 
1 
1 
0 
0 
0 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0.442315 
0.442 
0.442315 
 
2 
1 
3 
1 
3 
1 
0 
0 
0 
0 
0 
0 
1 
0 
1 
2 
0 
0 
1 
1 
0.445081 
0.445 
0.445081 
 
2 
1 
2 
3 
1 
1 
0 
1 
0 
0 
0 
0 
0 
1 
0 
2 
1 
1 
0 
0 
0.4456564 
0.446 
0.4456564 
 
2 
3 
2 
2 
1 
1 
0 
1 
1 
0 
0 
1 
0 
0 
0 
3 
2 
4 
0 
0 
0.4462117 
0.446 
0.4462117 
 
1 
1 
1 
3 
2 
0 
0 
0 
0 
1 
0 
0 
0 
1 
0 
1 
0 
0 
0 
0 
0.4462708 
0.446 
0.4462708 
 
1 
1 
3 
1 
3 
0 
0 
0 
0 
0 
0 
0 
1 
0 
1 
1 
0 
0 
1 
1 
0.4515021 
0.452 
0.4515021 
 
2 
1 
1 
3 
1 
1 
0 
0 
0 
0 
0 
0 
0 
1 
0 
1 
0 
0 
0 
0 
0.4564778 
0.456 
0.4564778 
 
1 
1 
2 
3 
1 
0 
0 
1 
0 
0 
0 
0 
0 
1 
0 
1 
0 
0 
0 
0 
0.4627643 
0.463 
0.4627643 
 
2 
3 
2 
1 
2 
1 
0 
1 
0 
1 
0 
1 
0 
0 
0 
3 
2 
4 
0 
0 
0.4628794 
0.463 
0.4628794 
 
1 
1 
1 
3 
1 
0 
0 
0 
0 
0 
0 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0.4628989 
0.463 
0.4628989 
 
2 
2 
2 
1 
3 
1 
1 
1 
0 
0 
0 
0 
0 
0 
1 
3 
2 
4 
0 
0 
0.4647619 
0.465 
0.4647619 
 
2 
1 
2 
2 
3 
1 
0 
1 
1 
0 
0 
0 
0 
0 
1 
3 
2 
4 
0 
0 
0.4672137 
0.467 
0.4672137 
 
1 
3 
1 
2 
2 
0 
0 
0 
1 
1 
0 
1 
0 
0 
0 
2 
1 
1 
0 
0 
0.4681997 
0.468 
0.4681997 
 
1 
2 
1 
2 
3 
0 
1 
0 
1 
0 
0 
0 
0 
0 
1 
2 
1 
1 
0 
0 
0.4700822 
0.470 
0.4700822 
 
2 
3 
1 
2 
1 
1 
0 
0 
1 
0 
0 
1 
0 
0 
0 
2 
1 
1 
0 
0 
0.4784067 
0.478 
0.4784067 
 
1 
3 
2 
2 
1 
0 
0 
1 
1 
0 
0 
1 
0 
0 
0 
2 
1 
1 
0 
0 
0.4846932 
0.485 
0.4846932 
 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 50 of 60 
2 
3 
1 
1 
2 
1 
0 
0 
0 
1 
0 
1 
0 
0 
0 
2 
1 
1 
0 
0 
0.4950744 
0.495 
0.4950744 
 
1 
3 
1 
2 
1 
0 
0 
0 
1 
0 
0 
1 
0 
0 
0 
1 
0 
0 
0 
0 
0.4955146 
0.496 
0.4955146 
 
2 
2 
1 
1 
3 
1 
1 
0 
0 
0 
0 
0 
0 
0 
1 
2 
1 
1 
0 
0 
0.4969569 
0.497 
0.4969569 
 
1 
2 
3 
2 
2 
0 
1 
0 
1 
1 
0 
0 
1 
0 
0 
3 
2 
4 
0 
0 
0.4973219 
0.497 
0.4973219 
 
2 
1 
1 
2 
3 
1 
0 
0 
1 
0 
0 
0 
0 
0 
1 
2 
1 
1 
0 
0 
0.4994087 
0.499 
0.4994087 
 
1 
3 
2 
1 
2 
0 
0 
1 
0 
1 
0 
1 
0 
0 
0 
2 
1 
1 
0 
0 
0.5013609 
0.501 
0.5013609 
 
