Clinical trial NCT01412333
Conditions: Relapsing Multiple Sclerosis
Sponsor: Hoffmann-La Roche
Start date: 2011-09-20; Completion date: 2022-12-30
Enrollment: 835 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized, double-blind, double-dummy, parallel-group study will evaluate the efficacy and safety of ocrelizumab in comparison with interferon beta-1a (Rebif) in participants with relapsing multiple sclerosis. Participants will be randomized to receive either ocrelizumab 600 mg or matching placebo intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week; or interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).

Detailed description:

Arms: arm 1: Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks). arm 2: Ocrelizumab 600 mg or matching placebo intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Interventions: intervention 1: Interferon beta-1a intervention 2: Ocrelizumab-matching placebo intervention 3: Ocrelizumab intervention 4: Interferon beta-1a-matching placebo
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol documents:
Prot_000.pdf: 
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unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and; therefore, is 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.
Ocrelizumab—F. Hoffmann-La Roche Ltd
Protocol WA21093J, Version 10
PROTOCOL
TITLE:
A RANDOMIZED, DOUBLE-BLIND, 
DOUBLE-DUMMY, PARALLEL-GROUP STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF 
OCRELIZUMAB IN COMPARISON WITH 
INTERFERON BETA-1A (REBIF®) IN PATIENTS
WITH RELAPSING MULTIPLE SCLEROSIS
PROTOCOL NUMBER:
WA21093
VERSION NUMBER:
J
TEST COMPOUND:
Ocrelizumab (RO4964913)
STUDY PHASE:
Phase III
EUDRACT NUMBER:
2010-020315-36
IND NUMBER:
100,593
NCT NUMBER:
NCT01412333
MEDICAL MONITOR:
, M.D.
SPONSOR NAME AND 
LEGAL REGISTERED 
ADDRESS:
F. Hoffmann-La Roche, Ltd
Grenzacherstrasse 124
4070 Basel, Switzerland
APPROVAL DATE:
See electronic date stamp below.
 
Approver's Name
Title
Date and Time (UTC)
19-Nov-2021 15:53:10


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PROTOCOL HISTORY
Protocol
Version
Date Final
J
See electronic date stamp on title page.
I
27 July 2020
H
18 December 2019
G
3 August 2018
F
4 October 2017
E
4 March 2016
D
4 September 2014
C
28 March 2013
B
15 June 2012
A
27 May 2011


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PROTOCOL WA21093 COORDINATING INVESTIGATOR:
Prof. Dr. Ludwig Kappos
Chair Neurology
 Clinical Neuroimmunology and Neurobiology
Department of Biomedicine
University Hospital
Petersgraben 4
CH-4031 Basel
Switzerland
Phone: 41 61 265 44 64


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PROTOCOL AMENDMENT, VERSION J:
RATIONALE
Protocol WA21093 (OPERA II) has been amended to introduce the option of a rollover 
study (MN43964), into which all ongoing participants can enroll during the course of 
2022.  As already stated in the current protocol, ocrelizumab treatment via this study is 
due to finish by December 2022.  The Sponsor has now made the decision not to extend 
this study further and; therefore, this study will end on 31 December 2022.  Instead, the 
new rollover extension study (MN43964) is being set up to ensure that participants of 
Study WA21093 (together with participants from other Parent studies) can continue their 
ocrelizumab treatment or safety follow-up as applicable without interruption and allowing 
for valuable long-term data to continue to be collected.
In addition, a reduction in the safety follow-up period and the incorporation of the risk 
assessment of vaccination against severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) for the participant population are implemented through this amendment.  
Please see below for a summary of the substantive changes to the protocol, along with a 
rationale for each change:

To introduce the option for all ongoing participants of Study WA21093 to enroll into 
a new open-label extension study (MN43964) prior to or following the closure of 
Study WA21093

To clarify that participants who discontinue treatment early for any reason and that
participants who complete the study treatment period will be followed up for up to
48 weeks after the last infusion of ocrelizumab.  The requirement for continued 
B cell monitoring for participants whose B cells are not repleted (i.e., returned to 
baseline levels or the lower limit of normal, whichever is lower) at the end of the 
safety follow-up period has been removed because no increased safety risk was 
identified in the ocrelizumab clinical development program following cessation of 
treatment.

To clarify that after entering safety follow-up and upon treatment initiation with 
another disease-modifying therapy (DMT), participants will be discontinued from the 
safety follow-up and from the study.  The rationale for this change is that, given the 
low numbers of participants in the clinical development program who have switched 
to alternative DMTs, and data consisting of several different DMTs with various 
treatment durations, the Sponsor considers that such data would not allow for any 
meaningful interpretation and it is unlikely that prolonged data collection would 
facilitate this.  Participants who switch to commercial ocrelizumab (OCREVUS)
after entering safety follow-up, will also be discontinued from safety follow-up and 
the study.

To incorporate the risk assessment for concomitant use of SARS-CoV-2 vaccines:  
Section 2.2 has been updated to include the benefitrisk assessment of the 
concomitant use of SARS-CoV-2 vaccines on the conduct of this study.  Based on 
that assessment, no impact is anticipated on the efficacy and safety in participants 
enrolled in ocrelizumab clinical trials.  The existing information on identified risks, 


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safety monitoring, and risk mitigation measures related to administration of vaccines 
(including those for SARS-CoV-2) provided in the study protocol are considered 
adequate.
Additional minor changes have been made to improve clarity and consistency. 
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.




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4.1
Overview of Study Design and Dosing Regimen................... 51
4.1.1
Screening .............................................................................. 51
4.1.2
Treatment Period................................................................... 51
4.1.2.1
Double-Blind, Double-Dummy, Comparative 
Treatment Period................................................................... 51
4.1.3
Open-Label Extension Phase Screening Period.................... 52
4.1.4
Open-Label Extension Phase................................................ 53
4.1.5
Safety Follow-Up Period........................................................ 53
4.1.6
Rationale for Study Design.................................................... 55
4.1.6.1
Rationale for the Use of an Active Comparator ..................... 55
4.1.6.2
Rationale for Choice of Active Comparator............................ 55
4.1.6.3
Rationale for Double-Blind, Double-Dummy 
Study Design ......................................................................... 56
4.1.6.4
Rationale for Choice of Study Population .............................. 56
4.1.6.5
Rationale for Study Endpoints ............................................... 56
4.1.6.6
Rationale for the Duration of the Double-Blind, 
Double-Dummy Treatment Period......................................... 56
4.1.6.7
Rationale for the Open-Label Extension Phase..................... 57
4.1.6.8
Rationale for the Safety Follow-Up Period............................. 57
4.1.6.9
Rationale for the Use of Methylprednisolone and 
Antihistamines ....................................................................... 57
4.1.6.10
Additional Measures to Mitigate Bias..................................... 58
4.1.7
Rationale for Dose Selection ................................................. 59
4.1.7.1
Conclusion............................................................................. 60
4.1.8
End of Double-Blind, Double-Dummy, Treatment 
Period of the Study................................................................ 60
4.1.9
End of Study.......................................................................... 60
4.2
Number of PARTICIPANTS/Assignment to 
Treatment Groups ................................................................. 61
4.3
Centers.................................................................................. 61
5.
STUDY POPULATION................................................................................ 61
5.1
Overview................................................................................ 61
5.1.1
Recruitment Procedures........................................................ 61
5.2
Inclusion Criteria.................................................................... 62


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5.3
Exclusion Criteria................................................................... 63
5.3.1
Exclusions Related to General Health ................................... 63
5.3.2
Exclusions Related to Medications........................................ 64
5.3.3
Exclusions Related to Laboratory Findings............................ 65
5.4
Eligibility Criteria for Open-Label Extension 
Phase .................................................................................... 66
5.5
Concomitant Medication and Treatment................................ 66
5.5.1
Definition of Concomitant Treatment ..................................... 66
5.5.2
Treatment for Symptoms of Multiple Sclerosis ...................... 67
5.5.2.1
Prohibited Concomitant Treatments for MS........................... 67
5.5.3
Immunization ......................................................................... 68
5.6
Criteria for Premature Withdrawal ......................................... 69
5.6.1
Withdrawal of Participants from the Roche 
Clinical Repository................................................................. 70
5.6.2
Withdrawal from the Research Biosample 
Repository ............................................................................. 70
5.6.3
Patient Agreement for Continuation in the Study 
(in Case of Confirmed Disability Progression) ....................... 70
5.7
Replacement Policy (Ensuring Adequate 
Numbers of Evaluable Subjects) ........................................... 71
5.7.1
For Participants ..................................................................... 71
5.7.2
For Centers............................................................................ 71
5.8
Screening Examination and Eligibility Screening 
Form ...................................................................................... 71
5.9
Procedures for Enrollment of Eligible Participants................. 72
5.10
Clinical Assessments and Procedures during the 
Double-Blind, Double-Dummy Treatment Period................... 72
5.10.1
Overview of Clinical Visits During the Double-
Blind, Double-Dummy Treatment Period ............................... 73
5.10.1.1
Delayed Dosing Visit ............................................................. 74
5.10.1.2
Unscheduled Visits ................................................................ 74
5.10.1.3
Withdrawal Visits in the Double-Blind, Double-
Dummy Treatment Period...................................................... 74
5.10.2
Assessment of Efficacy.......................................................... 75
5.10.2.1
Assessment of Relapse......................................................... 75
5.10.2.2
Assessment of Disability........................................................ 76


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5.10.2.3
Kurtzke Expanded Disability Status Scale............................. 76
5.10.2.4
The Multiple Sclerosis Functional Composite 
Scale...................................................................................... 77
5.10.2.5
Low-Contrast Visual Acuity Testing....................................... 77
5.10.2.6
The Symbol Digit Modalities Test .......................................... 77
5.10.3
Brain Magnetic Resonance Imaging...................................... 77
5.10.4
Safety .................................................................................... 78
5.10.4.1
Electrocardiogram ................................................................. 79
5.10.4.2
Physical Examination ............................................................ 79
5.10.4.3
Neurological Examination...................................................... 79
5.10.4.4
Telephone Interviews ............................................................ 80
5.10.4.5
Columbia-Suicide Severity Rating Scale ............................... 80
5.10.5
The Karnofsky Performance Scale (Clinician-
Reported Version) ................................................................. 80
5.11
Laboratory Assessments ....................................................... 81
5.11.1
Standard Laboratory Assessments........................................ 81
5.11.2
Hepatitis Screening and Liver Function 
Monitoring.............................................................................. 83
5.11.3
Plasma and Urine Banking for JC Virus ................................ 83
5.11.4
Pharmacokinetic/Pharmacodynamic 
Assessments ......................................................................... 84
5.11.5
Type I Interferon Neutralizing Antibody Assay....................... 84
5.12
Optional Samples for Research Biosample 
Repository ............................................................................. 84
5.12.1
Overview of the Roche Research Biosample 
Repository ............................................................................. 84
5.12.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 85
5.12.3
Sample Collection.................................................................. 85
5.12.4
Confidentiality........................................................................ 86
5.12.5
Consent to Participate in the Research 
Biosample Repository............................................................ 86
5.12.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 86
5.12.7
Monitoring and Oversight....................................................... 87
5.13
Protein Biomarker Samples................................................... 87


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5.14
Participant-Reported Outcomes ............................................ 88
5.14.1
Modified Fatigue Impact Scale .............................................. 88
5.14.2
The Center for Epidemiologic Studies Depression 
Scale...................................................................................... 88
5.14.3
The Short Form-36 Health Survey......................................... 89
5.14.4
Participant’s Assessment of Treatment Benefit ..................... 89
5.15
Pharmacoeconomic Assessments/EQ-5D............................. 89
5.16
Optional Exploratory Substudies ........................................... 89
5.16.1
Optical Coherence Tomography Exploratory 
Substudy................................................................................ 90
5.17
Open-Label Extension Phase................................................ 90
5.17.1
Open-Label Extension Phase Screening Period.................... 90
5.17.2
Open-Label Extension Phase................................................ 91
5.17.3
Overview of Schedule of Activities in the Open-
Label Extension Phase.......................................................... 92
5.17.3.1
Delayed Dosing Visit in the Open-Label 
Extension Phase.................................................................... 92
5.17.3.2
Unscheduled Visits in the Open-Label Extension 
Phase .................................................................................... 93
5.17.3.3
Withdrawal Visits in the Open-Label Extension 
Phase .................................................................................... 93
5.17.3.4
Continued Access to Study Treatment After the 
End of the Study.................................................................... 94
6.
INVESTIGATIONAL MEDICINAL PRODUCT............................................. 94
6.1
Ocrelizumab .......................................................................... 95
6.1.1
Preparation and Administration of Ocrelizumab 
Infusions ................................................................................ 95
6.1.1.1
Preparation of infusion........................................................... 96
6.1.1.2
Infusion Procedures............................................................... 96
6.1.1.3
Dual Infusion Cycle (Cycle 1 and OLE Cycle 5) .................... 96
6.1.1.4
Single Infusion Cycles (Cycles 2 - 4, and OLE 
Cycle 6 Onwards) .................................................................. 97
6.1.1.5
Alternative Shorter Infusion of Subsequent 600 
mg Ocrelizumab Doses ......................................................... 97
6.1.2
Prevention and Treatment of Infusion-Related 
Reactions............................................................................... 98


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6.1.3
Ocrelizumab Dose Modifications, Interruptions, 
and Delays........................................................................... 100
6.1.3.1
Handling Infusion Reactions................................................ 100
6.1.4
Criteria for Re-Treatment with Ocrelizumab ........................ 100
6.2
Rebif .................................................................................... 101
6.2.1
Dose and Schedule of Rebif................................................ 101
6.2.2
Rebif Dose Modifications, Interruptions, and 
Delays.................................................................................. 102
6.3
Formulation, Packaging, and Labeling ................................ 105
6.3.1
Ocrelizumab ........................................................................ 105
6.3.1.1
Formulation.......................................................................... 105
6.3.1.2
Packaging............................................................................ 105
6.3.1.3
Storage of Ocrelizumab and Placebo Vials for 
Infusion................................................................................ 106
6.3.2
Rebif .................................................................................... 106
6.3.2.1
Formulation and Packaging................................................. 106
6.3.2.2
Storage of Rebif................................................................... 107
6.4
Blinding and Unblinding....................................................... 107
6.5
Accountability of Investigational Medicinal 
Product and Assessment of Compliance............................. 107
6.5.1
Accountability of Investigational Medicinal 
Product ................................................................................ 107
6.5.2
Assessment of Compliance ................................................. 108
6.6
Destruction of the Investigational Medicinal 
Product/Comparator ............................................................ 108
7.
SAFETY INSTRUCTIONS AND GUIDANCE............................................ 109
7.1
Adverse Events and Laboratory Abnormalities.................... 109
7.1.1
Clinical Adverse Events....................................................... 109
7.1.1.1
Intensity of Clinical Adverse Events..................................... 109
7.1.1.2
DrugAdverse Event Relationship....................................... 110
7.1.1.3
Serious Adverse Events (Immediately Reportable 
to Sponsor).......................................................................... 110
7.1.1.4
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 111
7.1.2
Treatment and Follow-Up of Adverse Events ...................... 111


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7.1.3
Laboratory Test Abnormalities............................................. 111
7.1.3.1
Follow-Up of Abnormal Laboratory Test Values .................. 112
7.1.3.2
Abnormal Liver Function Tests............................................ 112
7.2
Handling of Safety Parameters............................................ 113
7.2.1
Reporting of Adverse Events............................................... 113
7.2.2
Reporting of Serious Adverse Events.................................. 113
7.2.2.1
Immediate Reporting to the Sponsor ................................... 113
7.2.2.2
Emergency Medical Contacts.............................................. 114
7.2.2.3
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 114
7.2.3
Pregnancy and Lactation..................................................... 115
7.3
Warnings and Precautions................................................... 117
7.3.1
Ocrelizumab ........................................................................ 117
7.3.1.1
Identified Risks and Adverse Drug Reactions 
Associated with Ocrelizumab Use ....................................... 117
7.3.1.2
Potential Risks Associated with Ocrelizumab Use............... 120
7.3.2
Rebif .................................................................................... 120
7.3.3
Corticosteroids..................................................................... 121
7.3.4
Antihistamines ..................................................................... 121
7.3.5
Progressive Multifocal Leukoencephalopathy...................... 121
7.3.5.1
Guidance for Diagnosis of Progressive Multifocal 
Leukoencephalopathy ......................................................... 122
8.
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN ................ 128
8.1
Study Endpoints .................................................................. 128
8.1.1
Primary Efficacy Endpoint.................................................... 128
8.1.2
Secondary Efficacy Endpoints............................................. 129
8.1.3
Exploratory Efficacy Endpoints............................................ 129
8.1.4
Safety .................................................................................. 131
8.2
Statistical and Analytical Methods ....................................... 131
8.2.1
Primary Efficacy Analysis .................................................... 132
8.2.2
Secondary Efficacy Analyses .............................................. 132


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8.2.2.1
The Time to Onset of Confirmed Disability 
Progression for at least 12 Weeks during the 96-
Week Comparative Treatment Period ................................. 132
8.2.2.2
Total Number of T1 Gadolinium-Enhanced 
Lesions as Detected by Brain MRI at Weeks 24, 
48, and 96............................................................................ 133
8.2.2.3
The Total Number of New and/or Enlarging T2 
Hyperintense Lesions as Detected by Brain 
Magnetic Resonance Imaging at Weeks 24, 48, 
and 96.................................................................................. 134
8.2.2.4
Proportion of Participants who have Disability 
Improvement Confirmed for At Least 12 Weeks.................. 134
8.2.2.5
The Time to Onset of Confirmed Disability 
Progression for At Least 24 Weeks During the 
96-Week Comparative Treatment Period ............................ 134
8.2.2.6
Total Number of New T1-Hypo-Intense Lesions 
(Chronic Black Holes) at Weeks 24, 48, and 96 .................. 135
8.2.2.7
The Change in MSFCS Score from Baseline to 
Week 96 .............................................................................. 135
8.2.2.8
The Percentage Change in Brain Volume as 
Detected by Brain Magnetic Resonance Imaging 
Scan from Week 24 to Week 96.......................................... 135
8.2.2.9
Change in Quality of Life As Measured by the 
Short Form-36 Version 2 Physical Component 
Summary Score from Baseline to Week 96......................... 135
8.2.2.10
Proportion of Participants Who Have No 
Evidence of Disease Activity by Week 96............................ 135
8.2.3
Exploratory Analyses........................................................... 136
8.2.4
Sample Size ........................................................................ 136
8.2.5
Hypothesis Testing.............................................................. 136
8.2.6
Analysis Populations ........................................................... 137
8.2.6.1
Safety Population ................................................................ 137
8.2.6.2
Intent-to-Treat Population.................................................... 137
8.2.6.3
Per Protocol Population....................................................... 137
8.2.7
Interim Analysis ................................................................... 137
8.2.8
Safety Data Analysis ........................................................... 138
8.2.9
Safety Follow-Up Period...................................................... 138
8.2.10
Open-Label Extension Phase.............................................. 139


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8.2.11
Other Analyses.................................................................... 139
8.2.11.1
Pharmacokinetic Analysis.................................................... 139
8.2.11.2
Pharmacodynamic Analysis................................................. 139
8.2.11.3
Roche Clinical Repository/Protein Biomarker 
Samples............................................................................... 140
8.2.11.4
Research Biosample Repository ......................................... 140
9.
DATA COLLECTION, MANAGEMENT AND QUALITY 
ASSURANCE............................................................................................ 140
9.1
Assignment of Preferred Terms and Original
Terminology......................................................................... 140
10. STUDY COMMITTEES............................................................................. 141
10.1
Steering Committee............................................................. 141
10.2
Data Monitoring Committee................................................. 141
11. REFERENCES ......................................................................................... 142
12. ETHICAL ASPECTS ................................................................................. 147
12.1
Local Regulations/Declaration of Helsinki............................ 147
12.2
Informed Consent................................................................ 147
12.2.1
Study Informed Consent...................................................... 147
12.2.2
RBR Informed Consent........................................................ 148
12.2.3
Death or Loss of Competence of Participant who 
has Donated a Specimen(s) that is Stored in the 
RCR..................................................................................... 148
12.3
Independent Ethics Committees and Institutional 
Review Board ...................................................................... 149
13. CONDITIONS FOR MODIFYING THE PROTOCOL................................. 149
14. CONDITIONS FOR TERMINATING THE STUDY .................................... 150
15. STUDY DOCUMENTATION, CASE REPORT FORMS, AND 
RECORD KEEPING.................................................................................. 150
15.1
Investigator's Files/Retention of Documents........................ 150
15.2
Source Documents and Background Data........................... 151
15.3
Audits and Inspections......................................................... 151
15.4
Electronic Case Report Forms............................................. 151
15.5
Financial Disclosure ............................................................ 152


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16. MONITORING THE STUDY ..................................................................... 152
17. CONFIDENTIALITY OF TRIAL DOCUMENTS AND 
PARTICIPANT RECORDS ....................................................................... 152
18. CLINICAL STUDY REPORT..................................................................... 153
19. PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS................................................................................................. 153
LIST OF TABLES
Table 1
Schedule of Activities:  Screening through the End of the 
Double-Blind, Double-Dummy Treatment Period........................ 23
Table 2
Schedule of Activities:  Safety Follow-Up.................................... 29
Table 3
Schedule of Activities:  Open-Label Extension Phase ................ 31
Table 4
Summary of the Most Frequent Rebif Adverse Reactions by 
MedDRA System Organ Class.................................................... 46
Table 5
Overview of Dosing Regimen in the Double-Blind, Double-
Dummy, Treatment Period.......................................................... 54
Table 6
Overview of Dosing Regimen in the OLE Phase Screening 
Period and the OLE Phase ......................................................... 55
Table 7
Treatment Groups and Schedule of Study Medication during 
the Double-Blind, Double-Dummy Treatment Period.................. 95
Table 8
Infusions of Ocrelizumab 300 mg................................................ 97
Table 9
Subsequent Infusions of Ocrelizumab 600 mg............................ 97
Table 10
Alternative Shorter Infusions of Ocrelizumab 600 mg................. 98
Table 11
Overview of Rebif Dosing Regimen .......................................... 102
Table 12
Clinical Features to Distinguish between MS Relapse and 
PML .......................................................................................... 126
Table 13
MRI Lesion Characteristics Typical of PML and MS ................. 127
LIST OF FIGURES
Figure 1
Overview of the Study Design..................................................... 22
Figure 2
Diagnostic Algorithm Framework for PML................................. 125
LIST OF APPENDICES
Appendix 1
Adverse Event Categories for Determining Relationship to 
Test Drug .................................................................................. 155
Appendix 2
ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 .. 156


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Appendix 3
Common Terminology Criteria (CTCAE)................................... 158
Appendix 4
Telephone Interviews................................................................ 159
Appendix 5
Modified Fatigue Impact Scale (MFIS)...................................... 162
Appendix 6
The Center for Epidemiologic Studies Depression Scale 
(CES-D) .................................................................................... 165
Appendix 7
The Short Form-36 (SF-36) Health Survey ............................... 167
Appendix 8
Optical Coherence Tomography Exploratory Substudy ............ 173
Appendix 9
Optical Coherence Tomography Exploratory Substudy 
Schedule of Activities................................................................ 181
Appendix 10
Abbreviations ............................................................................ 182


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PROTOCOL AMENDMENT ACCEPTANCE FORM
PROTOCOL TITLE:
A RANDOMIZED, DOUBLE-BLIND, DOUBLE-
DUMMY, PARALLEL-GROUP STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF 
OCRELIZUMAB IN COMPARISON WITH 
INTERFERON-BETA-1A (REBIF®) IN PATIENTS
WITH RELAPSING MULTIPLE SCLEROSIS
PROTOCOL NUMBER:
WA21093
VERSION NUMBER:
J
TEST COMPOUND:
Ocrelizumab (RO4964913)
MEDICAL MONITOR:
, M.D.
SPONSOR NAME:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator's Name (print)
Principal Investigator's Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy 
of the signed form as instructed by your local study monitor.


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1.
PROTOCOL SUMMARY
1.1
SYNOPSIS
PROTOCOL TITLE:
A Randomized, Double-Blind, Double-Dummy, Parallel-Group 
Study to Evaluate the Efficacy and Safety of Ocrelizumab in 
Comparison with Interferon-Beta-1a (Rebif®) in Patients with 
Relapsing Multiple Sclerosis
Study Rationale
This study is a pivotal Phase III clinical trial, and is composed of the following periods: 
a double-blind, double-dummy, treatment period, a safety follow-up period, and an open-label 
extension (OLE) phase. The double-blind, double-dummy, treatment period is designed to 
demonstrate the efficacy and safety of ocrelizumab in relapsing multiple sclerosis (RMS) in 
comparison with high-dose, high-frequency (HDHF) interferon (IFN; Rebif).  The OLE phase 
serves to evaluate the long-term safety, tolerability, and efficacy of ocrelizumab treatment in 
participants with relapsing forms of multiple sclerosis (MS).
This study is part of a broader, confirmatory clinical development program investigating the 
safety and efficacy of ocrelizumab in participants with both RMS and primary progressive MS 
(PPMS).  An OLE phase of the Phase II Study WA21493/ACT4422G is ongoing for eligible 
participants with relapsing-remitting MS (RRMS).  There are 3 ongoing Phase III pivotal trials 
(including the one presented in this protocol), 2 trials in RMS and 1 trial in PPMS.
Objectives
Primary Objective
The primary objective of this study is to assess whether the efficacy of ocrelizumab 600 mg 
(given as dual IV infusions of 300 mg on Days 1 and 15 of the first 24-week treatment cycle and 
as a single infusion of 600 mg on Day 1 of each 24-week treatment cycle thereafter) every 
24 weeks is superior to Rebif as measured by the protocol-defined annualized relapse rate 
(ARR) during nearly 2 years (96 weeks) in participants with RMS.
Secondary Objectives
The key secondary objectives of this study are to evaluate whether the efficacy of ocrelizumab 
is superior to that of Rebif, as reflected by the following measures:

The time to onset of confirmed disability progression for at least 12 weeks with the initial 
event of neurological worsening occurring during the 96-week, double-blind, 
double-dummy, treatment period

The total number of T1 gadolinium (Gd)-enhancing lesions as detected by brain magnetic 
resonance imaging (MRI) at Weeks 24, 48, and 96

The total number of new and/or enlarging T2 hyperintense lesions as detected by brain MRI 
at Weeks 24, 48, and 96

The proportion of participants who have confirmed disability improvement for at least 
12 weeks with the initial event of neurological improvement occurring during the 96-week,
double-blind, double-dummy, treatment period

The time to onset of confirmed disability progression for at least 24 weeks, with the initial 
event of neurological worsening occurring during the 96-week, double-blind, 
double-dummy, treatment period

The total number of new T1hypointense lesions (chronic black holes) at Weeks 24, 48, 
and 96

The change in Multiple Sclerosis Functional Composite Scale (MSFCS) score from baseline 
to Week 96

The percentage change in brain volume as detected by brain MRI from Week 2496

The change in Short Form-36 (SF-36) Health Survey Physical Component Summary (PCS) 
score from baseline to Week 96


Ocrelizumab—F. Hoffmann-La Roche Ltd
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
The proportion of participants who have no evidence of disease activity (NEDA) by 
Week 96
Safety
To evaluate the safety and tolerability of IV ocrelizumab 600 mg (given as dual infusions of 
300 mg on Days 1 and 15 of the first 24-week treatment cycle and as a single infusion of 
600 mg on Day 1 of each 24-week treatment cycle thereafter) every 24 weeks in participants 
with RMS (including exploratory endpoints, long-term safety, and tolerability in those 
participants entering the OLE phase).
Overall Design
Screening
Consenting participants will enter a screening period to be evaluated for eligibility.  
The screening period will last approximately 2 weeks, but it may be prolonged for up to 8 weeks 
for relevant clinical, administrative, or operational reasons.  Procedures at screening will include 
collecting a medical history, medical examination including a thorough neurological exam, 
Expanded Disability Status Scale (EDSS) testing, ECG, and blood and urine sampling.
Double-Blind, Double-Dummy, Comparative Treatment Period
Eligible participants will be randomized via an interactive voice or Web-based response system 
(IxRS) into 1 of 2 treatment groups: an ocrelizumab 600 mg regimen (Group A) or an IFN -1a 
(Group B) regimen.
During the double-blind, double-dummy, comparative treatment period, participants will be 
assessed at clinical visits as per the schedule of activities.
Before the next cycle of study drug, participants will be evaluated for pre-specified conditions 
and laboratory abnormalities to allow for re-treatment.
Participants who discontinue taking study medication within the 96-week, double-blind, 
double-dummy, comparative phase (treatment period) of the study will enter the safety follow-up 
period; they will not be eligible for the OLE phase.
Open-Label Extension Phase Screening Period
Participants who complete the 96-week treatment period may become eligible for the 
OLE phase of the study. Participants will be consented for participation in the OLE phase if
they may benefit from treatment with ocrelizumab.  Participants who are not willing to participate 
in the OLE phase of the study will be entered into the safety follow-up period (see below).  
Participant treatment allocation during the double-blind, double-dummy, treatment period should 
not be unblinded regardless of participation in the OLE phase.
In the case of a participant who initially declines participation in the OLE phase and 
subsequently reconsiders the decision, the participant will have up to 24 weeks after the 
Week 96 visit to enter the OLE phase.  In this instance, he or she should not have taken any 
prohibited medication.  Participants who decline participation in the OLE phase should enter the 
safety follow-up period.
Participants who have consented to participate in the OLE phase will enter an 
OLE phase screening period to be evaluated for eligibility.  The OLE phase screening period will 
start after all assessments at the Week 96 visit have been performed.  This screening period will 
last up to 4 weeks. The OLE phase screening period could be longer than 4 weeks.  If a 
prolongation of the OLE phase screening period is needed, it should be discussed with the 
Sponsor on a case-by-case basis.
Information from assessments performed during the Week 96 visit will be utilized to verify the 
eligibility of the participant for the OLE phase of the study.
During the OLE phase screening period, all participants should receive Rebif/Rebif placebo 
(depending on initial arm they were assigned to) until the first infusion of Cycle 5.
Participants who withdraw from the OLE phase screening period will be entered into the safety 
follow-up period.


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Open-Label Extension Phase
Duration: the OLE phase will continue as per local regulation or should the Sponsor decide to 
terminate the ocrelizumab program for MS.  Unless terminated earlier for any of the reasons 
mentioned above, all participants may continue their treatment with open-label ocrelizumab as 
per the protocol until 31 December 2022.  All participants must discontinue open-label 
ocrelizumab treatment within this study before 31 December 2022. However, participants will 
be offered continuation of ocrelizumab treatment or a safety follow-up period via a rollover 
study (MN43964, OLERO).
Participants who start treatment with commercial ocrelizumab or another disease-modifying 
therapy (DMT) will discontinue from the study completely and will not enter the safety follow-up 
period.
Treatment: during the OLE phase, all participants will receive the ocrelizumab 600-mg dosing 
regimen every 24 weeks.
Withdrawal: participants who withdraw from the OLE phase will be entered into the safety 
follow-up period.
Safety Follow-Up
Participants who discontinue treatment prematurely for any reason during the following periods 
will be entered into the safety follow-up period:

Before completion of the 96-week double-blind, double-dummy, treatment period

During the OLE phase screening period

During the OLE phase

Participants who choose not to enter the OLE phase or are not eligible for the OLE phase 
after completing the 96-week, double-blind, double-dummy, treatment period
In the OLE phase screening period, in the case of a participant who initially declines 
participation in the OLE phase and subsequently reconsiders the decision, the participant will 
have up to 24 weeks after the Week 96 visit to enter the OLE phase.  In this instance, he or she 
should not have taken any prohibited medication.
The safety follow-up period will last for 48 weeks starting from the date of the last infusion of 
ocrelizumab/ocrelizumab placebo.  Safety follow-up visits will be performed at 12-week intervals 
starting from the date of the participant’s last visit (the withdrawal from Treatment Visit).  
Because this study will be closed on 31 December 2022, participants already in safety follow-
up may complete this study period in the rollover Study MN43964.
Participants who start treatment with commercial ocrelizumab or another DMT will discontinue 
participation in the study completely and will not enter or continue in the safety follow-up period.
During safety follow-up participants will be assessed at clinical visits every 12 weeks.  
Telephone interviews will be performed every 4 weeks.
Number of Participants
Approximately 800 participants (400 per treatment arm) will be recruited over a planned 
recruitment period of 16 months.
Participants will be randomized in 2 groups in a 1:1 ratio.  An independent IxRS provider will 
conduct randomization and hold the treatment assignment code.  Participants will be stratified 
by region (U.S. vs. Rest of World [ROW]) and baseline EDSS (4 and 4).
Study Treatment
The investigational medicinal product (IMP) for this study is ocrelizumab.
Ocrelizumab is a humanized, glycosylated, monoclonal antibody directed against the cluster of 
differentiation (CD)20 antigen present on select B cells.  Ocrelizumab binds to the CD20 
antigen, thereby resulting in B-cell depletion via antibody-dependent cellular cytotoxicity 
(ADCC), complement-dependent cytotoxicity (CDC), and enhanced apoptosis.
Ocrelizumab was constructed with use of a recombinant DNA technique.  This antibody shares 
an overlapping epitope on CD20 with the chimeric monoclonal antibody, Mabthera®/Rituxan®
(rituximab), as determined by direct competition and epitope-mapping experiments.  In vitro, 
ocrelizumab was shown to be approximately 5 times more potent than rituximab in ADCC 


Ocrelizumab—F. Hoffmann-La Roche Ltd
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activity in a B-cell tumor line over-expressing CD20, approximately 3 less potent via CDC, and 
approximately equal in inducing apoptosis in a B cell lymphoma cell line.
Substantial proof-of-concept clinical data support the use of B-cell depleting therapies in 
participants with RMS.  Ocrelizumab shares the same basic mechanism of action as rituximab.  
In a proof-of-concept study, rituximab treatment resulted in a robust reduction in MRI-based 
measures of CNS inflammation and clinical benefit versus placebo in participants with RRMS.  
Study WA21493/ACT4422g, a Phase II study of ocrelizumab in participants with RRMS,
provides proof-of-concept support for ocrelizumab efficacy and safety in participants with 
RRMS.
Ocrelizumab is also known as RO4964913, PRO70769, and rhuMAb 2H7 (refer to the 
Ocrelizumab Investigator’s Brochure [IB] for further information).
Duration of Participation
The double-blind, double-dummy treatment duration is 96 weeks followed by an OLE phase.
Independent Data Monitoring Committee
An independent Data Monitoring Committee is not being used.


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1.2
STUDY SCHEMA
Figure 1
Overview of the Study Design
BLbaseline; OLEopen-label extension; Wksweeks.
a Screening for the study may be prolonged for up to 8 weeks for relevant clinical, administrative, or operational reasons.
b The OLE phase screening period will start after all assessments at the Week 96 visit have been done.  It will last up to 4 weeks.  For particular 
reasons, the OLE phase screening period may be longer than 4 weeks.  If a prolongation of the OLE phase screening period is needed, it should 
be discussed with the Sponsor on a case-by-case basis.  Note that during the OLE phase screening period, participants should receive 
Rebif/Rebif placebo until the first infusion of Cycle 5.  
c To verify that participants meet re-treatment criteria, those in the OLE phase of the study should come to the clinic approximately 2 weeks before 
the infusions of Cycles 6, 7, etc.
d The OLE phase of the study can be terminated at any time.  Cycle N represents a typical cycle that occurs every 24 weeks.








Table 1
Schedule of Activities:  Screening through the End of the Double-Blind, Double-Dummy Treatment Period (cont.)
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-hCGhuman chorionic gonadotropin; BLbaseline; CD4cluster of differentiation 4; CES-DCenter for Epidemiologic Studies Depression 
Scale; C-SSRSColumbia-Suicide Severity Rating Scale; eCRF electronic Case Report Form; EDSSExpanded Disability Status Scale; 
EDTAethylenediaminetetraacetic acid; EQ-5DEuroQoL 5-Dimension; FACSfluorescence-activated cell sorting; FSHfollicle-stimulating 
hormone; HAHAhuman anti-human antibodies; HBcAbhepatitis B core antibody; HBsAghepatitis B surface antigen; HBVhepatitis B virus;
HepCAbhepatitis C antibody; JCVJohn Cunningham virus; LCVALow-Contrast Visual Acuity; MFISModified Fatigue Impact Scale; 
MRImagnetic resonance imaging; MSFCSMultiple Sclerosis Functional Composite Scale; OLEopen-label extension; PCRpolymerase chain 
reaction; PKpharmacokinetic; RPRrapid plasma reagin; SAEserious adverse event; SDMT Symbol Digit Modalities Test; SF-36Short Form 
36; sTSHsensitive thyroid-stimulating hormone; wweek.
Please note: based on local Ethics Committees or National Competent Authority requirements, additional diagnostic testing may be required for 
selected participants or selected centers to exclude tuberculosis, Lyme disease, HTLV-1 associated myelopathy (HAM), AIDS, hereditary 
disorders, connective tissue disorders, or sarcoidosis.  Other specific diagnostic tests may be requested when deemed necessary by the 
investigator.
a A delayed dosing visit will be performed and recorded in the Delayed Dosing Visit eCRF form when dosing cannot be administered at the 
scheduled dosing visit.  Other tests or assessments may be done as appropriate.
b Unscheduled Visit:  assessments performed at unscheduled (non-dosing) visits will depend on the clinical needs of the participant.  
All participants with new neurological symptoms suggestive of relapse should have EDSS performed by Examining Investigator, whenever 
possible within 7 days of the onset of the relapse.  Other tests/assessments may be done as appropriate.  Please note: in case of ALT elevations 
dose modification should be necessary, additional visits may be required for dispensing of study medication.
c Informed Consent must be obtained in written form from all participants at screening (prior to any study–related procedure) in order to meet 
eligibility for the study.
d At the Week 84 Visit, a discussion with the participant regarding participation in the OLE phase should occur if the Treating Investigator is of the 
opinion that the participant may benefit from treatment with ocrelizumab.  An informed consent for the OLE phase should be provided to the 
participant.  It is recommended that the Informed Consent Form of the OLE phase be signed at the Week 96 Visit.
e Vital signs (i.e., pulse rate, systolic and diastolic blood pressure, respiration rate and temperature) will be obtained while the participant is in the 
semi-supine position (after 5 minutes).  On infusion visits, the vital signs should be taken within 45 minutes prior to the methylprednisolone 
infusion in all participants.  In addition, vital signs should be obtained prior to ocrelizumab/ocrelizumab placebo infusion, then every 15 minutes 
(5 minutes) for the first hour; then every 30 minutes (10 minutes) until 1 hour after the end of the infusion.  On non-infusion days, the vital 
signs may be taken at any time during the visit.
f
ECG (pre- and postdose):  on infusion visits ECG should be taken within 45 minutes prior to the methylprednisolone infusion in all participants, 
and within 60 minutes after completion of the ocrelizumab/ocrelizumab placebo infusion.  On non-infusion days, the ECG may be taken at any 
time during the visit.
g MRI:  brain MRI scans should occur within a window or 4 weeks of the scheduled visit.  Also, brain MRI scans will be obtained in participants 
withdrawn from the treatment period (at a withdrawal visit) if not performed during last 4 weeks.


Table 1
Schedule of Activities:  Screening through the End of the Double-Blind, Double-Dummy Treatment Period (cont.)
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h A structured telephone interview will be conducted by site personnel every 4 weeks (3 days) from Week 8 through the study to identify and 
collect information on any changes in the participant’s health status that warrant an unscheduled visit (including new or worsening neurological 
symptoms).
i
Serum -hCG must be performed at screening in women of childbearing potential.  Subsequently, urine -hCG [sensitivity of at least 25 mIU/mL] 
will be performed.  On infusion visits, the urine pregnancy test should be performed prior to methylprednisolone infusion in all women of 
childbearing potential.  If positive, the participant will not receive the scheduled dose and confirmation, a serum pregnancy test, will be 
performed.
j
Antibody Titers:  measurement of antibody titers against common antigens (mumps, rubella, varicella and Streptococcus pneumoniae) will be 
performed.
k Protein biomarker sampling: 1 serum sample (6 mL) will be collected from all participants for analysis of protein biomarkers.  On infusion 
visits, samples should be collected 530 minutes prior to methylprednisolone infusion.
l
HAHA:  On infusion visits, serum samples are collected 530 minutes prior to the methylprednisolone infusion.
m Plasma and urine samples for JCV will be collected at specified timepoints and analyzed in batches, if decided by the Sponsor.
n PK samples:  on the infusion day at Week 72, two serum samples should be collected, one sample collected 530 minutes prior to the 
methylprednisolone infusion and the second sample 30 minutes (10 minutes) following the completion of the ocrelizumab/ocrelizumab placebo 
infusion.  For all other infusion visits, a blood sample should be collected 530 minutes before the methylprednisolone infusion.  At other times 
(non-infusion visits) samples may be collected at any time during the visit.
o sTSH will be tested at screening and during the double-blind, double-dummy treatment period.  Thyroid autoantibodies will be assayed only at 
screening.
p FSH:  only applicable to women to confirm the postmenopausal status.
q Hepatitis screening and monitoring:  all participants must have negative HBsAg result and negative HepCAb screening tests prior to enrollment.  
If total HBcAb is positive at screening, HBV DNA measured by PCR must be negative to be eligible.  For those participants enrolled with 
negative HBsAg and positive total HBcAb, HBV DNA (PCR) must be repeated every 12 weeks during the treatment period.
r
FACS:  including CD19 and other circulating B-cell subsets, T cells, natural killer cells, and other leukocytes.  On infusion visits, blood samples 
should be collected prior to the infusion of methylprednisolone.
s Routine safety laboratory:  hematology, chemistry and urinalysis:  on infusion visits, all urine and blood samples should be collected prior to 
the infusion of methylprednisolone.  At other times, samples may be collected at any time during the visit.
t
Type I interferon neutralizing antibody assay:  at baseline (Visit 2), sample should be collected before first Rebif/Rebif placebo injection.  
At subsequent visits, samples should be collected at least 36 hours following last injection of Rebif/Rebif placebo.


Table 1
Schedule of Activities:  Screening through the End of the Double-Blind, Double-Dummy Treatment Period (cont.)
Ocrelizumab—F. Hoffmann-La Roche Ltd
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u All participants receive prophylactic treatment with 100 mg of methylprednisolone IV prior to infusion of ocrelizumab /ocrelizumab placebo.  
In the rare case when the use of methylprednisolone is contraindicated for the participant, use of an equivalent dose of an alternative steroid 
should be used as premedication prior to the infusion.  It is also recommended that participants receive an analgesic/antipyretic such as 
acetaminophen/paracetamol (1 g) and an IV or oral antihistaminic, such as diphenhydramine 50 mg, 3060 minutes prior to 
ocrelizumab/ocrelizumab placebo.
v Administration (infusion) of IV ocrelizumab/ocrelizumab placebo:  the Treating Investigator must review the clinical and laboratory 
re-treatment criteria prior to subsequent infusion of ocrelizumab/ocrelizumab placebo.
w If the participant enters OLE phase screening period, Rebif / Rebif placebo should be provided to the participant at the Week 96 visit
(please see Section 5.17.1).




Table 2
Schedule of Activities:  Safety Follow-Up (cont.)
Ocrelizumab—F. Hoffmann-La Roche Ltd
30/Protocol WA21093J, Version 10
CDcluster of differentiation; EDSSExpanded Disability Status Scale; EDTAethylenediaminetetraacetic acid; FACSfluorescence-activated 
cell sorting; HAHAhuman anti-human antibodies; HBcAbhepatitis C antibody; HBsAghepatitis B surface antigen; HBVhepatitis B virus; 
MRImagnetic resonance imaging.
a Safety follow-up will be carried out for 48 weeks starting from the date of last infusion of ocrelizumab.  Visits will be performed at 12-week 
intervals starting from the date of the participant’s Withdrawal from Treatment Visit.  As this study will be closed on 31 December 2022 
participants already in safety follow-up may complete this study period in the rollover Study MN43964.  Safety follow-up applies to study 
participants who have completed the blinded treatment period (or open-label treatment period, if applicable) and to participants who withdraw 
early from treatment.  The last scheduled safety follow-up visit will become the End of Observation visit and the participant will have completed 
the study.  Participants who start treatment with commercial ocrelizumab or another DMT will discontinue from the study completely and 
will not enter or continue in the safety follow-up period.  A Withdrawal from Study visit will be performed at the time of study closure for 
participants not rolling over to Study MN43964.
b Routine safety laboratory examination: hematology, chemistry and urinalysis.
c FACS including CD19 and other circulating B-cell subsets, T cells, natural killer cells and other leukocytes.
d HAHA and ocrelizumab drug concentration samples: in case of anaphylaxis, anaphylactoid reaction, or serious or severe hypersensitivity 
reaction, HAHA and ocrelizumab concentration samples should be collected as close as possible to the event and then at 4 and 16 weeks 
postdose.
e Hepatitis monitoring: hepatitis to be monitored only in participants with screening results of HBsAg-negative, HBcAb-positive and HBV DNA 
negative, inclusive.
f
Needs to be assessed only every 24 weeks.
g Protein biomarker sampling: 6 mL blood sample in a plain tube without EDTA for serum isolation will be collected from all participants for 
analysis of protein biomarkers.
h MRI should only be performed for participants who begin an alternative treatment for MS, within the time window of one month prior to the start 
of an alternative MS treatment (unless MRI has already been performed within prior 8 weeks).
i
A structured telephone interview will be performed by site personnel every 4 weeks (3 days) between visits until 48 weeks after the last 
infusion to identify and collect information on any changes in the participant’s health status that warrant an unscheduled visit (including new or 
worsening neurological symptoms).