1 
2 
2 
1 
3 
0 
1 
1 
0 
0 
0 
0 
0 
0 
1 
2 
1 
1 
0 
0 
0.5032434 
0.503 
0.5032434 
 
1 
1 
2 
2 
3 
0 
0 
1 
1 
0 
0 
0 
0 
0 
1 
2 
1 
1 
0 
0 
0.5056952 
0.506 
0.5056952 
 
2 
2 
3 
2 
1 
1 
1 
0 
1 
0 
0 
0 
1 
0 
0 
3 
2 
4 
0 
0 
0.5075289 
0.508 
0.5075289 
 
2 
3 
2 
1 
1 
1 
0 
1 
0 
0 
0 
1 
0 
0 
0 
2 
1 
1 
0 
0 
0.5115679 
0.512 
0.5115679 
 
1 
3 
1 
1 
2 
0 
0 
0 
0 
1 
0 
1 
0 
0 
0 
1 
0 
0 
0 
0 
0.5121823 
0.512 
0.5121823 
 
1 
2 
1 
1 
3 
0 
1 
0 
0 
0 
0 
0 
0 
0 
1 
1 
0 
0 
0 
0 
0.5140648 
0.514 
0.5140648 
 
1 
1 
1 
2 
3 
0 
0 
0 
1 
0 
0 
0 
0 
0 
1 
1 
0 
0 
0 
0 
0.5165166 
0.517 
0.5165166 
 
2 
3 
1 
1 
1 
1 
0 
0 
0 
0 
0 
1 
0 
0 
0 
1 
0 
0 
0 
0 
0.5223893 
0.522 
0.5223893 
 
2 
2 
3 
1 
2 
1 
1 
0 
0 
1 
0 
0 
1 
0 
0 
3 
2 
4 
0 
0 
0.5241966 
0.524 
0.5241966 
 
2 
1 
3 
2 
2 
1 
0 
0 
1 
1 
0 
0 
1 
0 
0 
3 
2 
4 
0 
0 
0.5266484 
0.527 
0.5266484 
 
1 
3 
2 
1 
1 
0 
0 
1 
0 
0 
0 
1 
0 
0 
0 
1 
0 
0 
0 
0 
0.5286758 
0.529 
0.5286758 
 
1 
3 
1 
1 
1 
0 
0 
0 
0 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0.5288104 
0.529 
0.5288104 
 
2 
1 
2 
1 
3 
1 
0 
1 
0 
0 
0 
0 
0 
0 
1 
2 
1 
1 
0 
0 
0.5325699 
0.533 
0.5325699 
 
2 
1 
1 
1 
3 
1 
0 
0 
0 
0 
0 
0 
0 
0 
1 
1 
0 
0 
0 
0 
0.5433913 
0.543 
0.5433913 
 
1 
2 
3 
2 
1 
0 
1 
0 
1 
0 
0 
0 
1 
0 
0 
2 
1 
1 
0 
0 
0.5460104 
0.546 
0.5460104 
 
1 
1 
2 
1 
3 
0 
0 
1 
0 
0 
0 
0 
0 
0 
1 
1 
0 
0 
0 
0 
0.5496778 
0.550 
0.5496778 
 
1 
1 
1 
1 
3 
0 
0 
0 
0 
0 
0 
0 
0 
0 
1 
0 
0 
0 
0 
0 
0.5498124 
0.550 
0.5498124 
 
1 
2 
3 
1 
2 
0 
1 
0 
0 
1 
0 
0 
1 
0 
0 
2 
1 
1 
0 
0 
0.5626781 
0.563 
0.5626781 
 
1 
1 
3 
2 
2 
0 
0 
0 
1 
1 
0 
0 
1 
0 
0 
2 
1 
1 
0 
0 
0.5651299 
0.565 
0.5651299 
 
2 
2 
3 
1 
1 
1 
1 
0 
0 
0 
0 
0 
1 
0 
0 
2 
1 
1 
0 
0 
0.5728851 
0.573 
0.5728851 
 
2 
1 
3 
2 
1 
1 
0 
0 
1 
0 
0 
0 
1 
0 
0 
2 
1 
1 
0 
0 
0.5753369 
0.575 
0.5753369 
 
1 
2 
3 
1 
1 
0 
1 
0 
0 
0 
0 
0 
1 
0 
0 
1 
0 
0 
0 
0 
0.589993 
0.590 
0.589993 
 
2 
1 
3 
1 
2 
1 
0 
0 
0 
1 
0 
0 
1 
0 
0 
2 
1 
1 
0 
0 
0.5920046 
0.592 
0.5920046 
 
1 
1 
3 
2 
1 
0 
0 
0 
1 
0 
0 
0 
1 
0 
0 
1 
0 
0 
0 
0 
0.5924448 
0.592 
0.5924448 
 
2 
2 
2 
2 
2 
1 
1 
1 
1 
1 
0 
0 
0 
0 
0 
4 
4 
16 
0 
0 
0.5971891 
0.597 
0.5971891 
 
1 
1 
3 
1 
2 
0 
0 
0 
0 
1 
0 
0 
1 
0 
0 
1 
0 
0 
0 
0 
0.6091125 
0.609 
0.6091125 
 
2 
1 
3 
1 
1 
1 
0 
0 
0 
0 
0 
0 
1 
0 
0 
1 
0 
0 
0 
0 
0.6193195 
0.619 
0.6193195 
 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 51 of 60 
1 
1 
3 
1 
1 
0 
0 
0 
0 
0 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0 
0.6257406 
0.626 
0.6257406 
 
2 
2 
1 
2 
2 
1 
1 
0 
1 
1 
0 
0 
0 
0 
0 
3 
3 
9 
0 
0 
0.6721313 
0.672 
0.6721313 
 
1 
2 
2 
2 
2 
0 
1 
1 
1 
1 
0 
0 
0 
0 
0 
3 
3 
9 
0 
0 
0.6784178 
0.678 
0.6784178 
 
2 
2 
2 
2 
1 
1 
1 
1 
1 
0 
0 
0 
0 
0 
0 
3 
3 
9 
0 
0 
0.6886248 
0.689 
0.6886248 
 
2 
2 
2 
1 
2 
1 
1 
1 
0 
1 
0 
0 
0 
0 
0 
3 
3 
9 
0 
0 
0.7052925 
0.705 
0.7052925 
 
2 
1 
2 
2 
2 
1 
0 
1 
1 
1 
0 
0 
0 
0 
0 
3 
3 
9 
0 
0 
0.7077443 
0.708 
0.7077443 
 
1 
2 
1 
2 
2 
0 
1 
0 
1 
1 
0 
0 
0 
0 
0 
2 
2 
4 
0 
0 
0.7319864 
0.732 
0.7319864 
 
2 
2 
1 
2 
1 
1 
1 
0 
1 
0 
0 
0 
0 
0 
0 
2 
2 
4 
0 
0 
0.7421934 
0.742 
0.7421934 
 
1 
2 
2 
2 
1 
0 
1 
1 
1 
0 
0 
0 
0 
0 
0 
2 
2 
4 
0 
0 
0.7484799 
0.748 
0.7484799 
 
2 
2 
1 
1 
2 
1 
1 
0 
0 
1 
0 
0 
0 
0 
0 
2 
2 
4 
0 
0 
0.7588611 
0.759 
0.7588611 
 
2 
1 
1 
2 
2 
1 
0 
0 
1 
1 
0 
0 
0 
0 
0 
2 
2 
4 
0 
0 
0.7613129 
0.761 
0.7613129 
 
1 
2 
2 
1 
2 
0 
1 
1 
0 
1 
0 
0 
0 
0 
0 
2 
2 
4 
0 
0 
0.7651476 
0.765 
0.7651476 
 
1 
1 
2 
2 
2 
0 
0 
1 
1 
1 
0 
0 
0 
0 
0 
2 
2 
4 
0 
0 
0.7675994 
0.768 
0.7675994 
 
2 
2 
2 
1 
1 
1 
1 
1 
0 
0 
0 
0 
0 
0 
0 
2 
2 
4 
0 
0 
0.7753546 
0.775 
0.7753546 
 
2 
1 
2 
2 
1 
1 
0 
1 
1 
0 
0 
0 
0 
0 
0 
2 
2 
4 
0 
0 
0.7778064 
0.778 
0.7778064 
 