Table 3
Schedule of Activities:  Open-Label Extension Phase (Cont.)
Ocrelizumab—F. Hoffmann-La Roche Ltd
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f
During the OLE phase screening period, SC administration Rebif / Rebif placebo 3 times per week should occur until one day prior to the first 
infusion of ocrelizumab of Cycle 5 (beginning of OLE phase).  If during this period, the participant decides not to participate in the OLE phase, 
then administration of Rebif/Rebif placebo 3 times per week should stop immediately, and the participant will be entered in the safety follow-up 
period.
g All participants receive prophylactic treatment with 100 mg of methylprednisolone IV and an oral or IV antihistamine (such as diphenhydramine 
50 mg or an equivalent dose of an alternative) prior to infusion of ocrelizumab.  The methylprednisolone administration is to be completed 
approximately 30 minutes before the start of each ocrelizumab infusion; antihistamines should be administered 3060 minutes prior to the start 
of an infusion.  In the rare case when the use of methylprednisolone is contraindicated for the participant, use of an equivalent dose of an 
alternative steroid should be used as premedication prior to the infusion.  It is also recommended that participants receive an 
analgesic/antipyretic such as acetaminophen/paracetamol (1 g).
h Administration (infusion) of IV ocrelizumab:  the investigator must review the clinical and laboratory re-treatment criteria prior to subsequent 
infusion of ocrelizumab.  The participant will need to remain under observation at the clinical for at least 1 hour after infusion.  It is anticipated 
that the participant will need to stay at the hospital or clinical site for a full day for the infusion visit.
i
Vital signs (i.e., pulse rate, systolic and diastolic blood pressure, respiration rate, and temperature) will be obtained while the participant is in the 
semi-supine position (after 5 minutes).  Vital signs should be collected within 45 minutes prior to the methylprednisolone infusion in all 
participants.   In addition, vital signs should be obtained prior to ocrelizumab infusion, then every 15 minutes (5 minutes) for the first hour; then 
every 30 minutes (10 minutes) until 1 hour after the end of the infusion.  Weight measurement is to be performed at OLE Visit 0 (Cycle 1) and 
OLE Withdrawal from Treatment Visit only.
j
ECGs (pre- and postdose):  ECG should be performed within 45 minutes prior to the methylprednisolone infusion in all participants, and within 
60 minutes after completion of the ocrelizumab infusion.  From OLE Week 72 Visit 20 onwards, ECG assessment is not mandatory; it should 
only be performed if clinically indicated. 
k Routine safety laboratory tests:  hematology, chemistry, and urinalysis.  On infusion visits at Cycle 5, all urine and blood samples should be 
collected prior to the infusion of methylprednisolone.  At other times, samples may be collected at any time during the visit.
l
Urine -hCG [sensitivity of at least 25 mIU/mL] will be performed.  On infusion visits, the urine pregnancy test should be performed prior to 
methylprednisolone infusion in all women of childbearing potential.  If positive, the participant will not receive the scheduled dose and for 
confirmation a serum pregnancy test will be performed.
m Antibody Titers:  measurement of antibody titers against common antigens (mumps, rubella, varicella, and Streptococcus pneumoniae) will be 
performed.
n HAHA and ocrelizumab drug concentration samples:  in any case of anaphylaxis, anaphylactoid reaction, or serious or severe 
hypersensitivity reaction, HAHA and ocrelizumab concentration samples should be collected as close as possible to the event and then at 4 and 
16 weeks postdose.
o A structured telephone interview will be conducted by site personnel every 4 weeks (3 days) from Cycle 5 (Week 8 of OLE phase) through 
the study to identify and collect information on any changes in the participant’s health status that warrant an unscheduled visit (including new or 
worsening neurological symptoms).


Table 3
Schedule of Activities:  Open-Label Extension Phase (Cont.)
Ocrelizumab—F. Hoffmann-La Roche Ltd
35/Protocol WA21093J, Version 10
p SF-36, The Short Form Health Survey, is to be performed once yearly during the OLE phase.
q Protein biomarker sampling:  1 serum sample (6 mL) will be collected from all participants for analysis of protein biomarkers.  On infusion 
visits, samples should be collected 530 minutes prior to methylprednisolone infusion.
r
FACS:  including CD19 and other circulating B-cell subsets, T cells, natural killer cells, and other leukocytes.
s Hepatitis monitoring:  for those participants enrolled with negative HBsAg and positive total HBcAb, HBV DNA (PCR) must be repeated every 
24 weeks during the treatment period.
t
MRI:  brain MRI scans should occur within a window of 4 weeks of the scheduled visit.  Also, brain MRI scans will be obtained in participants 
withdrawn from the OLE phase (at a withdrawal visit) if not performed during last 4 weeks.
u SDMT, Single Digit Modalities Test, is to be performed once yearly during the OLE phase.
v Optional samples for RBR (CSF and blood):  one-time optional CSF sample, paired plasma samples, and blood samples for the RBR 
collected at any timepoint during the OLE phase.  These samples should be collected after the participant's consent and at the next possible visit 
during the OLE phase.


Ocrelizumab—F. Hoffmann-La Roche Ltd
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PART I:
STUDY DESIGN AND CONDUCT
2.
BACKGROUND AND RATIONALE
2.1
BACKGROUND
2.1.1
Multiple Sclerosis
Multiple sclerosis (MS) is an inflammatory and degenerative demyelinating disease of 
the human CNS.  Multiple sclerosis affects approximately 2.5 million people worldwide: 
it is one of the most common neurological disorders and causes of disability of young 
adults, especially in Europe and North America (World Health Organization 2010).  
The condition manifests as neurological deficits related to damage to the spinal cord, 
brainstem, optic nerves, cerebellum, and cerebrum.  Resulting symptoms may include 
weakness, pain, visual loss, bowel/bladder dysfunction, and cognitive dysfunction.  
Diagnosis of MS typically occurs through the application of highly structured diagnostic 
criteria that rely on clinical observation, neurological examination, brain and spinal cord 
magnetic resonance imaging (MRI) scans, evoked potentials, and examination of 
cerebrospinal fluid (CSF; McDonald et al. 2001; Polman et al. 2011).
Multiple sclerosis is clinically subcategorized into 4 phenotypic disease patterns 
distinguished by the occurrence and timing of relapses relative to disease onset and 
disability progression (Lublin and Reingold 1996).  These include relapsing-remitting MS 
(RRMS), primary progressive MS (PPMS), progressive relapsing MS; and secondary 
progressive MS (SPMS).
Approximately 80% of patients with MS present with RRMS.  If left untreated, most 
patients with RRMS will transition into SPMS (with progressive loss of neurologic 
function in the absence of relapses) within 20 years.  The term relapsing MS (RMS) 
applies to those patients with either RRMS or SPMS who continue to suffer relapses.  
Patients with RMS, whether or not they suffer from neurologic progression in the 
absence of relapses, have a common, inflammatory pathophysiology and, therefore, 
constitute a common target for treatment.
Currently available first-line therapies for the treatment of either RMS or RRMS include 
Rebif® and Avonex® (interferon [IFN])-1a, Betaferon®/Extavia® (IFN-1b) and 
Copaxone® (glatiramer acetate). The currently approved first-line treatments are only 
modestly effective in reducing the frequency of relapses and preventing disability in 
patients with RMS.  The magnitude of these disease-modifying effects are an 
approximately 30% relative improvement versus placebo (Filippini et al. 2003).  
The first-line disease-modifying agents reduce the frequency of new episodes but do not 
reverse fixed deficits and have variable effects on long-term disability progression 
(Compston and Coles 2008).
Gilenya(fingolimod; FTY720) is an oral modulator of sphingosine-1 phosphate (S1P) 
receptors, a ubiquitous group of transmembrane receptors involved with cellular growth 


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and differentiation.  Fingolimod’s immunomodulatory effects are believed to be due to 
binding to and internalization of the S1P receptor on lymphocytes, thereby rendering 
them insensitive to S1P gradients in lymph and inhibiting egress from lymph nodes and 
other secondary lymphoid organs.  Fingolimod is known to readily cross the blood-brain 
barrier, and S1P receptors are present on glial cells and neurons. However, the 
implications of any possible direct CNS S1P receptor modulation effects are currently 
unknown.  Fingolimod was shown to reduce the annualized relapse rate (ARR) by 
approximately 50% versus both placebo and intramuscular (IM) IFN -1a 30 mcg weekly 
in confirmatory Phase III clinical trials.  Because of the presence of S1P receptors on 
many different cell types, the adverse event profile of fingolimod is complex and may 
include effects on cardiac, ophthalmic, hepatic, and pulmonary function, as well as an 
increased risk of infection due to inhibition of lymphocyte trafficking.  Fingolimod was 
approved in 2010 by the U.S. Food and Drug Administration (FDA) for patients with 
relapsing forms of MS and by the European Medicines Agency in 2011 for use in 
patients who have previously failed first-line disease-modifying therapy (DMT) or who 
have highly active disease.
Tysabri® (natalizumab) is a monoclonal antibody directed against -4 -1 integrin 
(VLA-4), an adhesion molecule expressed on activated lymphocytes.  Natalizumab binds 
to VLA-4, inhibiting trafficking of activated lymphocytes into the CNS and other 
extravascular tissues.  Natalizumab was shown to produce a 66% relative reduction in 
ARR versus placebo in a Phase III clinical trial.  Natalizumab use is generally limited to 
patients with RRMS who have failed to respond to first-line DMT or to patients with 
highly active RRMS due to a risk of progressive multifocal leukoencephalopathy (PML).
Aubagio® (teriflunomide) is a once-daily, oral immunomodulator that inhibits 
dihydroorotate dehydrogenase, a key mitochondrial enzyme involved in de novo 
pyrimidine synthesis for DNA replication, and reduces T-cell and B-cell proliferation and 
function in response to autoantigens.  Teriflunomide was approved by the FDA in 2012 
for the treatment of relapsing forms of MS.  Two Phase III trials showed a significant 
reduction in ARR of teriflunomide against placebo (O’Connor et al. 2011; 
Kappos et al. 2012).  A third Phase III trial, TENERE, showed that teriflunomide was not 
statistically different than IFN -1a in terms of risk of treatment failure (NCT00883337).  
Risk of treatment failure was defined as the occurrence of a confirmed relapse or 
permanent treatment discontinuation for any cause, whichever came first.
Novantrone® (mitoxantrone), a chemotherapeutic agent, is also approved for the 
treatment of relapsing MS in the United States but is generally reserved for secondary 
progressive and severe relapsing-remitting forms of disease.  Other drugs have been 
used with varying degrees of success, including corticosteroids, methotrexate (MTX), 
cyclophosphamide, azathioprine, and IV immunoglobulin.


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Despite significant advances in MS therapy, many patients continue to experience 
disease activity; thus, a need to develop more effective and better tolerated therapies for 
the treatment of RMS remains.
2.1.2
Ocrelizumab
Ocrelizumab is a humanized, glycosylated, monoclonal antibody directed against the 
cluster of differentiation (CD)20 antigen present on select B cells.  Ocrelizumab binds to 
the CD20 antigen, thereby resulting in B-cell depletion via antibody-dependent cellular 
cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and enhanced 
apoptosis.
Ocrelizumab was constructed with use of a recombinant DNA technique.  This antibody 
shares an overlapping epitope on CD20 with the chimeric monoclonal antibody, 
Mabthera®/Rituxan® (rituximab), as determined by direct competition and 
epitope-mapping experiments.  In vitro, ocrelizumab was shown to be approximately 
5 times more potent than rituximab in ADCC activity in a B-cell tumor line 
over-expressing CD20, approximately 3 less potent via CDC, and approximately equal 
in inducing apoptosis in a B cell lymphoma cell line.
Substantial proof-of-concept clinical data support the use of B-cell depleting therapies in 
participants with RMS.  Ocrelizumab shares the same basic mechanism of action as 
rituximab.  In a proof-of-concept study, rituximab treatment resulted in a robust reduction 
in MRI-based measures of CNS inflammation and clinical benefit versus placebo in 
participants with RRMS (Hauser et al. 2008).  Study WA21493/ACT4422g, a Phase II 
study of ocrelizumab in participants with RRMS, provides proof-of-concept support for 
ocrelizumab efficacy and safety in participants with RRMS; please see Section 2.1.4.1 
for more details.
Ocrelizumab is also known as RO4964913, PRO70769, and rhuMAb 2H7 (refer to the 
Ocrelizumab Investigator’s Brochure [IB] for further information).
2.1.3
Rationale for Targeting B Cells in Multiple Sclerosis
Humoral immunity has been implicated in MS for decades, as evidenced by inclusion of 
CSF oligoclonal bands (OCBs) and increased intrathecal IgG synthesis in diagnostic 
criteria for MS (Sidén 1979; McDonald et al. 2001; Polman et al 2011).  Although, until 
very recently, the prevailing view of MS pathophysiology held that the CNS inflammation 
seen in MS is principally mediated by CD4pro-inflammatory (Th1, Th17) T cells, 
rapidly expanding evidence suggests that B cells may contribute to MS pathogenesis 
much more fundamentally than was previously believed, potentially through either 
antibody-dependent or -independent mechanisms (Meinl et al. 2006; 
Franciotta et al. 2008; McFarland 2008).  B lymphocytes have been detected within 
MS lesions and in the CSF of participants with MS.  Molecular analysis of both lesional 
and CSF B-cell repertoires reveals dominant, clonally-expanded B cell populations 
exhibiting somatic hypermutation in the antigen-recognizing third complementarity 


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determining regions (CDR3) of Ig heavy chains, predominately within the variable heavy
4 (VH4) gene family (Owens et al. 1998; Baranzini et al. 1999; Colombo et al. 2000; 
Ritchie et al. 2004; Lambracht-Washington et al. 2007; Owens et al. 2007).
Detection of these affinity-matured, clonally-expanded repertoires in the CSF but not 
peripheral blood of participants with MS suggests that a localized, antigen driven B cell 
response is present in the CNS compartment.  Cerebrospinal fluid clonal B cell 
expansion has been reported in participants with both RRMS and PPMS shortly after 
diagnosis, implying a role for B cells early in MS pathogenesis rather than as a late 
response to longstanding tissue damage (Monson et al. 2005).  More recently, 
complementary DNA (cDNA) transcriptomes of clonally-expanded, affinity-matured 
B cells isolated from the CSF of participants with MS have been sequence-matched to 
specific IgG OCBs from the same CSF samples, indicating that this longstanding 
hallmark of MS diagnosis derives from identifiable B cell clones present in the 
CNS compartment (Obermeier et al. 2008).
Both antibody-dependent and independent hypotheses for the role of B cells in MS 
pathophysiology have been postulated and are currently the subject of intensive 
research.  B cells may differentiate into plasma cells and produce CNS-directed 
auto-antibodies, potentially triggering cellular- and CDC.  Although a pathogenic role of 
anti-myelin antibodies in MS has not been established, they have been detected in the 
CSF of participants with MS (Reindl et al. 1999; Egg et al. 2001; Andersson et al. 2002)
and in active MS lesions (Genain et al. 1999) and remain potential candidates as 
effectors of myelin sheath damage.  B cells may also function as antigen-presenting 
cells and thereby modulate effector T cell responses because they exhibit regulated 
secretion of both pro-inflammatory and anti-inflammatory cytokines, a function that 
appears to be abnormal in patients with MS (Meinl et al. 2006).  Finally, B cells may be a 
site of latent viral infections such as Epstein-Barr virus, which may drive CNS 
autoimmune responses through molecular mimicry or other pro-inflammatory 
mechanisms (Franciotta et al. 2008).
Post-mortem pathological studies have identified the presence of ectopic follicular 
lymphoid structures in the meninges anatomically proximal to sites of grey-matter 
demyelination in a subset of patients with SPMS (Qin et al. 1998; Serafini et al. 2004; 
Magliozzi et al. 2007).  Similar tertiary lymphoid structures form de novo in various 
tissues of many autoimmune disorders and represent potential de novo sites of chronic 
auto-antigenic B cell activation, maturation, and clonal expansion 
(Aloisi and Pujol-Borrell 2006).  Patients with SPMS who exhibit these lymphoid 
structures have been found to have worse progression rates compared with controls 
without such follicular structures (Howell et al. 2009) and a pathomechanistic link to 
grey-matter demyelination typical for SPMS has been suggested.  Whether or not an 
anti-CD20 therapeutic antibody can affect the formation or persistence of meningeal 
lymphoid follicles or the grey-matter demyelination prominent in progressive forms of MS 
is unknown.


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In summary, B lymphocytes are believed to contribute to the pathogenesis of all 
subtypes of MS.  Removing select peripheral B cells from circulation may beneficially 
disrupt inflammatory processes that potentially involve chronic antigenic stimulation or 
other regulatory functions promoting chronic autoimmunity.  Ocrelizumab specifically 
depletes CD20B cells, which makes it a potentially attractive pharmacological agent to 
test for therapeutic potential in patients with MS.
2.1.4
Sponsor Experience with Anti-CD20 Compounds in Multiple 
Sclerosis
2.1.4.1
Ocrelizumab in RRMS
Study WA21493/ACT4422G was a 220-participant Phase II, multicenter, randomized, 
parallel-group, placebo-controlled, proof-of-concept study to evaluate the safety and 
efficacy of 2 dosing regimens of ocrelizumab (1000 mg2 [administered on Day 1 and 
Day 15, followed by single infusions of 1000 mg for subsequent cycles] and 
300 mg2 [administered on Day 1 and Day 15, followed by single infusions of 600 mg 
for subsequent cycles]), with an additional randomized open-label arm of IFN 1-a 
30 g IM every week.  The primary objective was to evaluate the efficacy of 2 dosing
regimens of ocrelizumab compared with placebo in reducing brain inflammation, as 
measured by the total number of gadolinium (Gd)-enhancing T1 lesions observed on 
serial MRI scans of the brain at Weeks 12, 16, 20, and 24.  Key secondary objectives 
were to evaluate the efficacy of both dosing regimens of ocrelizumab compared with 
placebo in reducing ARR at Week 24 and to evaluate the safety and tolerability of both 
dosing regimens of ocrelizumab in participants with RRMS.  Exploratory outcomes 
included analysis of both dosing regimens of ocrelizumab compared with IFN -1-a 
30 g IM weekly for various study measures.  Treatment with ocrelizumab was planned 
for 7296 weeks total, depending on the study arm (participants from both the placebo 
and the IFN -1a group switched to ocrelizumab 300 mg2 after Week 24).  
Additional MRI scans of the brain will be obtained at Weeks 96 and 144 for a subgroup 
of participants.
Week 24 results demonstrated that both doses of ocrelizumab achieved the primary 
endpoint by significantly reducing the number of Gd-enhancing lesions compared with 
placebo (p0.0001).  Both ocrelizumab dose groups showed statistically significant 
reductions in ARR compared with the placebo group (ARR0.125 for the ocrelizumab
300 mg2 group [p0.0005] and ARR 0.169 for the ocrelizumab 1000 mg2 group 
[p0.0014] compared with ARR0.637 for the placebo group), representing a relative 
reduction (RR) of 80% and of 73% in ARR versus the placebo group for the low-dose
and the high-dose ocrelizumab groups, respectively.  In exploratory analyses, both 
ocrelizumab groups were superior to the IFN -1a group for the primary endpoint 
(p0.0001) and the 300 mg2 group for ARR (ARR0.364 for the IFN -1a group, 
representing an RR of 66% in ARR with p0.03 for the ocrelizumab 300 mg2 group 
versus the IFN -1a group and a RR of 53.6% in the ARR with p0.086 for the 
ocrelizumab 1000 mg 2 group versus the IFN -1a group; Kappos et al. 2011).


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Participants from both the placebo and IFN -1a groups switched to ocrelizumab 
300 mg2 after Week 24.  By 48 weeks, the level of benefit of ocrelizumab in reduction 
of ARR was maintained; participants in the ocrelizumab 300 mg2 group continued to 
have a suppressed ARR of 0.086 from Weeks 2448, and participants who switched to 
ocrelizumab from either placebo or IFN -1a derived a similar degree of efficacy to those 
randomized to ocrelizumab from onset (ARR for placebo-to-ocrelizumab 0.161 and for 
IFN -1a-to-ocrelizumab 0.137 after the switch, representing a RR of 74% and 62.4% 
compared with ARR before the switch, respectively).  From Weeks 072, participants 
originally randomized to ocrelizumab 300 mg 2 maintained clinical efficacy with an ARR 
of 0.186.
The most commonly reported adverse events in ocrelizumab-treated participants were 
infusion-related reactions (IRRs).  Infusion-related reactions were reported during/after 
the first infusion (Day 1) for 30%43.6% of participants treated with ocrelizumab.  
Fewer participants (2.1%9.4%) experienced IRRs during/after the second infusion 
(Day 15).  The most common symptoms were rash, pruritus, flushing, tachycardia, 
headache, pyrexia, and throat irritation.  No unanticipated, clinically significant 
abnormalities in vital signs, ECGs, or laboratory parameters were observed in 
association with ocrelizumab treatment.
On review of the placebo-controlled, double-blinded, 24-week safety data, no imbalance 
in adverse events (or infection adverse events) or serious adverse events (or infection 
serious adverse events) between the placebo and the active ocrelizumab arms was 
observed.  The rate of adverse events (or infection adverse events) and serious adverse 
events (or infection serious adverse events) did not increase in ocrelizumab-treated 
participants at Week 48 compared with Week 24.  No trend toward an increased risk of 
adverse events (or infection adverse events) or serious adverse events (or infection 
serious adverse events) was found for ocrelizumab-treated participants with previous 
IFN treatment (for 6 months).
By the time all participants finished Week 48 of treatment, the incidence of infections and 
serious infections was 92.41/100 participant-years (PY) (95% CI: 76.59 to 111.5) and 
3.39/100 PY (95% CI: 1.27 to 9.04) in participants exposed to low-dose ocrelizumab, 
including participants who switched from placebo or IFN -1a.  The incidence of 
infections and serious infections was 97.38/100 PY (95% CI: 74.76 to 126.84) and 
5.31/100 PY (95% CI: 1.71 to 16.47) in those exposed to the high dose of ocrelizumab.  
The most common infections in ocrelizumab-treated participants included urinary tract 
infections, upper respiratory infections, and nasopharyngitis.
To date, in Study WA21493, after over 250 participant-years of exposure to ocrelizumab, 
no reports of opportunistic or fatal infections have been made.