1 
2 
1 
2 
1 
0 
1 
0 
1 
0 
0 
0 
0 
0 
0 
1 
1 
1 
0 
0 
0.7806749 
0.781 
0.7806749 
 
2 
1 
2 
1 
2 
1 
0 
1 
0 
1 
0 
0 
0 
0 
0 
2 
2 
4 
0 
0 
0.7944741 
0.794 
0.7944741 
 
1 
2 
1 
1 
2 
0 
1 
0 
0 
1 
0 
0 
0 
0 
0 
1 
1 
1 
0 
0 
0.7973426 
0.797 
0.7973426 
 
1 
1 
1 
2 
2 
0 
0 
0 
1 
1 
0 
0 
0 
0 
0 
1 
1 
1 
0 
0 
0.7997944 
0.800 
0.7997944 
 
2 
2 
1 
1 
1 
1 
1 
0 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
0 
0 
0.8075496 
0.808 
0.8075496 
 
2 
1 
1 
2 
1 
1 
0 
0 
1 
0 
0 
0 
0 
0 
0 
1 
1 
1 
0 
0 
0.8100014 
0.810 
0.8100014 
 
1 
2 
2 
1 
1 
0 
1 
1 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
0 
0 
0.8138361 
0.814 
0.8138361 
 
1 
1 
2 
2 
1 
0 
0 
1 
1 
0 
0 
0 
0 
0 
0 
1 
1 
1 
0 
0 
0.8162879 
0.816 
0.8162879 
 
1 
2 
1 
1 
1 
0 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0.8246575 
0.825 
0.8246575 
 
2 
1 
1 
1 
2 
1 
0 
0 
0 
1 
0 
0 
0 
0 
0 
1 
1 
1 
0 
0 
0.8266691 
0.827 
0.8266691 
 
1 
1 
1 
2 
1 
0 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0.8271093 
0.827 
0.8271093 
 
1 
1 
2 
1 
2 
0 
0 
1 
0 
1 
0 
0 
0 
0 
0 
1 
1 
1 
0 
0 
0.8329556 
0.833 
0.8329556 
 
2 
1 
2 
1 
1 
1 
0 
1 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
0 
0 
0.8431626 
0.843 
0.8431626 
 
1 
1 
1 
1 
2 
0 
0 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0.843777 
0.844 
0.843777 
 
2 
1 
1 
1 
1 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0.853984 
0.854 
0.853984 
 
1 
1 
2 
1 
1 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0.8602705 
0.860 
0.8602705 
 
1 
1 
1 
1 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
-1 
0 
0 
0 
0 
0.8604051 
1.000 
1 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 52 of 60 
 
7.3 Procedure to identify the clinical relapse of optic neuritis occurred in the double-
blind period: 
The clinical relapse of optic neuritis occurred in the double-blind period of SA-309JG study will be 
identified by satisfying with either or both of followings. The Relapse Assessment Form (RAF) 
completed by study sites will be used for the identification. 
- 
Lower box “New or worsening neurological symptoms relating to this functional area reported by 
the patient at this visit. Please describe:” is ticked in the Section A-1 “Visual (optic) functions: 
Symptoms” of the RAF, and then the information is described per the instruction. 
- 
The information on new or worsening neurological symptoms in visual (optic) functions are 
described in section B of RAF. 
 
[Reference: Section A-1 of RAF] 
 
 
 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 53 of 60 
7.4 MedDRA basket 
Opportunistic infections 
Meningomyelitis 
herpes 
Capnocytophaga 
test positive 
Eye infection 
toxoplasmal 
Histoplasmosis 
disseminated 
Mycobacterium 
ulcerans 
infection 
Pulmonary 
trichosporonosis 
Abscess fungal 
Central nervous 
system fungal 
infection 
Eye infection 
viral 
Human 
anaplasmosis 
Mycotic corneal 
ulcer 
Pulmonary 
tuberculoma 
Acid fast bacilli 
infection 
Central nervous 
system viral 
infection 
Female genital 
tract tuberculosis 
Human 
bocavirus 
infection 
Mycotic 
endophthalmitis 
Pulmonary 
tuberculosis 
Acinetobacter 
bacteraemia 
Cerebral 
aspergillosis 
Flavobacterium 
infection 
Human 
ehrlichiosis 
Myocarditis 
mycotic 
Pyelonephritis 
fungal 
Acinetobacter 
infection 
Cerebral 
candidiasis 
Focal epithelial 
hyperplasia 
Human 
herpesvirus 8 
infection 
Myocarditis 
toxoplasmal 
Q fever 
Acute 
haemorrhagic 
conjunctivitis 
Cerebral fungal 
infection 
Fungaemia 
Indeterminate 
leprosy 
Nasal herpes 
Raoultella 
ornithinolytica 
infection 
Acute hepatitis B 
Cerebral 
toxoplasmosis 
Fungal abscess 
central nervous 
system 
Infection in an 
immunocompro
mised host 
Necrotising 
fasciitis fungal 
Renal 
tuberculosis 
Acute hepatitis C 
Cervix warts 
Fungal cystitis 
Intestinal 
tuberculosis 
Necrotising 
herpetic 
retinopathy 
Respiratory 
moniliasis 
Acute pulmonary 
histoplasmosis 
Chromoblastomy
cosis 
Fungal 
endocarditis 
Isosporiasis 
Neurocryptococc
osis 
Respiratory tract 
infection fungal 
Adrenal gland 
tuberculosis 
Chronic 
pulmonary 
histoplasmosis 
Fungal 
labyrinthitis 
JC virus granule 
cell 
neuronopathy 
Neutropenic 
infection 
Retinitis 
histoplasma 
Aeromonas 
infection 
Coccidioides 
encephalitis 
Fungal 
oesophagitis 
JC virus 
infection 
Neutropenic 
sepsis 
Retinitis viral 
Aeromonas test 
positive 
Coccidioidomyc
osis 
Fungal 
peritonitis 
JC virus test 
Nocardia sepsis 
Rhodococcus 
infection 
Alcaligenes 
infection 
Colitis herpes 
Fungal 
pharyngitis 
JC virus test 
positive 
Nocardia test 
positive 
Rhodococcus 
test positive 
Allescheriosis 
Conjunctivitis 
tuberculous 
Fungal retinitis 
Joint 
tuberculosis 
Nocardiosis 
Salpingitis 
tuberculous 
Alternaria 
infection 
Coxiella 
infection 
Fungal sepsis 
Kaposi's sarcoma 
Oesophageal 
candidiasis 
Scedosporium 
infection 
Amoebiasis 
Creutzfeldt-
Jakob disease 
Fungal tracheitis 
Kaposi's sarcoma 
AIDS related 
Oesophageal 
tuberculosis 
Sepsis 
pasteurella 
Amoebic brain 
abscess 
Cronobacter 
infection 
Fusarium 
infection 
Kaposi's 
varicelliform 
eruption 
Ophthalmic 
herpes simplex 
Shewanella algae 
bacteraemia 
Amoebic colitis 
Cronobacter 
necrotising 
enterocolitis 
Gastritis fungal 
Keratitis fungal 
Ophthalmic 
herpes zoster 
Sinusitis 
aspergillus 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 54 of 60 
Amoebic 
dysentery 
Cryptococcal 
cutaneous 
infection 
Gastritis herpes 
Keratitis viral 
Opportunistic 
infection 
Sinusitis fungal 
Amoebic lung 
abscess 
Cryptococcal 
fungaemia 
Gastroenteritis 
cryptococcal 
Keratouveitis 
Oral candidiasis 
Sphingomonas 
paucimobilis 
infection 
Amoebic skin 
ulcer 
Cryptococcosis 
Gastroenteritis 
cryptosporidial 
Laryngitis fungal 
Oral fungal 
infection 
Spleen 
tuberculosis 
Anal fungal 
infection 
Cryptococcus 
test 
Gastrointestinal 
candidiasis 
Legionella 
infection 
Oral hairy 
leukoplakia 
Splenic 
candidiasis 
Angina 
gangrenous 
Cryptococcus 
test positive 
Gastrointestinal 
fungal infection 
Lepromatous 
leprosy 
Oral herpes 
Splenic infection 
fungal 
Angiostrongylus 
infection 
Cryptosporidiosi
s infection 
Genital herpes 