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2.1.4.2
Long-Term Results of Phase II Study WA21493/ACT4422G
To further understand the long-term effect of ocrelizumab therapy, the Phase II 
Study WA21493/ACT4422G was designed with a 48-week treatment-free period after 
the 96-week treatment period with ocrelizumab.  Across all treatment groups, 86%91% 
of the 220 initially randomized participants entered the treatment-free period.  
This included participants who had withdrawn from treatment.  Subsequently, 73%82% 
of participants completed Week 120; 69%80% completed Week 144; and 36%56% of 
participants entered a 24-week, drug-free observation period after B-cell repletion at 
Week 144.  During the treatment-free period, ARR remained at low levels similar to 
those during the treatment period (0.04–0.29 across treatment groups), with no 
indication of increase or rebound.  The mean number of Gd-enhancing T1 lesions 
remained at 0 at Week 144 in the ocrelizumab 600 mg group and increased from 0 at 
Week 96 to 0.3 at Week 144 in the ocrelizumab 1000 mg group. Furthermore, no 
imbalance was found in the rates of adverse events or serious adverse events across all 
treatment groups over 144 weeks.  No new serious infections and no opportunistic 
infections were reported since the last ocrelizumab administration.  Infection rates did 
not increase over time; at Week 144, infection rates were 6.5% and 11.1% with the 
ocrelizumab 600 mg and 1000 mg regimens, respectively.  The most common types of 
infections were upper respiratory tract infections, nasopharyngitis, and urinary tract 
infections (Kappos et al. 2012).
The long-term efficacy data from the Phase II Study WA21493/ACT4422G show that the 
low-level of disease activity observed after ocrelizumab treatment was sustained through 
Week 144.  This includes the observation that no Gd-enhancing T1 lesions were 
observed in the ocrelizumab 600 mg group at Week 144, which indicates a long-term 
anti-inflammatory effect of ocrelizumab on the CNS.  Up to Week 144, no new safety 
issues were observed with ocrelizumab.  In particular, no increases in infections and no 
new serious adverse events occurred, which indicates a positive benefit/risk profile.  
Currently, eligible participants continue to receive ocrelizumab treatment in the 
open-label extension (OLE) phase of this study.
2.1.4.3
Rituximab in RRMS
Two clinical trials of rituximab have been conducted in participants with RRMS. 
Rituximab is a chimeric mouse/human monoclonal antibody that shares the same basic 
mechanism of action as ocrelizumab.  Findings briefly highlighted below offer additional 
support for the therapeutic potential of the anti-CD20 mechanism in MS.
Study U3264g (HERMES Jr.) was a Phase I, open-label, multicenter study in 26 adults 
with RRMS to evaluate the safety and tolerability of 2 treatment cycles of rituximab 
administered at baseline and after 24 weeks.  Re-treatment with rituximab (1000 mg 2) 
at 24 weeks was safe and well-tolerated and resulted in an observed decrease in 
relapses and Gd-enhancing lesions through 72 weeks (Bar-Or et al. 2008).


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Study U2787g (HERMES) was a Phase II, proof-of-concept, randomized, double-blind, 
parallel-group, placebo-controlled, multicenter study to evaluate the safety and efficacy 
of rituximab in 104 adults with RRMS.  The primary objectives were to investigate the 
efficacy of rituximab compared with placebo, as measured by the total number of 
Gd-enhancing T1 lesions observed on serial MRI scans of the brain at Weeks 12, 16, 
20, and 24, and to evaluate the safety and tolerability of rituximab in participants with 
RRMS.  Secondary objectives were to evaluate additional MRI parameters and the 
proportion of participants relapsing.  The trial met its primary efficacy endpoint and all 
secondary endpoints.  Rituximab was safe and generally well-tolerated in this study 
through 48 weeks, although the rate of infusion-associated adverse events, particularly 
after the first infusion, was higher in rituximab-treated participants (78%) than in 
participants who received placebo (40%). Corticosteroid premedication was not 
administered before or at the time of infusion.  Study U2787g provides proof of the 
principle that an anti-CD20 therapeutic approach can reduce both MRI and clinical 
evidence of inflammatory activity in adults with RRMS (Hauser et al. 2008).
2.1.4.4
Rituximab in PPMS
A single, Phase II/III, randomized, double-blinded, placebo-controlled trial of rituximab 
for PPMS was conducted.  The findings summarized below represent the largest and 
longest duration trial experience to date evaluating the safety and efficacy of anti-CD20 
therapy in individuals with MS.
Study U2786g (OLYMPUS) was a Phase II/III, randomized, double-blind, parallel-group, 
placebo-controlled, multicenter study evaluating the safety and efficacy of rituximab in 
participants with PPMS over a 96-week treatment period consisting of 4 treatment cycles 
with dual infusions of 1000 mg (2000 mg/cycle).  Although the trial did not demonstrate 
significant primary efficacy on time to confirmed disease progression as measured by 
the Expanded Disability Status Scale (EDSS), a difference was observed: 38.5% of 
participants in the placebo group experienced confirmed disease progression versus
30.2% in the rituximab group.  Biological activity was evidenced by significantly lower T2 
lesion volume accumulation on brain MRI, a secondary efficacy endpoint, in 
rituximab-treated participants compared with those who received placebo (p0.0008).  
Subgroup analyses suggest that participants with PPMS and evidence of active disease 
may have shown significant clinical treatment response as measured by time to 
confirmed disease progression over a 96-week timeframe.  Factors that appeared 
prognostic for disease progression and potentially predictive of treatment response in 
the rituximab group included younger age, presence of contrast-enhancing lesions at 
baseline on brain MRI, and higher MS severity score.
Rituximab was generally safe and well-tolerated in Study U2786g.  The proportions of 
participants with at least 1 adverse event (100% for placebo vs. 99% for rituximab) and 
1 serious adverse event (13.6% for placebo vs. 16.1% for rituximab) were comparable 
between treatment groups.  Three adverse events that occurred during the study led to 
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and 2 adverse events in the placebo group due to pneumonia and cardiopulmonary 
failure.  More infusion-associated adverse events were observed in rituximab-treated 
participants (73.6% for rituximab vs. 40.3% for placebo), particularly after the first 
infusion, but rates declined in both groups to similar levels upon successive infusions.  
Participants were not pre-medicated with glucocorticoids before rituximab infusions in 
Study U2786g.  The vast majority (92%) of infusion-associated events in 
rituximab-treated participants were mild to moderate in severity; no Grade 4 or 5 
infusion-associated events were observed.  The proportion of participants with at least 
1 infection was comparable between groups (68.2% for rituximab vs. 65.3% for placebo), 
but a higher proportion of participants with at least 1 serious infection was observed in 
the rituximab-treated group (4.5%) compared with placebo (1%).  No opportunistic 
infections occurred.
Treatment with rituximab was associated with rapid and near-complete depletion of 
circulating CD19B lymphocytes beginning 2 weeks post-treatment through 96 weeks.  
Approximately 35% of rituximab-treated participants had recovered peripheral CD19 
B cell counts to 80 cells/L (the laboratory defined lower limit of normal [LLN] in healthy 
volunteers) within 48 weeks after the last dose.  Median circulating CD3 T-lymphocyte 
counts were not appreciably altered by rituximab.  At any time in the trial, IgM levels 
were below the LLN in 31.7% of rituximab-treated participants and 5.9% of 
placebo-treated participants.  The proportions of participants with IgG and IgA levels 
below LLN were not different between groups.  The incidence of infectious adverse 
events and infectious serious adverse events did not appear higher in participants with 
Ig levels (all isotypes) below LLN in either treatment group compared with participants 
with Ig levels in the normal range or above upper limit of normal 
(ULN; Hawker et al. 2009).
2.1.5
Rebif
The active comparator for this study is Rebif (IFN -1a), which has been approved for 
treatment of RMS.
The efficacy and safety of Rebif was demonstrated in the PRISMS study (The Prevention 
of Relapses and Disability by Interferon -1a Subcutaneously in Multiple Sclerosis),
which led to the approval of Rebif in RMS.  This was a multicenter controlled trial of 
560 participants with an EDSS score between 1.0 and 5.0 and at least 2 relapses in the 
preceding 2 years.  Participants were randomized to 2-year treatment with placebo or 
IFN -1a (22 or 44 g SC 3weekly).  Following the 2 years of treatment, compared 
with placebo, both doses of Rebif showed significant beneficial effects on major efficacy 
outcome measures.  A non-significant trend towards greater efficacy with the higher 
dose was noted for most clinical measures, as was a statistically significant dose effect 
favoring the higher dose in terms of impact on the number of T2-active lesions.  In a 
subgroup of participants with more severe disease (baseline EDSS 3.5), the 44-g 
dose delayed progression of disability significantly better than either the placebo or the 


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22 g dose.  Neutralizing antibodies were significantly less frequent in the 44 g group 
than in the low-dose group (PRISMS Study Group 1998).
After 2 years, participants who had initially received placebo in the PRISMS study were 
re-randomized to receive Rebif (22 or 44 g SC 3weekly) and were followed up for an 
additional 2 years.  By the end of the 4-year period, participants who had switched from 
placebo to Rebif experienced an approximate 50% reduction in ARR compared with the 
ARR at the end of Year 2. Moreover, after 4 years, the higher dose approached 
significance for ARR (0.8 for 22 g vs. 0.72 for 44 g; p0.069).  The mean ARR was 
significantly lower in participants who had received Rebif for the full 4 years compared 
with those who had received placebo for the first 2 years.  During Years 3 and 4, relapse 
rates were significantly lower for the 44-g group, and relapse rates decreased .  
Progressively, each year of treatment had 0.92, 0.82, 0.57, and 0.44 relapses/year.  
Participants who received the highest cumulative dose of active therapy had the lowest 
rates of disability progression.  The time to first confirmed EDSS progression was 
42.1 months for the 44-g group compared with 24.2 months for the crossover group.  
The time to first confirmed progression did not differ significantly between the 22-g 
group (35.9 months) and the crossover group (PRISMS Study Group 2001).
Rebif showed superiority versus Avonex in the EVIDENCE trial.  This was a randomized, 
controlled, multicenter trial that compared the efficacy and safety of Rebif 44 g SC
3weekly and Avonex 30 g IM once weekly in 677 participants with RRMS.  
The primary endpoint was the proportion of participants who were relapse-free at 
24 weeks, and the principal MRI endpoint was the number of active lesions per 
participant per scan at 24 weeks.  After 24 weeks, 74.9% of participants receiving 
Rebif 44 g 3a week remained relapse free compared with 63.3% of those given 
Avonex 30 g IM once a week.  Participants receiving Rebif 44 g 3a week had fewer 
active MRI lesions (p0.001 at 24 and 48 weeks) compared with those receiving 
Avonex 30 g IM once a week.  Injection site reactions were more frequent with 
Rebif 44 g 3a week (83% vs. 28%, p0.001), and asymptomatic abnormalities of 
liver enzymes (18% vs. 9%, p0.002) and altered leukocyte counts (11% vs. 5%, 
p0.003) were noted, unlike with the Avonex 30 g IM once a week dose.  
Neutralizing antibodies developed in 25% of Rebif 44 g 3a week participants and in 
2% of participants receiving IFN -1a 30 g once a week (Panitch et al. 2002).
Rebif has also been studied in the SPMS population.  The SPECTRIMS study was a 
multicenter, randomized, parallel-group, placebo-controlled study which tested 2 doses 
of Rebif in participants with SPMS.  Participants had to have clinically definite SPMS,
which was defined as progressive deterioration of disability for at least 6 months with an 
increase of at least 1 EDSS point over the previous 2 years (or 0.5-point between EDSS
scores of 6.0 and 6.5), with or without relapses, following an initial course of RRMS.  
Baseline EDSS scores had to be from 3.06.5 and the pyramidal functional score at 
least 2.  Participants were randomized to 3-year treatment with placebo or IFN -1a 
(22 or 44 g SC 3weekly).  The primary outcome was time of confirmed progression, 


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defined as an increase from baseline of at least 1 EDSS point (or 0.5-point if baseline 
EDSS 5.5), confirmed 3 months later with no intervening score lower than the 
minimum required level.  The primary outcome was not significantly influenced by 
treatment with Rebif compared with placebo (p0.146).  A significant benefit was seen 
on relapse rate for both doses of Rebif.  These findings suggest that treatment with Rebif 
has clinical benefit in SPMS, predominantly by affecting relapses, but only a modest 
effect on disability (SPECTRIMS Study Group 2001).
In controlled clinical trials, the most commonly observed adverse reactions were: 
injection site reactions, influenza-like symptoms (headache, fatigue, fever, rigors, chest 
pain, back pain, and myalgia), elevated liver enzymes, hematological abnormalities, 
abdominal pain, and depression.  Most of these adverse reactions are unique to 
treatment with IFN -1a and thereby present potential difficulties in maintaining blinding 
in controlled clinical trials.  Summary of the most frequent Rebif adverse reactions by 
MedDRA System Organ Class have been summarized in Table 4.
Table 4
Summary of the Most Frequent Rebif Adverse Reactions by 
MedDRA System Organ Class
System Organ Class
Very Common ADR
Frequency of Occurrence 
1/10
Common ADR
Frequency of Occurrence 
1/100 to 1/10
General disorders and 
administration site conditions
Injection site inflammation, 
injection site reaction, 
influenza-like symptoms
Injection site pain, fatigue, 
rigors, fever
Investigations
Asymptomatic transaminase 
increase
Severe elevation of 
transaminase
Blood and lymphatic system 
disorders
Neutropenia, lymphopenia, 
leucopenia, thrombocytopenia, 
anaemia
Psychiatric disorders
Depression, insomnia
Nervous system disorders
Headache
Gastrointestinal disorders 
Diarrhoea, vomiting, nausea
Skin and subcutaneous tissue 
disorders
Pruritus, rash, erythematous 
rash, macula-papular rash
Musculoskeletal and 
connective tissue disorders
Myalgia, arthralgia
Source:  Rebif Summary of Product Characteristics 2010.  Please refer to local label for more 
details.
ADRadverse drug reaction.
Severe liver injury, including some cases of hepatic failure requiring liver transplantation, 
has been reported rarely in participants taking Rebif.  Treatment with Rebif should be 
stopped immediately if jaundice or other symptoms of liver dysfunction appear 


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(Rebif E.U. Summary of Product Characteristics; Rebif U.S. Package Insert [USPI]).  
Please see Section 6.2.2 for further details.
Neutralizing antibodies to IFN -1a can develop in some participants, usually following 
the first year of therapy.  Long-term consequences of these antibodies are still not 
known; however, current evidence shows that they may reduce the efficacy of the drug.  
The antibodies tend to cross-react with different IFN formulations.  For this reason, 
switching to another IFN drug is unlikely to be effective (Lim and Constantinescu 2010; 
Polman et al. 2010).
2.2
RATIONALE FOR THE STUDY AND BENEFITRISK 
ASSESSMENT
This study is a pivotal Phase III clinical trial, and is composed of the following periods: 
a double-blind, double-dummy, treatment period, a safety follow-up period, and an 
OLE phase. The double-blind, double-dummy, treatment period is designed to 
demonstrate the efficacy and safety of ocrelizumab in RMS in comparison with
high-dose, high-frequency (HDHF) IFN (Rebif).  The OLE phase serves to evaluate the 
long-term safety, tolerability, and efficacy of ocrelizumab treatment in participants with 
relapsing forms of MS.
This study is part of a broader, confirmatory clinical development program investigating 
the safety and efficacy of ocrelizumab in participants with both RMS and PPMS.  
An OLE phase of the Phase II Study WA21493/ACT4422G is ongoing for eligible 
participants with RRMS.  There are 3 ongoing Phase III pivotal trials (including the one 
presented in this protocol), 2 trials in RMS and 1 trial in PPMS.  Please see
Section 4.1.6 for further details on study design and choice of comparator.
A benefitrisk assessment was conducted to determine whether there is any impact on 
the concomitant use of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
vaccines on the conduct of this study.  Based on this assessment, no impact is 
anticipated to affect the efficacy and safety in participants enrolled in ocrelizumab 
clinical trials.  Existing information on identified risks, safety monitoring, and risk 
mitigation measures related to administration of vaccines (including those for SARS-
CoV-2) provided in the study protocol (namely, immunization [Section 5.5.3], 
concomitant therapy [Section 5.5], and impaired response to vaccination 
[Section 7.3.1.1]) are considered adequate.
Data from the pivotal Phase III studies of ocrelizumab in RMS and PPMS show that 
preexisting humoral immunity to common viral and bacterial antigens is not affected 
by ocrelizumab treatment.  The vaccination study (BN29739, VELOCE) showed that 
participants with MS treated with ocrelizumab were able to mount a humoral immune 
response to non-live vaccines and new antigens.  The antibody immune response was 
considered protective, albeit with reduced levels of antibodies compared with controls.  
In this study, vaccines were given as early as 12 weeks after the first ocrelizumab 


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infusion (and as early as 10 weeks after the second ocrelizumab infusion of the first 
dose).  Boosters were given at least 4 weeks before the next dose of ocrelizumab.  
Other immune responses such as cellular responses were not investigated in the 
Study BN29739.
Roche is continually collecting evidence from clinical and biological sources to better 
understand immune response mechanisms of the SARS-CoV-2 vaccine in 
ocrelizumab -treated participants.
As with any other medication or vaccine, SARS-CoV-2 vaccines should be reported as 
concomitant medication by using the standard fields in the clinical database 
(see Section 5.5).
3.
OBJECTIVES
3.1
PRIMARY OBJECTIVE
The primary objective of this study is to assess whether the efficacy of ocrelizumab 
600 mg (given as dual IV infusions of 300 mg on Days 1 and 15 of the first 24-week 
treatment cycle and as a single infusion of 600 mg on Day 1 of each 24-week treatment 
cycle thereafter) every 24 weeks is superior to Rebif as measured by the 
protocol-defined ARR (see Section 5.10.2.1 for the definition of protocol-defined relapse) 
during nearly 2 years (96 weeks) in participants with RMS.
3.2
SECONDARY OBJECTIVES
The key secondary objectives of this study are to evaluate whether the efficacy of 
ocrelizumab is superior to that of Rebif, as reflected by the following measures:

The time to onset of confirmed disability progression for at least 12 weeks with the 
initial event of neurological worsening occurring during the 96-week, double-blind, 
double-dummy, treatment period (see Section 5.10.2.2 for the definition of 
confirmed disability progression)

The total number of T1 Gd-enhancing lesions as detected by brain MRI at 
Weeks 24, 48, and 96

The total number of new and/or enlarging T2 hyperintense lesions as detected by 
brain MRI at Weeks 24, 48, and 96

The proportion of participants who have confirmed disability improvement for at 
least 12 weeks with the initial event of neurological improvement occurring during 
the 96-week, double-blind, double-dummy, treatment period

The time to onset of confirmed disability progression for at least 24 weeks, with the 
initial event of neurological worsening occurring during the 96-week, double-blind, 
double-dummy, treatment period (see Section 5.10.2.2 for the definition of 
confirmed disability progression)

The total number of new T1hypointense lesions (chronic black holes) at Weeks 24, 
48, and 96


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
The change in Multiple Sclerosis Functional Composite Scale (MSFCS) score from 
baseline to Week 96

The percentage change in brain volume as detected by brain MRI from Week 2496

The change in Short Form-36 (SF-36) Health Survey Physical Component Summary 
(PCS) score from baseline to Week 96

The proportion of participants who have no evidence of disease activity (NEDA) by 
Week 96
3.2.1
Safety
To evaluate the safety and tolerability of IV ocrelizumab 600 mg (given as dual infusions 
of 300 mg on Days 1 and 15 of the first 24-week treatment cycle and as a single infusion 
of 600 mg on Day 1 of each 24-week treatment cycle thereafter) every 24 weeks in 
participants with RMS (including exploratory endpoints, long-term safety, and tolerability 
in those participants entering the OLE phase).
3.2.2
Pharmacokinetics/Pharmacodynamics
To explore the pharmacokinetics, immunogenicity, and pharmacodynamics of 
ocrelizumab in participants with RMS.
3.3
EXPLORATORY OBJECTIVES

The change in low-contrast visual acuity from baseline to Weeks 48 and 96

The change in the Symbol Digit Modalities Test (SDMT) from baseline to Weeks 48 
and 96

The proportion of relapse-free participants by Week 96

The change in total T2 hyperintense lesion volume as detected by brain MRI from 
baseline to Week 96

The ARR, based on all clinical relapses at the end of the 96-week comparative 
treatment period (protocol-defined relapses are a subset of all clinical relapses)

The ARR of relapses requiring IV steroid therapy

The ARR of severe relapses

The percentage change in brain volume as detected by brain MRI from baseline to 
Week 96

The change in MSFCS score from baseline to Week 48

The cumulative change in EDSS scores measured in area under the 
concentrationtime curve (AUC) by Week 96

The change in EDSS from baseline to Week 96

The change in Timed 25-Foot Walk Test (T25FWT) from baseline to Week 96

The change in 9-Hole Peg Test (9-HPT) from baseline to Week 96

The change in paced auditory serial addition test (PASAT) from baseline to 
Weeks 48 and 96


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
The time to onset of a sustained 20% increase in 9-HPT for at least 12 weeks

The time to onset of a sustained 20% increase in T25FWT for at least 12 weeks

The change in fatigue, as measured by the Modified Fatigue Impact Scale (MFIS) 
total score from baseline to Week 96

The change in participant-reported depressive symptoms, as measured by the 
Center for Epidemiologic Studies Depression Scale (CES-D), from baseline to 
Week 96

Analyses of EQ-5D, collected at baseline, Week 48, and Week 96

The change in Karnofsky Performance Status Scale score from baseline to Week 96

The percentage change in cortical grey-matter volume from baseline to Week 96

The percentage change in white matter volume from baseline to Week 96

The proportion of participants who have confirmed disability improvement sustained 
for at least 24 weeks, with the initial event of neurological improvement occurring 
during the 96-week, double-blind, double-dummy, treatment period

The proportion of participants who have disability improvement sustained for at least 
12 weeks and sustained until the end of the 96-week, double-blind, double-dummy 
treatment period, with the initial event of neurological improvement occurring during 
the 96-week, double-blind, double-dummy, treatment period

The duration of the confirmed disability improvement

The proportion of participants who, at Week 96, have improved, stable, or worsened 
disability, compared with baseline

The change in Quality of Life, as measured by the SF-36 version 2 
Mental Component Summary (MCS) score from baseline to Week 96

The long-term effects of ocrelizumab on clinical and MRI parameters of disease 
activity and progression during the OLE phase of the study

The long-term safety of ocrelizumab treatment during the OLE phase of the study

The effects of switching from Rebif to ocrelizumab treatment
3.4
RESEARCH BIOSAMPLE REPOSITORY OBJECTIVES
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).
Specimens stored in the RBR will be used to:

Study the association of biomarkers with efficacy and/ or adverse events associated 
with ocrelizumab

Increase the knowledge and the understanding of the biology of MS and mode of 
action of ocrelizumab


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Similarly, the RBR samples collected in the OLE phase of this study will be used for 
research into MS disease progression mechanisms, identification of new MS disease 
progression biomarkers, and the development of new therapeutic agents.  
See Section 5.12 for details on the RBR.
3.5
OPTIONAL EXPLORATORY SUBSTUDIES
Consenting participants who enrolled in the main Study WA21093 and who are eligible 
will be offered the opportunity to participate in optional substudies.  See Section 5.16 for 
details.
3.5.1
Optical Coherence Tomography Exploratory Substudy
This substudy will be conducted at certain selected centers and will be used to evaluate 
the neuroprotective effect of ocrelizumab as measured by retinal nerve fiber layer 
(RNFL) thickness and macular volume in both eyes (see Section 5.16.1 and 
Appendix 8).  In July 2017, Roche determined that sufficient data had been collected 
from the optical coherence tomography (OCT) substudy.  During 2017 and 2018, 
participants will discontinue participation in the OCT substudy but may continue in the 
OLE phase.
4.
STUDY DESIGN
4.1
OVERVIEW OF STUDY DESIGN AND DOSING REGIMEN
A schematic of the study design is presented in Figure 1.  The study will consist of the 
following periods.
4.1.1
Screening
Consenting participants will enter a screening period to be evaluated for eligibility.  
The screening period will last approximately 2 weeks, but it may be prolonged for up to 
8 weeks for relevant clinical, administrative, or operational reasons.  Procedures at 
screening will include collecting a medical history, medical examination including a 
thorough neurological exam, EDSS testing, ECG, and blood and urine sampling.  
Please see Table 1 for further details.
Please note that based on local Ethics Committees (ECs) or National Competent 
Authority requirements, additional diagnostic testing may be required for selected 
participants or selected centers to exclude tuberculosis (TB), Lyme disease, 
human T-lymphotropic virus type 1 (HTLV-1) associated myelopathy (HAM), AIDS, 
hereditary disorders, connective tissue disorders, or sarcoidosis.
4.1.2
Treatment Period
4.1.2.1
Double-Blind, Double-Dummy, Comparative Treatment Period
Eligible participants will be randomized via an interactive voice or web-based response 
system (IxRS) into 1 of 2 treatment groups: an ocrelizumab 600 mg regimen (Group A) 
or an IFN -1a (Group B) regimen. See Table 7 and Table 11 for more details.


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During the double-blind, double-dummy, comparative treatment period, participants will 
be assessed at clinical visits as per the schedule of activities (Table 1).
Before the next cycle of study drug, participants will be evaluated for pre-specified 
conditions and laboratory abnormalities to allow for re-treatment (see Section 6.1.4 for 
more details).
Participants who discontinue taking study medication within the 96-week, double-blind, 
double-dummy, comparative phase (treatment period) of the study will enter the safety 
follow-up period (see below); they will not be eligible for the OLE phase.
4.1.3
Open-Label Extension Phase Screening Period
Participants who complete the 96-week treatment period may become eligible for the 
OLE phase of the study. Participants will be consented for participation in the 
OLE phase if they may benefit from treatment with ocrelizumab.  Participants who are 
not willing to participate in the OLE phase of the study will be entered into the safety 
follow-up period (see below).  Participant treatment allocation during the double-blind, 
double-dummy, treatment period should not be unblinded regardless of participation in 
the OLE phase.
In the case of a participant who initially declines participation in the OLE phase and 
subsequently reconsiders the decision, the participant will have up to 24 weeks after the 
Week 96 visit to enter the OLE phase.  In this instance, he or she should not have taken 
any prohibited medication as specified in Section 5.5.2.1.  Participants who decline 
participation in the OLE phase should enter the safety follow-up period.
Participants who have consented to participate in the OLE phase will enter an 
OLE phase screening period to be evaluated for eligibility.  The OLE phase screening 
period will start after all assessments at the Week 96 visit have been performed.  
This screening period will last up to 4 weeks. The OLE phase screening period could be 
longer than 4 weeks.  If a prolongation of the OLE phase screening period is needed, it 
should be discussed with the Sponsor on a case-by-case basis.
Information from assessments performed during the Week 96 visit will be utilized to 
verify the eligibility of the participant for the OLE phase of the study.  See Section 5.4.
During the OLE phase screening period, all participants should receive 
Rebif/Rebif placebo (depending on initial arm they were assigned to) until the first 
infusion of Cycle 5.  See Table 7 and Table 11 for more details regarding the 
Rebif/Rebif placebo regimen.
Participants who withdraw from the OLE phase screening period will be entered into the
safety follow-up period (see below).


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4.1.4
Open-Label Extension Phase
Duration: the OLE phase will continue as per local regulation or should the Sponsor 
decide to terminate the ocrelizumab program for MS.  Unless terminated earlier for any 
of the reasons mentioned above, all participants may continue their treatment with 
open-label ocrelizumab as per the protocol until 31 December 2022.  All participants 
must discontinue open-label ocrelizumab treatment within this study before 
31 December 2022. However, participants will be offered continuation of ocrelizumab 
treatment or a safety follow-up period via a rollover study (MN43964, OLERO).
Participants who start treatment with commercial ocrelizumab or another DMT will 
discontinue from the study completely and will not enter the safety follow-up period.
Treatment: during the OLE phase, all participants will receive the ocrelizumab 600-mg 
dosing regimen every 24 weeks (see Table 6 and Section 5.17 for more details).
Withdrawal: participants who withdraw from the OLE phase will be entered into the 
safety follow-up period (see below).
4.1.5
Safety Follow-Up Period
Participants who discontinue treatment prematurely for any reason during the following 
periods will be entered into the safety follow-up period:

Before completion of the 96-week double-blind, double-dummy, treatment period

During the OLE phase screening period

During the OLE phase

Participants who choose not to enter the OLE phase or are not eligible for the 
OLE phase after completing the 96-week, double-blind, double-dummy, treatment 
period
In the OLE phase screening period, in the case of a participant who initially declines 
participation in the OLE phase and subsequently reconsiders the decision, the 
participant will have up to 24 weeks after the Week 96 visit to enter the OLE phase.  
In this instance, he or she should not have taken any prohibited medication as specified 
in Section 5.5.2.1.
The safety follow-up period will last for up to 48 weeks starting from the date of the last 
infusion of ocrelizumab/ocrelizumab placebo.  Safety follow-up visits will be performed at 
12-week intervals starting from the date of the participant’s last visit (the withdrawal from 
Treatment Visit).  Because this study will be closed on 31 December 2022, participants 
already in safety follow-up may complete this study period in the rollover 
Study MN43964.


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Participants who start treatment with commercial ocrelizumab or another DMT will 
discontinue participation in the study completely and will not enter or continue in the 
safety follow-up period.
During safety follow-up participants will be assessed at clinical visits every 12 weeks.  
Telephone interviews will be performed every 4 weeks.
Please see the schedule of activities (Table 2) for further details.
Table 5
Overview of Dosing Regimen in the Double-Blind, Double-Dummy,
Treatment Period
Study 
Medication
Double-Blind, Double-Dummy, Treatment Period a, b
1st Cycle c
(Weeks 124)
2nd Cycle c
(Weeks 
2448)
3rd Cycle c
(Weeks
4872)
4th Cycle c
(Weeks 
7296)
Day 1
Infusion
Day 15
Infusion
Week 24
Infusion
Week 48
Infusion
Week 72
Infusion
A
Ocrelizumab 
600 mg regimen
Ocrelizumab
300 mg IV
Ocrelizumab
600 mg IV
B
Rebif regimen d
Rebif SC
3 week

Please note:  100 mg of methylprednisolone IV will be administered in both treatment arms 
before each infusion of ocrelizumab/ocrelizumab placebo.
a The double-blind, double-dummy, treatment period consists of 96 weeks of treatment 
(4 treatment cycles).
b Each treatment cycle has a duration of 24 weeks.  The first cycle consists of two 300-mg 
ocrelizumab IV infusions separated by 14 days.  Cycles 24 consist of a single IV infusion of 
600 mg ocrelizumab.
c Before each infusion, a clinical evaluation will be performed to ensure that the participant 
remains eligible for treatment.
d See Table 11 for the detailed Rebif dosing regimen.


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Table 6
Overview of Dosing Regimen in the OLE Phase Screening Period 
and the OLE Phase
Study 
Medication
OLE Phase 
Screening 
Period
OLE Phase a
5th Cycle b, c
6th Cycle 
b, c
7th Cycle b, 
c
Nth 
Cycle 
bd
Day 1 
Infusion
Day 15 
Infusion
Ocrelizumab 
600-mg 
regimen
e
Ocrelizumab 300 mg 
IV
Ocrelizumab 600 mg IV
Rebif regimen
Rebif SC 
3 week f
g
OLEopen-label extension.
Please note:  100 mg of methylprednisolone IV and an oral or IV antihistamine (such as 
diphenhydramine 50 mg or an equivalent dose of an alternative) will be administered in both 
treatment arms before each infusion of ocrelizumab/ocrelizumab placebo.
a The OLE phase can terminate at any moment or cycle (see Section 4.1.9).
b The assessments requested for N represents the typical schedule of activities during a cycle.
c Before each infusion, a clinical evaluation will be performed to ensure that the participant 
remains eligible for treatment.
d Each treatment cycle has a duration of 24 weeks.  The first cycle of the OLE phase consists of 
two 300-mg ocrelizumab IV infusions separated by 14 days.  Cycle 6 onwards consists of a 
single IV infusion of 600 mg ocrelizumab.
e During the OLE phase screening period, ocrelizumab will not be administered.
f
See Table 11 for the detailed Rebif dosing regimen.
g During the OLE phase, Rebif verum or placebo will not be administered.
4.1.6
Rationale for Study Design
4.1.6.1
Rationale for the Use of an Active Comparator
The consensus in the MS research community is that the use of placebo in Phase III 
studies of participants with RMS is (except in exceptional circumstances) ethically 
indefensible because of the availability of established, effective therapies 
(Polman et al. 2008).
4.1.6.2
Rationale for Choice of Active Comparator
Interferon -1-a 44 g SC 3 weekly (Rebif) has been chosen as the active comparator 
for the ocrelizumab in RMS, Phase III clinical program based on its consistent evidence 
of efficacy in reducing MRI activity, relapses, and disability progression in participants 
with relapsing forms of MS (see Section 2.1.5).


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4.1.6.3
Rationale for Double-Blind, Double-Dummy Study Design
The use of a double-blind, double-dummy study design minimizes the potential for bias 
and safeguards the integrity of the clinical data generated from this study.  Although this 
approach increases the participant’s burden, this design reduces the risk of concluding 
that superiority to the active comparator was driven by participant and assessor bias.  
Regulatory agencies have mandated this study design be implemented throughout the 
Phase III clinical program.  For additional measures intended to minimize bias, please 
see below.
4.1.6.4
Rationale for Choice of Study Population
This study plans to enroll participants with RMS who have an EDSS score of 05.5 at 
screening and who have had 2 documented clinical attacks within the previous 2 years 
or 1 clinical attack that occurred within the last year before screening.  These criteria 
have been implemented to further characterize the benefits of treatment with 
ocrelizumab in a wide range of participants with RMS with varying degrees of disease 
activity and severity.
The age range will be limited to 55 years to avoid confounding by neurological 
conditions prevalent in older individuals, including but not limited to, microvascular 
disease.
Exclusion of participants in whom Rebif has failed or who cannot tolerate Rebif prevents 
these participants from being randomized to further Rebif therapy and reduces the 
potential for unbalanced dropout rates.  Additional exclusion criteria relating to 
concomitant diseases, laboratory parameters, and previous medications help to ensure 
participant safety in the study.  See Section 5.3 for more details.
4.1.6.5
Rationale for Study Endpoints
The proposed study endpoints are widely accepted as clinically relevant and have been 
used in numerous pivotal clinical trials in RMS.  The primary endpoint for the study will 
be ARR over 96 weeks based on protocol-defined relapses.  Key secondary endpoints 
will include the time to onset of confirmed disability progression, confirmed at scheduled 
clinic visits, for at least 12 weeks.  Confirmed disability progression at 24 weeks will also 
be examined.  Prevention of relapses as well as the prevention or delay of accumulation 
of sustained neurological disability are meaningful goals in the treatment of participants 
with MS.
4.1.6.6
Rationale for the Duration of the Double-Blind, Double-Dummy
Treatment Period
The 96-week, double-blind, double-dummy treatment duration has been chosen to allow 
for the assessment of clinical efficacy and safety over 2 years of treatment, consistent 
with current regulatory guidelines.


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4.1.6.7
Rationale for the Open-Label Extension Phase
Multiple sclerosis is a chronic disease that requires lifelong treatment to reduce the 
frequency of relapse and accumulation of disability.  Once a participant is diagnosed 
with definite MS, accepted treatment guidelines propose that he/she be offered lifelong 
treatment because no evidence suggests that MS spontaneously remits
(Rio et al. 2011).
Results of long-term, follow-up, exploratory studies suggest that exposure to DMT for 
more than 2 years improves outcomes by delaying the time to disability progression.  
Furthermore, accumulating evidence indicates that, in MS, inflammatory damage is a 
continuous process leading to demyelination and axonal transection and is the substrate 
of permanent disability in MS (Trapp et al. 1998; Lindberg et al. 2004; Freedman 2011).
Based on the long-term efficacy and safety data in Phase II Study WA21493/ACT4422G 
(for details, please see Section 2.1.4.1), it is justified to offer ocrelizumab to participants 
who would otherwise receive treatment that, in most cases, is modestly effective in 
reducing the frequency of relapses and in preventing sustained disability 
(Scalfari et al. 2010; Kappos et al. 2012).
Thus, participants who complete the 96-week, double-blind, double-dummy, treatment 
period will be offered the option to participate in an OLE phase of the study.  
Providing participants with the opportunity to prolong treatment with ocrelizumab beyond 
2 years will provide more information on the long-term safety of ocrelizumab in RMS 
(e.g., the risk of infections/serious infections/opportunistic infections or potential loss of 
previously acquired immunity [e.g., hypogammaglobulinemia, specific serological titers]), 
as well as allow further collection of tolerability and efficacy information from participants 
with long-term exposure.  Furthermore, the OLE phase will increase the overall number 
of participants exposed and participant-year exposure, thus increasing the likelihood of 
detecting rare events and the understanding of the safety/efficacy profile.  Analyzing the 
long-term safety, tolerability, and efficacy of ocrelizumab is of critical importance to 
eventually help clinicians make informed decisions on therapy for participants 
(Day and Williams 2007).
4.1.6.8
Rationale for the Safety Follow-Up Period
Data collected during this period will allow for evaluation of B-cell repletion after stopping 
anti-CD20 treatment and allow collection of safety and efficacy data to document 
maintenance of the effect and/or the potential for a withdrawal effect.
4.1.6.9
Rationale for the Use of Methylprednisolone and 
Antihistamines
To reduce the frequency and severity of IRRs, participants will be pre-medicated with 
100 mg methylprednisolone IV and an oral or IV antihistamine (such as 
diphenhydramine 50 mg or an equivalent dose of an alternative).  
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the start of each ocrelizumab infusion; antihistamines should be administered 
3060 minutes before the start of an infusion.  A recent integrated analysis of 
participants with MS treated with ocrelizumab revealed that the addition of 
antihistamines to the pre-treatment with methylprednisolone decreased the incidence of 
IRRs by 2-fold (OCREVUS USPI).
To mitigate the risk that even a low dose of methylprednisolone may have a small effect 
on the efficacy outcomes of the study, methylprednisolone will be administered to 
participants. It is of note that the dose of methylprednisolone used for premedication will 
be up to 50smaller than that used for the symptomatic treatment of relapses in MS.  
In the event that methylprednisolone is contraindicated for the participant, an equivalent 
dose of an alternative steroid (e.g., dexamethasone) should be used as premedication 
before the infusion.
4.1.6.10
Additional Measures to Mitigate Bias
The use of HDHF IFN as the active comparator for this study during the double-blind, 
double-dummy treatment period presents some difficulties for maintaining participant
and physician blinding. See Section 2.1.5.
To prevent potential unblinding of the assigned arm in the double-blind, double-dummy,
treatment period as a result of adverse events or changes to laboratory results, the 
following, additional measures have been implemented:

The Examining Investigator/EDSS assessor will perform the neurological 
examination, document the Kurtzke Functional Systems (KFS) scores, and assess 
EDSS scores.  During the double-blind, double-dummy, treatment period, the 
Examining Investigator/EDSS assessor and their qualified designees (if applicable) 
will not be involved with any aspect of medical management of the participant and 
will not have access to participant data.  Every effort will be made to ensure that no 
change is made in the Examining Investigator/EDSS assessor throughout the 
course of the study for any individual participant.  The Examining Investigator/EDSS 
assessors will be trained and instructed not to discuss what adverse effects (if any) 
the participant is experiencing from their medication.  The Examining 
Investigator/EDSS assessors will receive training in performing EDSS assessments 
before the beginning of the study and must have successfully passed an 
examination on performance of the Neurostatus EDSS examination within 
24 months of participation.  All Examining Investigator/EDSS assessors will receive 
ongoing training on performance of the Neurostatus EDSS examination throughout 
the course of the study.

Participant education:  during the double-blind, double-dummy treatment period,
before being examined by the Examining Investigator/EDSS assessor, participants 
will be instructed not to discuss what (if any) adverse effects they may be 
experiencing.  Treating physicians and/or study coordinators should remind 
participants of these instructions before EDSS assessments, and this should be 
documented in the source documents.


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
Blinded, central MRI assessments:  during the double-blind, double-dummy,
treatment period, a blinded, central, MRI reader will assess all MRI scans done 
during the study.  These assessments will provide independent confirmation of the 
relative changes in immune-mediated, CNS damage.

Blinding of laboratory parameters: laboratory parameters that may lead to 
unblinding to treatment assignment, such as fluorescence-activated cell sorting 
(FACS) cell counts including CD19cells, lymphocyte count, IgM and IgG levels, 
and type I IFN neutralizing antibody levels, will be blinded for all participants, except 
those meeting unblinding criteria for safety reasons.  These laboratory parameters 
will remain blinded during the double-blind, double-dummy treatment period, safety 
follow-up period, the OLE phase screening period, and during the first cycle of the 
OLE phase (Cycle 5).
4.1.7
Rationale for Dose Selection
The dose for the ocrelizumab Phase III clinical program was chosen to bring the 
community with MS significant improvement in clinical efficacy versus that for the current 
standard of care, with acceptable safety.  The dose of ocrelizumab in the Phase III 
clinical program is 600 mg ocrelizumab every 24 weeks (administered as dual infusions 
of ocrelizumab 300 mg on Days 1 and 15 of the first 24-week treatment cycle, and 
600 mg on Day 1 of each 24-week treatment cycle thereafter).  This dose has been 
established as the lowest, maximally effective dose based on the results from
Study WA21493/ACT4422g.  The safety of this dose has substantial support from the 
Phase III clinical program in rheumatoid arthritis (RA), an analogous, although systemic 
autoimmune disease, in a population at greater risk.
Study ACT2847g was a Phase I/II, dose escalation study in participants with RA that 
examined 5 dosing regimens.  In Study ACT2847g, the 2 lowest dose groups 
(receiving less than 200 mg2) demonstrated reduced clinical benefits on some 
endpoints, earlier return of peripheral B cell counts, and higher rates of immunogenicity.  
In the RA Phase III program, with the exception of participants recruited from Asia, the 
dose of 200 mg2 established a safety profile comparable with that for placebo.  
The higher dose of 500 mg2 demonstrated apparently superior efficacy, especially in 
its effects on “high-hurdle” clinical endpoints and joint preservation, based on X-ray
imaging.
In the population with MS (Study WA21493/ACT4422g), 2 doses of ocrelizumab were 
studied, 2000 mg (administered as dual 1000 mg infusions on Days 1 and 15 of the first, 
24-week treatment cycle) and 600 mg (administered as dual 300 mg infusions on Days 1 
and 15 of the first treatment cycle).  Pre-specified primary and secondary efficacy 
analyses for Study WA21493/ACT4422g indicated that 300 mg2 of ocrelizumab is 
highly effective in suppressing MRI lesion activity and reducing the risk of clinical
relapses in participants with RRMS over 24 weeks.  No difference in efficacy was seen 
between the ocrelizumab 1000 mg2 and 300 mg2 doses in terms of either MRI or 
clinical endpoints in the intent-to-treat (ITT) study population.  However, exploratory 


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analyses stratifying groups according to baseline MRI activity suggest superior efficacy 
with 1000 mg2 versus 300 mg2 at 24 weeks in participants with MRI activity at 
baseline (4 enhancing lesions).  Similarly, in these participants, the 1000 mg2 dose 
was apparently more effective than the 300 mg2 dose at Week 24 and (to a lesser 
extent) at Week 48 in reducing the absolute number of clinical relapses.  Neither the MRI 
nor the clinical efficacy differences are statistically significant; however, these results 
suggest reduction of clinical efficacy at lower doses in participants with active MS.  
This apparent dose effect was seen even though linear kinetics (so that complete 
receptor occupancy can reasonably be assumed) and near-complete peripheral 
CD19 suppression were observed for both doses.  Nonclinical studies in primates have 
shown differential susceptibility of tissue resident versus circulating B cell populations in 
response to anti-CD20 antibodies (Gong et al. 2005; Ahuja et al. 2007; Kap et al. 2010).  
Because tissue resident B cell populations are beyond our ability to measure directly, 
peripheral CD19 count is likely to be a sensitive but non-specific PD marker for 
anti-CD20 efficacy.
4.1.7.1
Conclusion
Based on available data, the dose of 600 mg of ocrelizumab IV (given as dual infusions 
of 300 mg 14 days apart for the first 24 weeks and a single infusion of 600 mg 
every 24 weeks thereafter) is the most likely the dose that is able to demonstrate robust 
clinical efficacy, an acceptable safety profile, and a low risk of immunogenicity, thereby 
maximizing the likelihood of significant benefit versus that for standard of care in 
participants with RMS.
4.1.8
End of Double-Blind, Double-Dummy, Treatment Period of 
the Study
The end of the double-blind, double-dummy, treatment period of the study is defined as 
the date at which the last data point during double-blind, double-dummy treatment from 
the last participant is received, as required for statistical analysis defined in the 
Statistical Analysis Plan (SAP).
To maintain the integrity of the study data, all study sites and all EDSS assessors will 
remain blinded to participant treatment allocation until approximately 24 weeks after the 
Week 96 visit of the last participant randomized to allow the confirmation of the last 
24-week confirmed disability progression event (see Section 8.2).
4.1.9
End of Study
The end of study is now defined as 31 December 2022 or up until the approval of 
Study MN43964 (OLERO).
Irrespectively, the Sponsor may decide to terminate the study at any time.
The Sponsor has decided to provide the opportunity to all participants to rollover and 
continue their treatment and/or safety follow-up under the new extension protocol.


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4.2
NUMBER OF PARTICIPANTS/ASSIGNMENT TO TREATMENT 
GROUPS
Approximately 800 participants (400 per treatment arm) will be recruited over a planned 
recruitment period of 16 months.
Participants will be randomized in 2 groups in a 1:1 ratio.  An independent IxRS provider 
will conduct randomization and hold the treatment assignment code.  Participants will be 
stratified by region (United States vs. Rest of World [ROW]) and baseline EDSS 
(4 and 4).
4.3
CENTERS
This will be a multicenter, international study.  It is anticipated that approximately 
220 centers worldwide will participate.
5.
STUDY POPULATION
Under no circumstances are participants who enroll in this study permitted to be 
re-randomized to this study and enrolled for a second course of treatment.
5.1
OVERVIEW
Adult participants with RMS who fulfill the eligibility criteria specified in Sections 5.2
and 5.3 are eligible for enrollment in the study.  For the eligibility criteria for the OLE 
phase, please see Section 5.4.
5.1.1
Recruitment Procedures
Sites are encouraged to identify participants for potential recruitment with use of 
pre-screening enrollment logs or a pre-identification website.
Participants who are candidates for enrollment into the study will be evaluated for 
eligibility by the investigator to ensure they fulfill eligibility criteria (see Sections 5.2
and 5.3).
All participants must sign the Informed Consent Form before screening and before any 
changes to their existing medication for the purposes of enrollment in the trial.
No participant may begin treatment prior to randomization and assignment of a 
medication number.  Under no circumstances are participants who enroll in this study 
permitted to be re-randomized to this study.
The investigators will be notified by the Sponsor if the study is placed on clinical hold 
and when the study is completed or closed to further participant enrollment.
No replacement for participants who withdraw from the study after randomization is 
planned.