Leprosy 
Oral tuberculosis 
Stenotrophomon
as infection 
Anogenital warts 
Cutaneous 
coccidioidomyco
sis 
Genital herpes 
simplex 
Leptotrichia 
infection 
Oro-pharyngeal 
aspergillosis 
Stenotrophomon
as sepsis 
Anorectal human 
papilloma virus 
infection 
Cutaneous 
tuberculosis 
Genital herpes 
zoster 
Leuconostoc 
infection 
Oropharyngeal 
candidiasis 
Stomatococcal 
infection 
Anti-JC virus 
antibody index 
Cytomegalovirus 
chorioretinitis 
Granulicatella 
bacteraemia 
Listeria 
encephalitis 
Oropharyngitis 
fungal 
Stomatococcus 
test positive 
Arthritis fungal 
Cytomegalovirus 
colitis 
Granulicatella 
infection 
Listeria sepsis 
Orthopox virus 
infection 
Strongyloidiasis 
Aspergilloma 
Cytomegalovirus 
duodenitis 
Hepatic 
candidiasis 
Listeria test 
positive 
Osteomyelitis 
blastomyces 
Superinfection 
fungal 
Aspergillosis 
oral 
Cytomegalovirus 
enteritis 
Hepatic infection 
fungal 
Listeriosis 
Osteomyelitis 
fungal 
Superinfection 
mycobacterial 
Aspergillus 
infection 
Cytomegalovirus 
enterocolitis 
Hepatitis B 
Lower 
respiratory tract 
herpes infection 
Otitis media 
fungal 
Systemic 
candida 
Aspergillus test 
Cytomegalovirus 
gastritis 
Hepatitis C 
Lower 
respiratory tract 
infection fungal 
Pancreatitis 
fungal 
Systemic 
mycosis 
Aspergillus test 
positive 
Cytomegalovirus 
gastroenteritis 
Hepatitis 
toxoplasmal 
Lower 
respiratory tract 
infection viral 
Pantoea 
agglomerans 
infection 
Thyroid 
tuberculosis 
Atypical 
mycobacterial 
infection 
Cytomegalovirus 
gastrointestinal 
infection 
Hepatosplenic 
candidiasis 
Lupus vulgaris 
Paracoccidioides 
infection 
Tonsillitis fungal 
Atypical 
mycobacterial 
lower respiratory 
tract infection 
Cytomegalovirus 
gastrointestinal 
ulcer 
Herpes 
oesophagitis 
Lymph node 
tuberculosis 
Parasitic 
encephalitis 
Toxoplasmosis 
Atypical 
mycobacterial 
lymphadenitis 
Cytomegalovirus 
hepatitis 
Herpes 
ophthalmic 
Lymphadenitis 
fungal 
Parvimonas 
infection 
Tuberculoid 
leprosy 
Atypical 
mycobacterial 
pneumonia 
Cytomegalovirus 
infection 
Herpes 
pharyngitis 
Male genital 
tract tuberculosis 
Parvimonas 
micra infection 
Tuberculoma of 
central nervous 
system 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 55 of 60 
Atypical 
mycobacterium 
pericarditis 
Cytomegalovirus 
mucocutaneous 
ulcer 
Herpes sepsis 
Meningitis 
aspergillus 
Peliosis hepatis 
Tuberculosis 
Atypical 
pneumonia 
Cytomegalovirus 
myelomeningora
diculitis 
Herpes simplex 
Meningitis 
candida 
Penicillium 
infection 
Tuberculosis 
bladder 
Babesiosis 
Cytomegalovirus 
myocarditis 
Herpes simplex 
cervicitis 
Meningitis 
coccidioides 
Pericarditis 
fungal 
Tuberculosis 
gastrointestinal 
Bacillary 
angiomatosis 
Cytomegalovirus 
oesophagitis 
Herpes simplex 
colitis 
Meningitis 
cronobacter 
Pericarditis 
histoplasma 
Tuberculosis 
liver 
Balamuthia 
infection 
Cytomegalovirus 
pancreatitis 
Herpes simplex 
encephalitis 
Meningitis 
cryptococcal 
Pericarditis 
tuberculous 
Tuberculosis of 
central nervous 
system 
BK virus 
infection 
Cytomegalovirus 
pericarditis 
Herpes simplex 
gastritis 
Meningitis 
exserohilum 
Peritoneal 
candidiasis 
Tuberculosis of 
eye 
Blastocystis 
infection 
Cytomegalovirus 
syndrome 
Herpes simplex 
hepatitis 
Meningitis 
fungal 
Peritoneal 
tuberculosis 
Tuberculosis of 
genitourinary 
system 
Blastomycosis 
Cytomegalovirus 
test 
Herpes simplex 
meningitis 
Meningitis 
herpes 
Phaehyphomyco
sis 
Tuberculosis of 
intrathoracic 
lymph nodes 
Bone 
tuberculosis 
Cytomegalovirus 
test positive 
Herpes simplex 
meningoencepha
litis 
Meningitis 
histoplasma 
Pharyngeal 
abscess 
Tuberculosis of 
peripheral lymph 
nodes 
Borderline 
leprosy 
Cytomegalovirus 
urinary tract 
infection 
Herpes simplex 
meningomyelitis 
Meningitis 
listeria 
Pneumocystis 
jirovecii 
infection 
Tuberculosis 
ureter 
Botryomycosis 
Cytomegalovirus 
viraemia 
Herpes simplex 
necrotising 
retinopathy 
Meningitis 
toxoplasmal 
Pneumocystis 
jirovecii 
pneumonia 
Tuberculous 
abscess central 
nervous system 
Bovine 
tuberculosis 
Dengue fever 
Herpes simplex 
oesophagitis 
Meningitis 
tuberculous 
Pneumocystis 
test positive 
Tuberculous 
endometritis 
Brachyspira 
infection 
Disseminated 
Bacillus 
Calmette-Guerin 
infection 
Herpes simplex 
otitis externa 
Meningoencepha
litis herpes 
simplex neonatal 
Pneumonia 
blastomyces 
Tuberculous 
laryngitis 
Brevibacterium 
infection 
Disseminated 
cryptococcosis 
Herpes simplex 
pharyngitis 
Meningoencepha
litis herpetic 
Pneumonia 
cryptococcal 
Tuberculous 
pleurisy 
Bronchitis fungal 
Disseminated 
cytomegaloviral 
infection 
Herpes simplex 
pneumonia 
Meningoencepha
litis viral 
Pneumonia 
cytomegaloviral 
Tuberculous 
tenosynovitis 
Bronchopulmona
ry aspergillosis 
Disseminated 
tuberculosis 
Herpes simplex 
sepsis 
Methylobacteriu
m infection 
Pneumonia 
fungal 
Upper 
respiratory 
fungal infection 
Burkholderia 
cepacia complex 
infection 
Disseminated 
varicella zoster 
vaccine virus 
infection 
Herpes simplex 
visceral 
Microsporidia 
infection 
Pneumonia 
herpes viral 
Urinary tract 
infection fungal 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 56 of 60 
Burkholderia 
cepacia complex 
sepsis 
Ear tuberculosis 
Herpes virus 
infection 
Miliary 
pneumonia 
Pneumonia 
legionella 
Variant 
Creutzfeldt-
Jakob disease 
Burkholderia 
gladioli infection 
Encephalitis 
cytomegalovirus 
Herpes zoster 
Mucocutaneous 
candidiasis 
Pneumonia 
toxoplasmal 
Varicella 
Burkholderia 
infection 
Encephalitis 
fungal 
Herpes zoster 
cutaneous 
disseminated 
Mucormycosis 
Polyomavirus-
associated 
nephropathy 
Varicella 
keratitis 
Burkholderia 
mallei infection 
Encephalitis post 
varicella 
Herpes zoster 
disseminated 
Mycetoma 
mycotic 
Porphyromonas 
infection 
Varicella zoster 
gastritis 
Burkholderia 
pseudomallei 
infection 
Endocarditis 
candida 
Herpes zoster 
infection 
neurological 
Mycobacterial 
infection 
Presumed ocular 
histoplasmosis 
syndrome 
Varicella zoster 
oesophagitis 
Burkholderia test 
positive 
Endocarditis 
histoplasma 
Herpes zoster 
meningitis 
Mycobacterial 
peritonitis 
Progressive 
multifocal 
leukoencephalop
athy 
Varicella zoster 
pneumonia 
Candida 
endophthalmitis 
Endocarditis Q 
fever 
Herpes zoster 
meningoencepha
litis 
Mycobacterium 
abscessus 
infection 
Progressive 
vaccinia 
Varicella zoster 
virus infection 
Candida 
infection 
Enterocolitis 
fungal 
Herpes zoster 
meningomyelitis 
Mycobacterium 
avium complex 
immune 
restoration 
disease 
Prostatitis 
tuberculous 
Viral 
keratouveitis 
Candida 
osteomyelitis 
Epididymitis 
blastomyces 
Herpes zoster 
necrotising 
retinopathy 
Mycobacterium 
avium complex 
infection 
Pseudallescheria 
infection 
Viral myelitis 
Candida 
pneumonia 
Epididymitis 
tuberculous 
Herpes zoster 
oticus 
Mycobacterium 
chelonae 
infection 
Pseudallescheria 
sepsis 
Viral 
oesophagitis 
Candida retinitis 
Exserohilum 
infection 
Herpes zoster 
pharyngitis 
Mycobacterium 
fortuitum 
infection 
Pseudomonal 
sepsis 
Viral sepsis 
Candida sepsis 
Extrapulmonary 
tuberculosis 
Histoplasmosis 
Mycobacterium 
kansasii 
infection 
Pseudomonas 
aeruginosa 
meningitis 
Viral uveitis 
Capnocytophaga 
infection 
Eye infection 
fungal 
Histoplasmosis 
cutaneous 
Mycobacterium 
marinum 
infection 
Pulmonary 
mycosis 
Yersinia sepsis 
 