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5.2
INCLUSION CRITERIA
Participants must meet the following criteria for study entry:

Ability to provide written, informed consent and be able to follow the schedule of 
protocol assessments
Participants who are unable to complete exploratory assessments 
(e.g., electronic participant-reported outcomes [ePROs]) because of 
physical/disease limitations will not be excluded from the study.

Age 1855 years, inclusive, at screening

Diagnosis of MS, in accordance with the revised McDonald criteria
(Polman et al. 2011)

At least 2 documented clinical attacks within the last 2 years before screening, or 
1 clinical attack in the year before screening (but not within 30 days before 
screening)

Neurological stability for 30 days before both screening and baseline

EDSS score from 05.5, inclusive, at screening

Documented MRI of brain with abnormalities consistent with MS before screening

Participants of reproductive potential must use reliable means of contraception as 
described below as a minimum (adherence to local requirements, if more stringent, 
is required):
–
For female participants:  2 methods of contraception throughout the trial, 
including the active treatment phase AND for 48 weeks after the last dose of 
ocrelizumab, or until their B cells have repleted, whichever is longer
–
For male participants:  2 methods of contraception throughout the trial, 
including the active treatment phase AND for 24 weeks after the last dose of 
ocrelizumab.  Acceptable methods of contraception include 1 primary 
(e.g., systemic hormonal contraception or tubal ligation of the female partner, 
vasectomy of the male partner) AND 1 secondary barrier method 
(e.g., latex condoms, spermicide) OR a double-barrier method 
(e.g., latex condom, intrauterine device, vaginal ring or pessary plus spermicide 
[e.g., foam, vaginal suppository, gel, cream]).
Based on local ECs or National Competent Authority feedback, additional 
requirements to assure contraception or to confirm menopause may be 
required (e.g., serum estradiol compatible with post-menopause status, longer 
duration of amenorrhea, higher level of follicle-stimulating hormone [FSH]).

For participants of non-reproductive potential (adherence to local requirements, if 
more stringent, is required):
–
Women may be enrolled if postmenopausal (i.e., spontaneous amenorrhea for 
12 months confirmed by a FSH level 40 mIU/mL, unless the participant is 
receiving a hormonal therapy for menopause or is surgically sterile 
(i.e., hysterectomy, complete bilateral oophorectomy)


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–
Men may be enrolled if they are surgically sterile (have been castrated)
5.3
EXCLUSION CRITERIA
Participants who meet the following criteria must be excluded from study entry:

Diagnosis of PPMS

Disease duration of more than 10 years in participants with an EDSS2.0 at 
screening

Inability to complete an MRI (contraindications for MRI include but are not restricted 
to weight 140 kg, pacemaker, cochlear implants, presence of foreign substances 
in the eye, intracranial vascular clips, surgery within 6 weeks of entry into the study, 
coronary stent implanted within 8 weeks before the time of the intended MRI, etc.)
–
Participants with contraindication to Gd can be enrolled in the study but cannot 
receive Gd contrast dyes during MRI scans.

Known presence of other neurological disorders that may mimic MS, including but 
not limited to, neuromyelitis optica, Lyme disease, untreated vitamin B12 deficiency, 
neurosarcoidosis, and cerebrovascular disorders
5.3.1
Exclusions Related to General Health

Pregnancy or lactation

Any concomitant disease that may require chronic treatment with systemic 
corticosteroids or immunosuppressants during the course of the study

History or currently active primary or secondary immunodeficiency

Lack of peripheral venous access

History of severe allergic or anaphylactic reactions to humanized or murine 
monoclonal antibodies

Significant or uncontrolled somatic disease or any other significant disease that may 
preclude participation in the study

Congestive heart failure (New York Heart Association III or IV functional severity)

Known active bacterial, viral, fungal, or mycobacterial infection or other infection, 
excluding fungal infection of nail beds

Infection requiring hospitalization or treatment with IV antibiotics within 4 weeks 
before baseline visit or oral antibiotics within 2 weeks before baseline visit

History or known presence of recurrent or chronic infection (e.g., HIV, syphilis, TB)
Please note: in Germany the following additional exclusion criteria apply:
–
Positive anti-HIV I at screening
–
Positive anti-HIV II at screening
–
Positive QuantiFERON-TB Gold test at screening
Participants in Germany with an indeterminate result are not eligible for the study 
unless additional testing demonstrating a negative result is provided.  Thus, these 


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participants should have either a tuberculin skin test or have the QuantiFERON-TB 
Gold test repeated before enrollment into the study.  If a tuberculin skin test is 
performed, an induration of 6 mm is a positive result for a participant with history of 
having received Bacille Calmette-Guérin (BCG) vaccine, whereas an induration of 
10 mm is a positive result for a participant without a history of having received 
BCG vaccine.
If necessary, a QuantiFERON-TB Gold test might be complemented by additional 
specific diagnostic tests according to standard procedures in Germany.

History of PML

History of malignancy, including solid tumors and hematological malignancies, 
except basal cell carcinoma, in situ squamous cell carcinoma of the skin, and in situ 
carcinoma of the cervix of the uterus that have been previously completely excised 
with documented, clear margins

History of alcohol or drug abuse within 24 weeks prior to baseline

History or laboratory evidence of coagulation disorders
5.3.2
Exclusions Related to Medications
Participants screened for this study should not be withdrawn from therapies for the sole 
purpose of becoming eligible for the trial.  Participants who discontinue their current 
therapy for non-medical reasons should specifically be informed of their treatment 
options before deciding to enter the study.
Exclusion related to medications include the following:

Receipt of a live vaccine within 6 weeks before the baseline visit
In rare cases when a participant requires vaccination with a live vaccine, the 
screening period may be extended but cannot exceed 8 weeks.

Treatment with any investigational agent within 24 weeks of screening (Visit 1) or 
5 half-lives of the investigational drug (whichever is longer; or treatment with any 
experimental procedures for MS [e.g., treatment for chronic cerebrospinal venous 
insufficiency])

Contraindications to or intolerance of oral or IV corticosteroids, according to the 
country label, including:
–
Psychosis not yet controlled by a treatment
–
Hypersensitivity to any of the constituents

Contraindication to Rebif or incompatibility with Rebif use, including:
–
Current severe depression and/or suicidal ideation
–
Hypersensitivity to natural or recombinant IFN-, or to any excipients
–
Previous suboptimal response to HDHF IFN or cessation of HDHF IFN therapy 
due to poor tolerability
–
Prior cessation of Rebif® therapy due to toxicity, which is likely to recur


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
Treatment with dalfamipridine (Ampyra®) unless receiving a stable dose for
30 days before screening.  Whenever possible, participants should continue to 
receive stable doses throughout the 96-week treatment period.

Previous treatment with B-cell targeted therapies (i.e., rituximab, ocrelizumab, 
atacicept, belimumab, or ofatumumab)

Systemic corticosteroid therapy within 4 weeks prior to screening
The screening period may be extended (but cannot exceed 8 weeks) for participants 
who have used systemic corticosteroids for MS before screening.  For a participant
to be eligible, systemic corticosteroids should not have been administered also 
between screening and baseline.

Any previous treatment with Campath(alemtuzumab), anti-CD4, cladribine, 
mitoxantrone, daclizumab, teriflunomide, laquinimod, total body irradiation, or bone 
marrow transplantation

Treatment with cyclophosphamide, azathioprine, mycophenolate mofetil, 
cyclosporine, MTX, or natalizumab within 24 months before screening.
Note:  Participants previously treated with natalizumab will be eligible for this study 
only if the duration of treatment with natalizumab was 1 year.

Treatment with fingolimod or other S1P receptor modulator (i.e., BAF312) or with 
BG12 within 24 weeks before screening
Note: Only participants with T lymphocyte count LLN will be eligible for this study.

Treatment with immunoglobulin IV within 12 weeks prior to baseline
5.3.3
Exclusions Related to Laboratory Findings
Retesting before baseline:  in rare cases in which the screening laboratory samples are 
rejected by the central laboratory (i.e., because of a hemolyzed sample) or the results 
are not assessable (i.e., indeterminate) or abnormal, the tests need to be repeated 
within 4 weeks.  Any abnormal screening laboratory value that is clinically relevant 
should be retested to rule out any progressive or uncontrolled underlying condition.  
The last value before randomization must meet study criteria.  In such circumstances, 
the screening period may need to be prolonged but should not exceed 8 weeks.
Exclusions related to laboratory findings include the following:

Positive serum -human chorionic gonadotropin (hCG) measured at screening

Positive screening tests for hepatitis B (hepatitis B surface antigen [HBsAg] positive, 
or total positive hepatitis B core antibody [HBcAb] confirmed by a positive viral DNA 
polymerase chain reaction [PCR]) or hepatitis C (HepCAb)

Positive rapid plasma reagin (RPR)

CD4 count 300/L

AST/SGOT or ALT/SGPT 2.0ULN

Platelet count 100,000/L (100109/L)


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
Levels of serum IgG 18% below the LLN (for central laboratory IgG 4.6 g/L)

Levels of serum IgM 8% below the LLN (for central laboratory IgM 0.37 g/L)

Total neutrophil count 1.5103/L
Please note: based on local ECs or National Competent Authority requirements, 
additional diagnostic testing may be required for selected participants or selected 
centers to exclude TB, Lyme disease, HAM, AIDS, hereditary disorders, connective 
tissue disorders, or sarcoidosis.  Other specific diagnostic tests may be requested when 
deemed necessary by the investigator.
5.4
ELIGIBILITY CRITERIA FOR OPEN-LABEL EXTENSION PHASE
Participants who meet the following entry criteria may participate in the OLE phase:

Completed the 96-week, double-blind, double-dummy, treatment period, and who, in 
the opinion of the investigator, may benefit from treatment with ocrelizumab

Are able and willing to provide written informed consent for the OLE phase 
(e.g., before the first infusion at Cycle 5) and to comply with the study protocol

Be willing to comply with the following contraception requirements:
–
Female participants who are of reproductive potential and sexually active must 
continue use of a reliable means of contraception as described below as a 
minimum (adherence to local requirements, if more stringent, is required)
One primary method of contraception is to be used throughout the 
OLE phase and 6 months after the last dose of ocrelizumab.
Acceptable methods of contraception include 1 primary 
(e.g., systemic hormonal contraception or tubal ligation, vasectomy of the 
male partner) OR a double-barrier method (e.g., latex condom, intrauterine 
device, vaginal ring or pessary plus spermicide [e.g., foam, vaginal 
suppository, gel, cream]).

For participants without reproductive potential
–
Women may be enrolled if postmenopausal (i.e., have had spontaneous 
amenorrhea for the last year confirmed by an FSH level 40 mIU/mL), unless 
the participant is receiving a hormonal therapy for her menopause or is 
surgically sterile (i.e., have had a hysterectomy and/or a complete bilateral 
oophorectomy)

Meet re-treatment criteria with ocrelizumab (see Section 6.1.4)
5.5
CONCOMITANT MEDICATION AND TREATMENT
5.5.1
Definition of Concomitant Treatment
A concomitant medication is any drug or substance taken during the study, including the 
screening period.  Over-the-counter medications and preventative vaccines received 
during the study are considered concomitant medications.


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A concomitant procedure is any therapeutic or elective intervention (e.g., surgery, 
biopsy) or diagnostic evaluation (e.g., blood gas measurements, bacterial cultures) 
performed during the study, including the screening period.
Concomitant medications and procedures will be reported at each visit in the relevant 
form of electronic Case Report Forms (eCRFs) starting from the baseline visit 
(including medication and procedures taken between screening and baseline).  
Medications taken for the treatment of MS in the 2-year period before the baseline visit 
and medications taken for the symptoms of MS in the 3-month period before the 
baseline visit will be recorded at the baseline visit.  Additionally, medications and 
medical/surgical procedures administered for any non-MS condition within 12 months 
before the baseline visit will also be recorded at the baseline visit.
5.5.2
Treatment for Symptoms of Multiple Sclerosis
The Treating Investigator should attempt to maintain therapies or treatments for 
symptoms related to MS (e.g., walking ability, spasticity, incontinence, pain, fatigue) 
reasonably constant throughout the study.  During the OLE phase of the study, initiation 
of therapy with Ampyra® (dalfampridine) is allowed, if indicated by the treating physician.
Treatment of relapses: participants who experience a relapse during the double-blind, 
double-dummy, treatment period, OLE phase screening period, or the OLE phase may 
receive treatment with oral or IV corticosteroids, if judged to be clinically appropriate by 
the investigator.  The following standardized treatment regimen may be used as 
warranted: 1 g methylprednisolone IV per day for a maximum of 5 consecutive days.  
In addition, at the discretion of the investigator, corticosteroids may be stopped abruptly 
or tapered over a maximum of 10 days.  Such participants should not discontinue the 
treatment period solely based on the occurrence of a relapse, unless the participant or 
investigator feels he or she has met the criteria for withdrawal (see Section 5.6 for 
further details).
5.5.2.1
Prohibited Concomitant Treatments for MS
Therapies for MS noted in the exclusion criteria under “Exclusions Related to 
Medications” (Section 5.3) are not permitted during the double-blind, double-dummy,
treatment period, the OLE phase screening period, or the OLE phase with the exception 
of systemic corticosteroids for the treatment of a relapse; IV Ig is also permitted.  
For participants who withdraw from treatment with ocrelizumab and enter safety 
follow-up, alternative treatments for MS judged clinically appropriate by the 
Treating Investigator are allowed. However, because sufficient data are not available to 
inform risks associated with switching to other products, the following recommendations 
are given:

Caution is advised while participants remain B-cell depleted

Because of the unknown safety risk of administering DMTs for MS after 
discontinuation of ocrelizumab, certain treatments for MS such as 


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lymphocyte-depleting agents or lymphocyte-trafficking blockers 
(e.g., alemtuzumab, natalizumab, fingolimod, dimethyl fumarate, cyclophosphamide, 
azathioprine, etc.) are strongly discouraged for as long as the participant remains 
B-cell depleted because of unknown effects on the immune system 
(e.g., increased risk, incidence, or severity of infection)
Participants who start treatment with commercial ocrelizumab or another DMT will 
discontinue participation in the study completely and will not enter or continue in the
safety follow-up period.
5.5.3
Immunization
Roche has completed a randomized, open-label vaccination study in 
ocrelizumab-treated participants with RMS (Study BN29739).  The results of this study 
indicate that participants being treated with ocrelizumab may have an attenuated 
humoral response when immunized with an inactivated vaccine.  The detailed 
Study BN29739 results can be found in the current version of the IB.
A recent integrated analysis of participants with MS treated with ocrelizumab revealed 
that after treatment with ocrelizumab over 2 years, the proportion of participants with 
positive antibody titers against Streptococcus pneumoniae, mumps, rubella, and 
varicella was generally similar to the proportion at baseline.
Physicians are advised to review the immunization status of participants being 
considered for treatment with ocrelizumab and follow local/national guidance for adult 
vaccination against infectious disease.  Known dates of immunizations will be recorded 
on specific eCRF pages.  Immunizations should be completed at least 6 weeks 
before the first administration of ocrelizumab.
Participants requiring de novo hepatitis B vaccination (which involves 3 separate doses 
of vaccine) should also have completed the course at least 6 weeks before the first 
infusion of study drug.
The safety of immunization with live viral vaccines after ocrelizumab or rituximab therapy 
has not been studied.  Immunization with any live or live-attenuated vaccine 
(i.e., measles, mumps, rubella, oral polio vaccine, BCG, typhoid, yellow fever, vaccinia, 
cold adapted live influenza strain vaccine, or any other vaccines not yet licensed but 
belonging to this category) is not recommended within 6 weeks before the first dosing 
(see exclusion criteria, Section 5.3), during ocrelizumab treatment, and for as long as the 
participant is B-cell depleted.
For details regarding vaccinations during ocrelizumab treatment, please see the current 
version of the Ocrelizumab IB.


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5.6
CRITERIA FOR PREMATURE WITHDRAWAL
Participants have the right to withdraw from the study at any time for any reason.
Participants must be withdrawn from treatment (regardless of whether they are in 
the double-blind, double-dummy, treatment period or in the OLE phase) under the 
following circumstances:

Life-threatening (Common Terminology Criteria for Adverse Events [CTCAE] 
Grade 4) infusion-related event that occurred during a previous ocrelizumab infusion

Participants who demonstrate active hepatitis B or C infection, either new onset or 
reactivation in the case of hepatitis B

Participants with PML

Participants with elevation in level of ALT10ULN, jaundice, or other clinical 
symptoms of liver dysfunction (please see Section 6.2.2 for more details)
Only applicable during the double-blind, double-dummy, treatment period

Participants with persisting elevation of ALT3ULN, or other clinical symptoms of 
liver dysfunction that did not resolve with Rebif/Rebif placebo dose modification 
(please see Section 6.2.2 for more details)
Only applicable during the double-blind, double-dummy treatment period

Participants who decide to discontinue the treatment

The participant’s Treating Investigator decides that discontinuation of treatment is in 
the best clinical interest of the participant
Participants who withdraw during the double-blind, double-dummy, treatment period, 
OLE phase screening period, or the OLE phase, for any reason, should complete the 
safety follow-up period.  If the participant insists on discontinuing participation in the 
study, he/she should be asked if he/she can still be contacted for further information.  
The outcome of that discussion should be documented in both the medical records and 
in the eCRF.  If lost to follow-up, the investigator should contact the participant or a 
responsible relative by telephone followed by registered mail or through a personal visit 
to establish as completely as possible the reason for the withdrawal.  A complete final 
evaluation at the time of the participant’s withdrawal should be made with an explanation 
of why the participant is withdrawing from the study.
When applicable, participants should be informed of circumstances under which their 
participation may be terminated by the investigator without the participant’s consent.  
The investigator may withdraw participants from the study in the event of intercurrent 
illness, adverse events, treatment failure, after a prescribed procedure, for lack of 
compliance with the study and/or study procedures (e.g., dosing instructions, study 
visits), because of a cure, or for any reason that leads the investigator to conclude that it 
is in the best interest of the participant to be terminated from the study.  
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to the participant.  If the reason for removal of a participant from the study is an adverse 
event, the principal specific event will be recorded on the eCRF.  If possible, the
participant should be followed up until the adverse event has resolved.
An excessive rate of withdrawals can render the study non-interpretable; therefore, 
unnecessary withdrawal of participants should be avoided.  Should a participant decide 
to withdraw, all efforts will be made to complete and report the observations before 
withdrawal as thoroughly as possible.
Please note: It is important to distinguish between “withdrawal from treatment” and 
“withdrawal from study”.  Participants who withdraw from treatment should be 
encouraged to remain in the study for the full duration of the safety follow-up period 
(48 weeks following the last infusion).
Participants who start commercial ocrelizumab or another DMT will discontinue 
participation in the study completely and will not enter or continue in the safety follow-up 
period.
It should be noted that upon withdrawal from the study, any untested routine samples 
will be destroyed.  However, information already obtained from samples until the time of 
withdrawal will be used.
5.6.1
Withdrawal of Participants from the Roche Clinical Repository
Participants who gave consent to provide Roche Clinical Repository (RCR) specimens 
have the right to withdraw their specimen from the RCR at any time for any reason.  If a 
participant wishes to withdraw his/her consent to the testing of his/her specimen(s), the 
investigator must inform Roche in writing of the participant’s wishes by with use of the 
RCR Participant Withdrawal Form and enter the date of withdrawal in the participant’s 
eCRF.  A participant’s withdrawal from the main trial does not, by itself, constitute 
withdrawal of the specimen from the RCR; likewise, a participant’s withdrawal from the 
RCR does not constitute a withdrawal from the main trial (see Section 5.12).
5.6.2
Withdrawal from the Research Biosample Repository
Participants who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason (see Section 5.12).
5.6.3
Patient Agreement for Continuation in the Study (in Case of 
Confirmed Disability Progression)
During the double-blind treatment period, in the event of confirmed disability progression 
on EDSS confirmed for 24 weeks, the benefits and risks of study treatment should be 
reassessed with the participant prior to any further dosing, including a discussion of 
alternative treatment options available for that participant.  The result of this discussion 
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If after the discussion, the participant decides not to continue with the study treatment, 
they should be discontinued from any further treatment, complete applicable Withdrawal 
from Treatment Visit procedures and be entered into the safety follow-up period.  
For definition of confirmed disability progression, please see Section 5.10.2.2.
5.7
REPLACEMENT POLICY (ENSURING ADEQUATE NUMBERS
OF EVALUABLE SUBJECTS)
5.7.1
For Participants
Participants prematurely discontinued from the study for any reason will not be replaced.
5.7.2
For Centers
A center may be replaced for the following administrative reasons:

Excessively slow recruitment

Poor protocol adherence

Sponsor’s discretion (Sponsor refers to F. Hoffmann-La Roche, Ltd and 
Genentech, Inc.)
5.8
SCREENING EXAMINATION AND ELIGIBILITY SCREENING 
FORM
All participants must sign and date the most current IRB/EC-approved written informed 
consent before any study specific assessments or procedures are performed.
Consenting participants will enter the 2-week screening period to be evaluated for 
eligibility (Table 1).  Participants must fulfill all entry criteria for participation in the study.
The screening period can be extended to a total period of 8 weeks in cases when a 
laboratory blood test or MRI scan needs to be repeated for confirmation during the 
screening interval, or for other relevant clinical, administrative, or operational reasons.
Please note that based on local ECs or National Competent Authority requirements, 
additional diagnostic testing may be required for selected participants or selected 
centers to exclude tuberculosis, Lyme disease, HAM, AIDS, hereditary disorders, 
connective tissue disorders, or sarcoidosis.
An Eligibility Screening Form (ESF) documenting the investigator’s assessment of each 
screened participant with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the investigator.
Each participant screened must be registered in the IxRS by the investigator or the 
investigator’s research staff at screening.  A screen failure record must be maintained by 
the investigator, and reasons must be captured in the IxRS.
It should be stated in the medical record that the participant is participating in this 
clinical study.


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5.9
PROCEDURES FOR ENROLLMENT OF ELIGIBLE 
PARTICIPANTS
Once a participant has fulfilled all eligibility criteria, he or she will be randomized via 
IxRS to 1 of 2 treatment groups:  ocrelizumab 600 mg (300 mg 2 given 14 days apart 
for the first 24 weeks and 600 mg 1 every 24 weeks thereafter) or Rebif.
Participant eligibility information will be provided to the IxRS by the investigator or the 
investigator’s research staff at randomization.  The participant will be randomized and 
assigned a unique treatment box number (medication number) and randomization 
number.  As confirmation, the site will be provided with a verification of each participant’s 
randomization.
The participant randomization numbers will be generated by Roche or its designee and 
incorporated into the double-blind labeling.
The participant randomization numbers are to be allocated sequentially in the order in 
which the participants are enrolled according to the specification document agreed with 
the external randomization company/center.
Treatment with the first study drug infusion should occur within 24 hours of
randomization.  In exceptional cases where all baseline assessments cannot be 
completed within 24 hours, the first study drug infusion can be administered within 
48 hours of randomization provided that the investigator assures that all inclusion and 
exclusion criteria are still met on the day of dosing.  In particular, there should be no 
evidence of an ongoing infection at the time of dosing.
No participant may begin treatment prior to randomization and assignment of a 
medication number.
5.10
CLINICAL ASSESSMENTS AND PROCEDURES DURING THE 
DOUBLE-BLIND, DOUBLE-DUMMY TREATMENT PERIOD
This is an assessor blinded study. During the double-blind, double-dummy treatment 
period, each site will have 2 investigators: a Principal (Treating) Investigator and an 
Examining Investigator or rater.

The Treating Investigator is the physician responsible for participant care and 
should be a neurologist experienced in the care of participants with MS.  
The Principal Investigator will have access to safety and blinded efficacy data and 
will make treatment decisions based on the participant’s clinical response and 
laboratory findings.

The Examining Investigator should be a neurologist or other health care 
practitioner and must be trained and certified in administering the Neurostatus 
Functional Systems Scale (FSS) and EDSS examination prior to study start


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The Examining Investigator will perform the neurological examination, document the 
FSS scores, and assess EDSS scores and the Karnofsky Performance Status Scale.  
The Examining Investigator or a qualified designee will also be responsible for 
performing and documenting results from the following:  MSFCS, low-contrast 
visual acuity testing, and the SDMT.  They will only have access to data from the 
assessments listed above.  Every effort will be made to ensure that there is no change in 
the EDSS rater throughout the course of the study for any individual participant.  
Whenever possible, the same person should perform the examination for the full study 
duration.
All efforts should be made to keep the Examining Investigator blinded to the treatment 
assignment during the double-blind, double-dummy treatment period. Participants will 
be instructed not to discuss any symptoms related to the study treatment with the 
Examining Investigator; the Examining Investigator should remind the participant at the 
start of the examination.  In view of the extended duration of this study, each site will 
identify a primary and back-up for Treating and Examining Investigator.  
The Treating Investigator and the Examining Investigator will not be allowed to 
switch roles.
5.10.1
Overview of Clinical Visits During the Double-Blind, 
Double-Dummy Treatment Period
After the screening visit, participants fulfilling the entry criteria will be scheduled for the
baseline assessments.  Randomization will occur only after the participant meets all 
inclusion and exclusion criteria on Day 1.  Visits will take place as described in the 
schedule of activities (Table 1).
Visits should be scheduled with reference to the date of the baseline visit (Day 1).  
A minimum interval of 20 weeks kept between the ocrelizumab/ocrelizumab placebo 
second infusion of Cycle 1 (i.e., infusion Week 2) and the next infusion on Cycle 2 
(Week 24).  A minimum of 22 weeks must occur between ocrelizumab/ocrelizumab 
placebo single infusions administered during Weeks 24, 48, and 72.
At infusion visits, participants treated with ocrelizumab/ocrelizumab placebo should 
remain in observation for at least 1 hour after the completion of the infusion.
If for logistical reasons the ocrelizumab/ocrelizumab placebo infusion at Week 24, 48, or 
72 cannot be administered on the same study visit day, the infusion should be given 
within the next 24 hours provided that the participant still meets re-treatment criteria 
(see Section 6.1.4).
Participants who cannot receive their infusion at the scheduled visit or within 24 hours of 
the visit should be rescheduled for a delayed dosing visit (see Section 5.10.1.1).  
Additional unscheduled visits for the assessment of potential relapses, new neurological 


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symptoms, safety events or for dispensing Rebif/Rebif placebo if down-titration is 
needed may occur at any time.
5.10.1.1
Delayed Dosing Visit
Delayed dosing visits may be scheduled only if the infusion cannot be administered at 
the timepoints defined in schedule of activities (Table 1).  Thus, a participant who had all 
assessments of a dosing visit performed, but could not receive his/her infusion, should 
be rescheduled for the infusion.  Delayed dosing visit should not be scheduled for the 
first infusion of the first treatment cycle (Day 1), as treatment with the first study drug 
infusion should occur within 24 hours of randomization (in exceptional cases within 
48 hours of randomization provided that the investigator assures that all inclusion and 
exclusion criteria are still met on the day of dosing; see Section 5.9).
In unforeseen situations, if the infusion of the first treatment cycle (Day 1) is delayed, 
then the visit for the second infusion should be scheduled 14 days after the delayed first 
infusion (2 days). In the event any subsequent infusion needs to be delayed, a 
minimum interval of 20 weeks between the second infusion of Cycle 1 (Week 2) and the 
next infusion on Cycle 2 (Week 24) is required; a minimum of 22 weeks must occur 
between infusions administered during Weeks 24, 48, and 72.
At the delayed dosing visit, additional tests or assessments, such as routine safety 
laboratory tests, may be performed when the investigator judges that these are 
warranted.
5.10.1.2
Unscheduled Visits
Participants developing new or worsening neurological symptoms should be seen at the 
investigational site as soon as possible regardless of the treatment group to which they 
were randomized, regardless of the dates of their pre-planned, scheduled study visits, 
and regardless of the study period.  Assessments performed at unscheduled 
(non-dosing) visits will depend on the clinical needs of the participant.
Participants with new neurological symptoms suggestive of relapse should have an 
EDSS performed by Examining Investigator, whenever possible within 7 days of the 
onset of the relapse.  Other tests/assessments may be done as appropriate.  
Please note: if during the double-blind, double-dummy treatment period, 
Rebif/Rebif placebo dose modification is necessary in case of ALT elevations, then 
unscheduled visits may be required for dispensing of study medication (see Section 6.2).
Please see Section 7.3.5.1 for guidance on the diagnosis of PML.
5.10.1.3
Withdrawal Visits in the Double-Blind, Double-Dummy 
Treatment Period
At the moment a participant meets one or more of the withdrawal criteria (Section 5.6), 
this participant is regarded withdrawn from treatment.  Participants who withdraw from 


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ocrelizumab treatment will need to complete all assessments as shown in schedule of 
activities and will enter the safety follow-up period.
At the termination of the study (see Section 4.1.9 for definition of end of the study), the 
participants will discontinue ocrelizumab treatment and should move into the safety 
follow-up period or will receive commercial ocrelizumab (if available in that country).  
All participants will undergo a complete final evaluation according to the 
‘Withdrawal from Treatment Visit’ in the schedule of activities, Table 3.  Thereafter, all 
participants will be treated according to individual center practice.
For participants who have withdrawn from the double-blind, double-dummy treatment 
period, OLE phase, the OLE phase screening period, or who are not eligible for 
treatment with ocrelizumab, it is at the discretion of the investigator to decide on further 
treatment of the underlying disease.
However, since sufficient data are not available to inform risks associated with switching 
to other products, certain treatments for MS such as lymphocyte-depleting agents or 
lymphocyte-trafficking blockers (for example, alemtuzumab, natalizumab, fingolimod, 
dimethyl fumarate, cyclophosphamide, azathioprine, etc.) are strongly discouraged for 
as long as the participant remains B-cell depleted because of unknown effects on the 
immune system (e.g., increased risk, incidence or severity of infection; 
see Section 5.5.2.1 for recommendations on alternative treatments for MS).
Please note: at the withdrawal from double-blind, double-dummy treatment period visit 
or OLE phase, an MRI scan will be required only if not performed in the prior 4 weeks.
5.10.2
Assessment of Efficacy
5.10.2.1
Assessment of Relapse
All new or worsening neurological events consistent with MS representing a 
clinical relapse are to be reported on the dedicated page of eCRF.  Participants with 
clinical relapses should be referred to the Examining Investigator who will assess the 
FSS/EDSS independently to allow confirmation as to whether or not the clinical 
relapse(s) meet the criteria for protocol-defined relapse(s).
Protocol-defined relapse is the occurrence of new or worsening neurological 
symptoms attributable to MS.  Symptoms must persist for 24 hours and should not be 
attributable to confounding clinical factors (e.g., fever, infection, injury, adverse reactions 
to medications) and immediately preceded by a stable or improving neurological state for 
at least 30 days.  The new or worsening neurological symptoms must be accompanied 
by objective neurological worsening consistent with an increase of at least half a step on 
the EDSS scale, or 2 points on one of the appropriate FSS, or 1 point on 2 or more of 
the appropriate FSS.  The change must affect the selected FSS 
(i.e., pyramidal, ambulation, cerebellar, brainstem, sensory, or visual).  Episodic spasms, 
sexual dysfunction, fatigue, mood change, or bladder or bowel urgency or incontinence 


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will not suffice to establish a relapse.  Note: Sexual dysfunction and Fatigue will not be 
scored.  Please note: adjudication of protocol-defined relapses will be performed by the 
Sponsor based on pre-specified criteria, applied to data collected by investigator, in a 
blinded fashion.
All participants with new neurological symptoms suggestive of a relapse should 
be referred to the Examining Investigator for EDSS assessment, whenever 
possible within 7 days of the onset of the relapse.  Any participant, complaining of 
a neurological symptom, defined at a visit or over the phone, should be referred to 
the Examining Investigator unless the Principal Investigator determines that the 
symptom is due to mitigating circumstances (such as an intensification of 
neurological symptoms from a transient systemic infection).
Please note: clinical relapses (i.e., regardless of whether they meet criteria for a 
protocol-defined relapse) will be recorded on a pre-specified eCRF “MS Relapse” 
electronic form (eForm).  Multiple sclerosis relapses should not be reported on the 
Adverse Event eForm eCRF.
5.10.2.2
Assessment of Disability
Disability progression has been defined as an increase of 1.0 point from the baseline 
EDSS score that is not attributable to another etiology (e.g., fever, concurrent illness, or 
concomitant medication) when the baseline score is 5.5 or less, and 0.5 when the 
baseline score is above 5.5.  Disability progression is considered confirmed when the 
increase in the EDSS is confirmed at a regularly scheduled visit at least 12 weeks or 
24 weeks, after the initial documentation of neurological worsening.
Confirmed disability progression, confirmed for 12 weeks, after the initial documentation 
of neurological worsening, will be analyzed as key secondary endpoint.  
Additionally, confirmed disability progression for 24 weeks will be assessed.  The initial 
event of neurological worsening must occur during the 96-week, double-blind, 
double-dummy, treatment period.
5.10.2.3
Kurtzke Expanded Disability Status Scale
The EDSS (Cohen et al. 2000) is based on a standard neurological examination, 
incorporating the following functional systems (pyramidal, cerebellar, brainstem, 
sensory, bowel and bladder, visual, and cerebral [or mental]) and ambulation rated and 
scored as FSS.  Each FSS is an ordinal clinical rating scale ranging from 05 or 6.  
These ratings are then used in conjunction with observations and information concerning 
ambulation and use of assistive devices to determine the EDSS score.  The EDSS is a 
disability scale that ranges in 0.5-point steps from 0 (normal) to 10 (death).
The EDSS will be assessed by the Examining Investigator.  All participants with new 
neurological symptoms suggestive of relapse should have an EDSS performed 
during an unscheduled visit whenever possible within 7 days of symptom onset.


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5.10.2.4
The Multiple Sclerosis Functional Composite Scale
The MSFCS consists of 3 subscales, including the 9-HPT, PASAT, and the T25FWT, 
which provide a global quantitative estimate of MS disability progression 
(Fischer et al. 1999).
The MFSCS will be performed by the Examining Investigator or a qualified designee who 
must remain blinded to the treatment assignment.
5.10.2.5
Low-Contrast Visual Acuity Testing
Low-contrast letter acuity charts (Sloan charts) have gained validity in the assessment of 
visual dysfunction in participants with MS not readily apparent on commonly used 
high-contrast acuity tests.  Reductions in low-contrast letter acuity are associated with 
MS and correlate with increasing disability, MRI abnormalities, and reduced RNFL
thickness as measured by OCT.
Low-contrast visual acuity testing will be performed with use of low-contrast letter acuity 
charts (low-contrast Sloan letter charts) by the Examining Investigator or a qualified 
designee at the timepoints indicated in the schedule of activities (Table 1).
5.10.2.6
The Symbol Digit Modalities Test
The SDMT has demonstrated sensitivity in detecting not only the presence of cognitive 
impairment, but also changes in cognitive functioning over time and in response to 
treatment.  The SDMT is brief, easy to administer, and involves a simple substitution 
task that normal children and adults can easily perform.  Using a reference key, the 
examinee has 90 seconds to pair specific numbers with given geometric figures.  
Responses can be written or oral, and for either response mode, administration time is 
just 5 minutes.
The SDMT will be administered by the Examining Investigator or a qualified designee at 
the timepoints indicated in the schedule of activities (Table 1 and Table 3).
5.10.3
Brain Magnetic Resonance Imaging
Magnetic resonance imaging is a useful tool for monitoring CNS lesions in MS.  
Different MRI derived parameters have been related to clinical activity and T1-weighted 
Gd-enhancing lesions or new and/or enlarging hyperintense T2 lesions have been 
related to relapses.  It is hypothesized that changes in brain volume may reflect brain 
atrophy as a result of MS-related tissue loss and may thereby correlate with long-term 
clinical outcome in these participants.
Brain MRI scans will be obtained in all participants as detailed in the schedule of 
activities (Table 1).  In addition, brain MRI scans will be obtained in participants 
withdrawn from the double-blind, double-dummy treatment period (at the withdrawal 
visit) if not performed during the previous 4 weeks.


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Scans will be performed by trained and certified MRI technicians.  The following time 
windows apply:

“Baseline” MRI should be performed after screening visit, but at least 10 days prior 
to the baseline visit

MRI at visits scheduled at Weeks 24, 48, 96 or at the withdrawal visit (if applicable) 
should be performed within a window of 4 weeks of the scheduled visit

In the OLE phase, MRI should be performed yearly (e.g., Cycles 7, 9, etc.) within a 
window of 4 weeks of the scheduled visit
If participants receive corticosteroids for an MS relapse, every effort should be made to 
obtain the scan prior to the first steroid dose if the pre-steroid scan is within 1 week of 
the scheduled visit.  In participants receiving corticosteroids for an MS relapse, there 
should be an interval of 3 weeks between the last dose of corticosteroids and the scan.
The MRI will include the acquisition of scans at each timepoint with and/or without 
IV administered Gd contrast enhancement.
Magnetic resonance imaging scans will be read by a centralized reading center for 
efficacy endpoints.  The centralized reading center is blinded to the treatment 
assignment and the reading is performed in the absence of clinical information.  
Further details on scanning acquisition sequences, methods, handling and transmission 
of the scans, certification of site MRI radiologist/technicians, and the procedures for the 
blinded analysis of the scans at the central reading center are described in a separate 
MRI Acquisition Procedures Manual.
All MRI scans will also be reviewed locally by a radiologist for safety.  During the 
double-blind, double-dummy treatment period, the MRI scan report containing only 
non-MS pathology will be provided to the Treating Investigator (see Section 5.10 for 
definition).  At the investigational site, only the local radiologist/technician assigned to 
this study may have access to the MRI scans post-randomization; 
the Treating Investigator should not review the MRI scans obtained after randomization 
unless a safety concern arises.  In the event that the Treating Investigator does become 
aware of these MRI results, this should be documented in the eCRF, indicating the 
reason.
Note that during the OLE phase, it is possible for the Treating Investigator to have 
access to MRI scans performed during the OLE phase.
5.10.4
Safety
Adverse events, vital signs, weight, physical and neurological examination, clinical 
laboratory tests (including pregnancy tests), 12-lead ECG, locally reviewed MRI for 
safety (non-MS CNS pathology), and data on concomitant medications and diseases will 
be collected throughout the study.


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Please note: On the infusion days, the vital signs should be taken within 45 minutes 
prior to the methylprednisolone infusion in all participants.  In addition, the vital signs 
should be obtained prior to the study drug infusion, then every 15 minutes (5 minutes) 
for the first hour; then every 30 minutes (10 minutes) until 1 hour after the end of the 
infusion.  On non-infusion days, the vital signs may be taken at any time during the visit.  
Additional vital signs readings may be taken at the discretion of the investigator in the 
event of an infusion-related reaction or if clinically indicated and should be recorded on 
the unscheduled vital signs eCRF.
Please see relevant sections of protocol for more details.
5.10.4.1
Electrocardiogram
A 12-lead ECG should be taken at the visits indicated in the schedule of activities
(Table 1 and Table 3).  Comments generated automatically by the ECG machine should 
not be recorded in the eCRF unless confirmed by a physician.  An ECG is also required 
if the participant prematurely withdraws from the study.
5.10.4.2
Physical Examination
The physical examination will be performed as per schedule of activities.  Diagnosis of 
new abnormalities or clinically significant worsening of preexisting abnormalities should 
be recorded as adverse events if appropriate.
5.10.4.3
Neurological Examination
A neurological examination will be performed at every planned visit and at unscheduled 
visit if applicable.

In the presence of newly identified or worsening neurological symptoms at any given 
time in the study (double-blind treatment, safety follow-up, or the OLE period), a 
neurological evaluation should be scheduled promptly.  In case of events suggestive 
of relapse, the Treating Investigator should request EDSS to be performed by the 
Examining Investigator, whenever possible within 7 days of the onset of the relapse.
Study investigators will screen participants for signs and symptoms of PML by evaluating 
neurological deficits localized to the cerebral cortex, such as cortical symptoms/signs, 
behavioral and neuropsychological alteration, retrochiasmal visual defects, hemiparesis, 
cerebellar symptoms/signs (e.g., gait abnormalities, limb incoordination).  A brain 
MRI scan and CSF analysis may be warranted to assist in the diagnosis of PML.  
See Section 7.3.5.1 for guidance on the diagnosis of PML.
Participants with suspected PML, defined as a new or worsening neurological symptom 
which necessitates MRI and or lumbar puncture and CSF analyses to rule out PML, 
should be withheld from study treatment until PML is ruled out by complete clinical 
evaluation and appropriate diagnostic testing (see Section 7.3.5.1).  The Sponsor’s 
Medical Responsible and Medical Monitor should be contacted by e-mail.  In addition, 
Sponsor medical responsible person should be immediately contacted by phone.


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A participant with confirmed PML should be withdrawn from treatment.  
Progressive multifocal leukoencephalopathy should be reported as a serious adverse 
event (with all available information) with immediate notification of the Medical Monitor 
(see Section 7.1.1.3).
5.10.4.4
Telephone Interviews
The purpose of this semi-structured interview is to identify and collect information on any 
changes in the participant’s health status that warrant an unscheduled visit 
(including new or worsening neurological symptoms).  The telephone interview will be 
conducted by site personnel familiar with the participant(s) every 4 weeks (3 days) 
between the study visits during the double-blind, double-dummy treatment period, 
OLE phase screening period, OLE phase, and throughout the entire safety follow-up 
period.
The site will record in the eCRF the telephone interview as “Done” or “Not Done” and 
documentation of the interview will be maintained in the participant’s study file.
Please see Appendix 4 for detailed information.
5.10.4.5
Columbia-Suicide Severity Rating Scale
The Columbia-Suicide Severity Rating Scale (C-SSRS) will be used during the 
double-blind, double-dummy treatment period and the OLE phase screening period for 
prospective suicidality assessment.  The C-SSRS is a tool used to assess the lifetime 
suicidality of a participant and to track suicidal events through the treatment.  
The structured interview prompts recollection of suicidal ideation, including the intensity 
of the ideation, behavior and attempts with actual/potential lethality.
The scale will be administered by the Principal Investigator or a qualified designee at the 
timepoints indicated in the schedule of activities.  The C-SSRS “baseline” will be 
collected at baseline and the C-SSRS “since last visit” will be collected at subsequent 
visits.
Please note: assessing the risk of suicide is a difficult and complex task when applied to 
the individual participant.  Certainly, no single clinical scale can replace a thorough 
medical examination and suicide risk assessment.  Ultimately, the determination of the 
presence of suicidality depends on clinical judgment.
5.10.5
The Karnofsky Performance Scale (Clinician-Reported Version)
The Karnofsky Performance Scale score allows participants to be classified as to their 
functional impairment.  This scale is usually used to compare effectiveness of different 
therapies and to assess the prognosis in individual participants.  The lower the 
Karnofsky score, the worse the survival for most serious illnesses.


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The scale will be administered by Examining Investigator at the timepoints indicated in 
the schedule of activities (Table 1).
5.11
LABORATORY ASSESSMENTS
Roche Clinical Repository biomarker samples will be shipped directly to Roche Clinical 
Sample Operations unit.  All other laboratory samples collected during the study will be 
shipped to central laboratory.
The procedures for the collection, handling and shipping of laboratory samples are 
specified in the Laboratory Manual.
The samples for this study should be classified, packed and shipped as UN3373 
Biological Substance, Category B.
Full details of the central laboratory sample handling, shipment and reporting of results 
will be described in the Laboratory Manual.
During the double-blind treatment period of the study, the total volume of blood loss for 
laboratory assessments will be approximately 341 mL over 2 years.  The amount of 
blood taken at each visit will vary, but will be no more than 56 mL.  During the 
OLE phase and in the safety follow-up period, the amount of blood taken at each visit 
will be no more than 41 mL.
5.11.1
Standard Laboratory Assessments
Please note: Some laboratory parameters that could reveal participant’s allocation to 
study treatment, such as FACS cell counts, absolute neutrophil counts, Ig levels, and 
type I IFN neutralizing antibody levels, will be blinded.  In order to ensure participants’ 
safety in the study and to allow for assessments of the re-treatment criteria, a central 
laboratory will provide study investigators and Medical Monitors with reflex messages 
triggered by critical blinded laboratory results.  Investigators notified of their participant’s 
critical laboratory test results will be instructed to suspend further treatment with study 
drug until the participant becomes eligible for re-treatment.  The reflex messages from a 
central laboratory, together with non-blinded laboratory results, should be carefully 
reviewed at every visit before continuing with study treatment.  The reflex messages will 
occur during the double-blind, double-dummy treatment period until the fifth cycle 
(first cycle of OLE phase).  The reflex messages will not be in effect from the sixth cycle 
onward.  Further details will be provided in Laboratory Manual.