7.5 Laboratory Data Conversion and Transformation Rules 
• Conversion to Système International (SI) Units 
Laboratory data should be stored on the database in the units in which they were 
originally delivered by the laboratory.  
For analysis and reporting purposes, the data will be converted to SI units to allow the 
comparison of data delivered in different original units.  
Results that include inequality sign will be converted into a numeric form removing 
inequality sign. 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 57 of 60 
Results that cannot be converted into an expected numeric form nor interpreted, such as 
alphabetic entries like “adequate”, will usually not be further processed, but displayed in 
patient listings. 
 
• Marked Laboratory Abnormalities 
For each laboratory test, a Marked Abnormality Range has been defined. A value outside 
of this range is considered to be potentially clinically relevant. This Marked Abnormality 
Range is wider than the Reference Range.  
In addition, for each laboratory test, a percentage change, as an increase and/or decrease, 
has been defined which represents a clinically relevant change from baseline. 
A Marked Abnormality is therefore defined as a test result: 
which is outside of the Marked Abnormality Range, and which also represents a 
clinically relevant change from baseline of at least the designated amount during or 
within 30 days after end of trial treatment.  
Baseline is taken as the last valid value before starting treatment. If no baseline is 
available, the midpoint of the Reference Range will be substituted for processing 
purposes for determination of Marked Abnormalities.  
For urinalysis a missing baseline value will be replaced by 0 (zero).  
NOTE: For calculating means and mean changes over time, missing values will not be 
included. If no baseline is available, no change from baseline will be calculated. 
Values above and below the Reference Range are flagged on the listing by H and L, 
respectively. Marked Abnormalities are flagged by HH or LL. 
  
• Reference Ranges 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 58 of 60 
 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 59 of 60 
 
 


Chugai Pharmaceutical Co. Ltd. 
 
SA-309JG 
Statistical Analysis Plan 
TP-GDO-WW-016-01 
Confidential 
Version 7.0 
Effective Date: 28Aug13 
 
Version Date: 28NOV2018 
Related to:  SOP-GDO-WW-019 
 
 
Page 60 of 60 
 
• Formula for Linear Transformation 
RT = SL + [(RU - IL) / (IH - IL)]*(SH - SL) 
RT: transformed value 
RU: untransformed value 
IL: IH investigator limits, low and high 
SL: SH reference limits, low and high 
For female to male transformation replace IL, IH by the reference limits for female, and 
SL, SH by the reference limits for male. 
 
7.6 Rule for summary of titer for anti AQP4 antibody status 
Titer for anti AQP4 antibody status except screening visit will be replaced by following 
rule. This rule will apply to throughout TFL. 
- 
If value is “<16”, value will be replaced as 4.  
- 
If titer is character (e.g. “>16384”, “>65536” except “<16”) or titer is numeric 
more than 16384 (e.g. “65536”, “262144”), value will be replaced as 65536.