Hematology: hemoglobin, hematocrit, RBC, WBC (absolute and differential), 
absolute neutrophil count, and quantitative platelet count

Blood chemistry: AST/SGOT, ALT/SGPT, gamma glutamyl transferase (GGT), 
alkaline phosphatase, amylase, lipase, total protein, albumin, cholesterol, total 
bilirubin, urea, uric acid, creatinine, random glucose, potassium, sodium, calcium, 
phosphorus, lactic dehydrogenase, creatine phosphokinase, and triglycerides


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
Thyroid function test: sensitive TSH will be tested at screening, and yearly during 
the double-blind, double-dummy treatment period.  Thyroid autoantibodies will be 
assayed only at screening.
FACS will include (but is not limited to) the following cells:

Total B cells (CD19pos)

Total T cell (CD3pos)

T helper cells (CD3pos, CD4pos)

TCTL (CD3pos, CD8pos)

Natural killer cells (CD3neg, CD16/56pos)

B-cell subsets: 
–
Memory B cells (CD19pos, CD27pos, CD38neg)
–
Naïve B cells (CD19pos, CD27neg, IgDpos)
–
Plasmablasts (CD19lo, CD27pos, CD38hi)

Quantitative Immunoglobulin: Ig levels (including Total Ig, IgG, IgM, and 
IgA isotypes)

Antibody titers: measurement of antibody titers to common antigens 
(mumps, rubella, varicella, S. pneumoniae) will be performed.  This information is 
used to assess the effect of ocrelizumab on specific humoral immunity to bacterial 
and viral antigens.

Human anti-human antibody (HAHA): serum samples will be collected for 
determination of antibodies against ocrelizumab (HAHA; also known as an anti-drug 
antibody [ADA]).  Since ocrelizumab concentrations affect the HAHA assay, the 
concentration of ocrelizumab will be measured as well at all timepoints with HAHA 
assessment to enable interpretation of the results (PK sample).  For details please 
see the schedule of activities.  As of protocol version I (v9), HAHA and concurrent 
PK analyses will be discontinued on the basis that immunogenicity incidence with 
ocrelizumab is very low (1%) with no safety risks identified, so continuous 
monitoring of HAHAs in this population is unnecessary.  However, in any case of 
anaphylaxis, anaphylactoid reaction, or serious or severe hypersensitivity reaction, 
HAHA and ocrelizumab concentration samples should be collected as close as 
possible to the event and then at 4 and 16 weeks postdose.

Pregnancy test: all women of childbearing potential must have regular pregnancy 
tests.  At screening, a serum pregnancy test will be performed in central laboratory.  
During the double-blind, double-dummy treatment period and safety follow-up, a 
urine pregnancy test (sensitivity of at least 25 mIU/mL -hCG) will be performed 
locally at the timepoints shown in schedule of activities (Table 1).  On infusion visits, 
the urine pregnancy test should be performed prior to the methylprednisolone 
infusion.  A positive urine pregnancy test should be confirmed with a serum test 
through the central laboratory prior to any further dosing with ocrelizumab.


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Please note: additional laboratory tests will be performed at screening in order to verify 
eligibility criteria.  Please see Table 1 for further details.
5.11.2
Hepatitis Screening and Liver Function Monitoring
Participants with recurrent or chronic hepatitis B or history/presence of hepatitis C 
infection must be excluded from enrollment into the study (see Section 5.3).  In addition, 
hepatitis B and C serology will be performed at screening.  A positive result to either 
HBsAg, or total HBcAb associated with positive viral DNA titers as measured by PCR, or
a positive result for HepCAb should result in the participant’s exclusion.  
Participants with evidence of past resolved hepatitis B infection (i.e., positive total 
HBcAb associated with a negative viral DNA) can be enrolled, and will have the hepatitis 
B viral DNA checked regularly as per the schedule of activities.  Participants in whom the 
viral DNA becomes positive but in whom the quantity is at the lower limit of detection of 
the assay should have the test repeated as soon as possible.  Participants found to have 
a confirmed viral DNAtest should be referred to a hepatologist for immediate 
assessment.  These participants will not receive further infusions of ocrelizumab and will 
enter the safety follow-up period.
Liver function, i.e., ALT/SGPT, AST/SGOT, GGT, alkaline phosphatase, total bilirubin, 
should be reviewed throughout the study.  Participants developing evidence of liver 
dysfunction should be assessed for viral hepatitis and, if necessary, referred to a 
hepatologist or other appropriately qualified expert.  Study drug should be withheld until 
the diagnosis of viral hepatitis has been excluded.  Participants developing hepatitis B or 
C should be withdrawn from the study and should enter the safety follow-up period.  
Should treatment be prescribed, this will be recorded in the eCRF.  Participants with viral 
hepatitis due to other agents, such as hepatitis A, may resume treatment after the 
participant’s recovery.
Please see Section 6.2.2 for further guidelines on liver function monitoring.
5.11.3
Plasma and Urine Banking for JC Virus
Long-term storage of plasma samples and urine is planned for John Cunningham virus 
(JCV) DNA and/or other relevant tests for JCV, independent of an occurrence of 
suspected PML case (see Section 7.3.5.1). Plasma samples (5 mL) and urine samples 
(10 mL) will be collected as per schedule of activities.  As the assay of the virus DNA 
has not been standardized, and a correlation between viremia and onset of PML has not 
been established, the JCV assessments in plasma and urine will be performed if 
deemed necessary in the future and not on an ongoing basis.  All samples collected for 
JCV testing will be stored for 1 year after the last participant’s last visit in the study.  
As of protocol version I (v9), collection of plasma and urine samples planned for 
JCV DNA will be discontinued.  In the event that PML is suspected, an additional 
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(see Section 7.3.5.1).  For details, please refer to the most up-to-date Laboratory Manual 
providing storage conditions and shipment instructions.
5.11.4
Pharmacokinetic/Pharmacodynamic Assessments
Blood samples will be collected to evaluate the PK and PD of ocrelizumab as described 
in the schedule of activities (Table 1).  The blood volume collected for PK assessments 
will be approximately 2 mL per sample.  These samples will be assayed for ocrelizumab 
concentration with use of an enzyme-linked immunosorbent assay.
Serum samples for determination of ocrelizumab concentrations will be collected at the 
timepoints detailed in the schedule of activities (Table 1).  On the infusion visit at 
Week 72, two serum samples should be collected, one sample 530 minutes prior to the 
methylprednisolone infusion and the second sample 30 minutes (10 minutes) following 
the completion of the ocrelizumab infusion.  For all other infusion visits, a blood sample 
should be taken 530 minutes before the methylprednisolone infusion.  At other times 
(non-infusion visits), samples may be taken at any time during the visit.
As of protocol version I (v9), HAHA and concurrent PK analyses will be discontinued on 
the basis that immunogenicity incidence with ocrelizumab is very low (1%) with no 
safety risks identified, so continuous monitoring of HAHAs in this population is 
unnecessary.  However, in any case of anaphylaxis, anaphylactoid reaction, or serious 
or severe hypersensitivity reaction, HAHA and ocrelizumab concentration samples 
should be collected as close as possible to the event and then at 4 and 16 weeks 
post-dose.
For sampling procedures, storage conditions, and shipment instructions, see the 
Sample Handling and Logistics Manual, which will be provided to each site.
5.11.5
Type I Interferon Neutralizing Antibody Assay
Type I IFN neutralizing antibody assay will be performed during the double-blind, 
double-dummy treatment period (Table 1).
5.12
OPTIONAL SAMPLES FOR RESEARCH BIOSAMPLE 
REPOSITORY
If the participant provides consent (see Section 5.12.5), a collection of biosamples for 
the RBR will be performed at a single timepoint during the OLE phase of the study.  
These samples will be used for research into MS disease progression mechanisms, 
identification of new MS disease progression biomarkers, and development of new 
therapeutic agents.
5.12.1
Overview of the Roche Research Biosample Repository
The RBR is a centrally administered group of facilities used for the long-term storage of 
human biological specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection, storage, and analysis of RBR 


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samples will facilitate the design of new pharmaceutical agents and the development of 
diagnostic tests, which may allow for individualized drug therapy for participants in the 
future.
Samples for the RBR will be collected from participants who give specific consent to 
participate in this optional research.  The RBR samples may be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy or MS disease progression

To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation

To increase knowledge and understanding of MS disease biology and drug safety

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
5.12.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's IRB or EC and, if applicable, an appropriate regulatory body.  If a site has 
not been granted approval for RBR sampling, this section of the protocol (Section 5.12) 
will not be applicable at that site.
5.12.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including but not limited to, research on biomarkers related to ocrelizumab and MS 
disease progression or drug safety.  These samples should be collected after the 
participant's consent and at the next possible visit during OLE phase.

CSF

Paired plasma samples for the CSF

Blood samples including leftover samples collected during the trial
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development.
For sampling procedures, storage conditions, and shipment instructions, see the 
Laboratory Manual.


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Research Biosample Repository samples are to be stored until they are no longer 
needed or until they are exhausted.  However, the RBR storage period will be in 
accordance with the IRB/EC-approved Informed Consent Form and applicable laws 
(e.g., health authority requirements).
5.12.4
Confidentiality
Research Biosample Repository samples and associated data will be labeled with a 
unique participant identification number.
Participant medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
participant, unless permitted or required by law.
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
participants unless required by law.  The aggregate results of any conducted research 
will be available in accordance with the effective Sponsor policy on study data 
publication.
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
5.12.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each participant the 
objectives, methods, and potential hazards of participation in the RBR.  Participants will 
be told that they are free to refuse to participate and may withdraw their consent at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a participant's agreement to provide optional RBR samples.  
Participants who decline to participate will not provide a separate signature.
The investigator should document whether or not the participant has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research.
5.12.6
Withdrawal from the Research Biosample Repository
Participants who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the participant.  However, if RBR samples 




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after the end of the study and then destroyed, unless a different regulation for storage 
time is in place at a given site.
5.14
PARTICIPANT-REPORTED OUTCOMES
Participant-reported outcomes data will be collected at the study visit with an electronic 
tablet device during the double-blind, double-dummy treatment period.  The tablet with 
the participant-reported outcome (PRO) instruments will be distributed by the 
investigator staff and completed in their entirety by the participant.
Please note:  all PROs are required to be administered prior to administration of study 
drug and prior to any other study assessment(s) to ensure the validity of the instruments 
is not compromised, and data quality meet requirements of regulatory authorities and 
best practices (FDA 2009; Fairclough 2010).
Participant-reported outcome data will be elicited from participants in this study to better 
characterize the clinical profile of ocrelizumab.  These PRO measurements are 
described in Sections 5.14.1, 5.14.2, and 5.14.3. Please note that the methods for 
collecting and analyzing PRO data are different from those for the ascertainment of 
observed or volunteered adverse events.  Due to these differences, PRO data will not be 
reported as adverse events and no attempt will be made to resolve any noticeable 
discrepancies between PRO data and observed or volunteered adverse events.
Participants who are unable to complete exploratory assessments (e.g., ePROs) due to 
physical/disease limitations will not be excluded from the study.
5.14.1
Modified Fatigue Impact Scale
The MFIS will assess change in the level of fatigue during the double-blind, 
double-dummy treatment period.  The MFIS is a 21-item instrument that asks 
participants to rate their fatigue over the past 4 weeks on a 5-point Likert scale, 
indicating “Never” to “Almost always.”  Four scores can be derived from the MFIS, 
including a total score as well as scores for 3 subscales:  physical, cognitive, and 
psychosocial functioning.  Changes from baseline will be calculated for the total scale 
scores as well as for the subscale scores.
English version of MFIS is provided in Appendix 5.
5.14.2
The Center for Epidemiologic Studies Depression Scale
The CES-D will be used to evaluate participants for depressive symptoms during the 
double-blind, double-dummy treatment period.  The CES-D is a 20-item self-report 
instrument that asks participants to rate their feelings and behaviors over the past week 
on a 4-point Likert scale, from “Rarely or none of the time (less than 1 day)” to “Most or 
all of the time (57 days).”  Only a total scale score is calculated for the CES-D.
English version of CES-D is provided in Appendix 6.


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5.14.3
The Short Form-36 Health Survey
The SF-36 Health Survey (version 2) is a generic quality of life instrument that has 
been widely tested for its psychometric properties and is widely used in clinical 
and epidemiological studies.  The SF-36 contains 36 items and measures 
8 health domains: vitality, physical functioning, bodily pain, general health perceptions, 
physical role functioning, emotional role functioning, social role functioning, and 
mental health.  The SF-36 yields a score for each domain, as well as summary scores 
for the physical and mental dimensions.  It can be completed in 510 minutes.
English version of the SF-36 Health Survey is provided in Appendix 7.
5.14.4
Participant’s Assessment of Treatment Benefit
The Participant Perception of Treatment Questionnaire will be assessed after 
administration of PRO instruments at each visit in which PRO assessments are made, 
except for baseline.  Specifically, participants will be asked whether they think their MS 
has become better, become worse or been stable since baseline.  This question will 
serve as a global assessment from the participant perspective and will provide a useful 
anchor to help interpret the clinical meaningfulness of PRO results.
5.15
PHARMACOECONOMIC ASSESSMENTS/EQ-5D
Pharmacoeconomic assessments will be included for purposes of deriving health 
utilities for economic modeling.  The EQ-5D will be used to derive utilities for health 
states included in MS economic models and will be administered as per schedule of 
activities.
The EQ-5D (formerly known as EuroQoL) is a generic, preference-based health-related 
quality of life instrument.  It has 5 dimensions assessing mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression.  Each dimension has 3 possible 
levels.  Different combinations of responses are utility-weighted to produce a single 
health utility index.  The Visual Analog Scale measures self-reported health on a scale 
between “worst imaginable” and “best imaginable” health states.
The EQ-5D is a PRO and should be performed before any other study assessments and 
before administration of study drug in order to minimize bias.
5.16
OPTIONAL EXPLORATORY SUBSTUDIES
Participants who are randomized to the main Study WA21093 have the option to 
participate in exploratory substudies upon separate consent and fulfillment of additional 
exploratory substudy protocol criteria.  The OCT Exploratory Substudy is included in the 
main study protocol (see Section 5.16.1 and Appendix 8).  Other exploratory substudies 
are run under separate study protocols: substudy of brain and spinal cord MRI in 
participants with MS participating in Study BE29352 (OPERA); B cell and T cell 
repertoires in ocrelizumab-treated participants with MS (Study BE29353); brain myelin 


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mapping to quantify demyelination and repair in MS in a Phase III trial of ocrelizumab 
(Study BE29340); and the assessment of ocrelizumab treatment effects on disability in 
participants with MS enrolled in the Phase III Orchestra program using multimodal 
evoked potentials and high-resolution electroencephalogram (EEG; Study BE29354).  
Substudies will be run only at the specifically assigned sites that are referred to in the 
substudy protocols.
5.16.1
Optical Coherence Tomography Exploratory Substudy
A Roche-sponsored, multicenter, OCT Exploratory Substudy is being conducted.  
Optical coherence tomography is a noninvasive imaging tool capable of measuring 
changes in structural architecture of the retina and retinal nerve fiber sensitively and 
rapidly (Frohman et al. 2008).  Optical coherence tomography can be of particular 
interest in MS, because optic neuritis is often the pivotal event in establishing the 
diagnosis of MS.  Optic nerve dysfunction is characterized by optic disc pallor, loss of 
contrast sensitivity, and visual field defects and may occur subclinically in many other 
participants.  It is estimated that nearly 20% of all participants with MS present initially 
with optical neuritis, and an additional 30%–100% will have optical neuritis at some point 
in their disease course (Sergott et al. 2007).  Optical coherence tomography outcome 
measures such as RNFL thickness and macular volumes have been shown to correlate 
with clinical measures of vision loss and may facilitate visualization of any process of 
neurodegeneration or repair as part of natural history of MS or as a consequence of 
neuroprotective interventions (Costello et al. 2008).
The procedures and schedule of activities are specified in the substudy protocol 
(Appendix 9) and in the Imaging Review Charter.
In July 2017, Roche determined that sufficient data had been collected from the 
OCT substudy.  During 2017 and 2018, participating participants will be discontinued 
from the OCT substudy but may continue in the OLE.
5.17
OPEN-LABEL EXTENSION PHASE
5.17.1
Open-Label Extension Phase Screening Period
Participants who have completed the 96-week, double-blind, double-dummy treatment 
period, and who, in the opinion of the Treating Investigator, may benefit from treatment 
with ocrelizumab, will be offered the opportunity to participate in the OLE phase of the 
study.  Eligible participants who are not willing to participate in the OLE phase of the 
study will be entered into the safety follow-up period (see below).
It should be noted that in the case of a participant who initially declines participation in 
the OLE phase and subsequently reconsiders the decision, the participant will have up 
to 24 weeks after the Week 96 visit to enter the OLE phase.  In this instance, he or she 
should not have taken any prohibited medication as specified in Section 5.5.2.1.


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Participants who have consented to participate in the OLE phase will enter an 
OLE phase screening period to be evaluated for eligibility.  The OLE phase screening 
period will start after all assessments at the Week 96 visit have been performed, and it 
should last up to 4 weeks.  It is possible that the OLE phase screening period could be 
longer than 4 weeks.  If a prolongation of the OLE phase screening period is needed, it 
should be discussed with the Sponsor on a case-by-case basis.
Information from assessments performed during the Week 96 visit will be used to verify 
the eligibility of the participant for the OLE phase of the study.  Please see Section 5.4.
During the OLE phase screening period, all participants should receive Rebif/Rebif 
placebo (depending on initial arm assigned to) until the first infusion of Cycle 5.  
Please see Table 7 and Table 11 for more details regarding the Rebif/Rebif placebo 
dosing regimen.
Participants who withdraw from the OLE phase screening period will also be entered into 
the safety follow-up period (see below).
5.17.2
Open-Label Extension Phase
The OLE phase starts on the first infusion of Cycle 5 with continued dosing cycles 
every 24 weeks and up to the end of study (see Section 4.1.9).  Participant treatment 
allocation during the double-blind, double-dummy treatment period will not be unblinded 
until the last data point from the last participant is received, as required for statistical 
analysis defined in Section 8.2 and the SAP (see Sections 4.1.8 and 6.4).
Study procedures at this visit will also include the following, but are not limited to:

Physical examination

Neurological exam

Routine safety laboratory examinations (blood and urine sampling), HBV DNA 
(if applicable), FACS analysis, immunoglobulin levels
The first cycle of the OLE phase (Cycle 5) will consist of 2 IV infusions of 300 mg 
ocrelizumab separated by 14 days.  Subsequent cycles (Cycles 6, 7, 8, etc.) will be with 
single IV infusions of 600 mg ocrelizumab to all participants enrolled in OLE phase of 
the study.
Note: This initial dual infusion is designed to both optimize the initial treatment effect 
and to minimize any IRRs for participants initially assigned to the ocrelizumab 
placebo/Rebif verum arm.  In order to avoid unblinding of the assigned arm in the 
double-blind, double-dummy treatment period, both arms should receive dual infusion as 
described above.
Participants who are pregnant and breastfeeding should continue to follow schedule of 
activities for the OLE; however, no infusions will occur.  If there is a concern with the 


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ability of a pregnant or breastfeeding participant to complete all scheduled assessments, 
or if assessments are contraindicated with pregnancy, the investigator must contact the 
Medical Monitor for further discussion.
5.17.3
Overview of Schedule of Activities in the Open-Label Extension
Phase
Participants participating in OLE phase will be assessed at clinical visits every 24 weeks 
as per the schedule of activities (see Table 1).  For the description of the assessments, 
please see Section 5.10.2.
The mechanisms necessary to guarantee assessor blindness are not necessary during 
the OLE phase.  All required assessments during the OLE phase should occur as 
described in Section 1.3.  It is recommended that the same EDSS assessor perform the 
test throughout the OLE phase.
Visits should be scheduled with reference to the date of first infusion during the 
OLE phase (Cycle 5).  The visit for the second infusion should be scheduled 14 days 
after the first infusion of Cycle 5.  A minimum interval of 20 weeks should be kept 
between the ocrelizumab second infusion of Cycle 5 and the next infusion at Cycle 6.  
A minimum of 22 weeks should occur between ocrelizumab single infusions 
administered during Cycle 6 onward.  In the unforeseen cases that an infusion is 
delayed, additional tests or assessments, such as routine safety laboratory tests, may be
performed when the investigator judges that these are warranted.  At infusion visits, 
participants should remain in observation for at least 1 hour after the completion of the 
infusion.
In order to verify re-treatment criteria for infusions in Cycle 6 onwards, participants 
should attend a scheduled visit 2 weeks prior to the infusion visit.
Additional unscheduled visits for the assessment of potential MS relapses, new 
neurological symptoms, or safety events may occur at any time.  
Assessments performed at unscheduled (non-dosing) visits will depend on the clinical 
needs of the participant.
Participants with new neurological symptoms suggestive of MS relapse should have an 
EDSS performed by the Examining Investigator, whenever possible within 7 days of the 
relapse onset date.  Other tests/assessments may be done as appropriate.
Please see Section 7.3.5.1 for guidance on the diagnosis of PML.
5.17.3.1
Delayed Dosing Visit in the Open-Label Extension Phase
Delayed dosing visits may be scheduled if the infusion cannot be administered at the 
timepoints defined in the schedule of activities (Table 3).  Thus, a participant who had all 


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assessments of a dosing visit performed, but could not receive his/her infusion, should 
be rescheduled for the infusion.
At the delayed dosing visit, additional tests or assessments, such as routine safety 
laboratory tests, may be performed when the investigator judges that these are 
warranted.
5.17.3.2
Unscheduled Visits in the Open-Label Extension Phase
Participants who develop new or worsening neurological symptoms should be seen at 
the investigational site as soon as possible regardless of the dates of their pre-planned, 
scheduled study visits.  Assessments performed at unscheduled (non-dosing) visits will 
depend on the clinical needs of the participant.
Participants with new neurological symptoms suggestive of relapse should have an 
EDSS performed by the Examining Investigator, whenever possible within 7 days of the 
relapse onset date.  Other tests/assessments may be done as appropriate.  It should be 
noted if, during the OLE screening period, Rebif/Rebif placebo dose modification is 
necessary in the case of ALT elevations, then unscheduled visits may be required for 
dispensing of study medication (please see Section 6.2).
See Section 7.3.5.1 for guidance on the diagnosis of PML.
5.17.3.3
Withdrawal Visits in the Open-Label Extension Phase
At the moment a participant meets one or more of the withdrawal criteria (Section 5.6), 
this participant is regarded as withdrawn from treatment.  Participants who withdraw 
from ocrelizumab treatment will need to complete all assessments as shown in schedule 
of activities (Table 3) and should be entered into the safety follow-up period.
For participants who have withdrawn from the OLE phase or who are not eligible for 
treatment with ocrelizumab, it is at the discretion of the investigator to decide on further 
treatment of the underlying disease.
However, since sufficient data are not available to inform risks associated with switching 
to other products, certain treatments for MS such as lymphocyte-depleting agents or 
lymphocyte-trafficking blockers (i.e., alemtuzumab, natalizumab, fingolimod, 
dimethyl fumarate, cyclophosphamide, azathioprine, etc.) are strongly discouraged for 
as long as the participant remains B-cell depleted because of unknown effects on the 
immune system (e.g., increased risk, incidence or severity of infection; 
see Section 5.5.2.1 for recommendations on alternative treatments for MS).
Participants who start treatment with commercial ocrelizumab or another DMT will 
discontinue from the study completely and will not enter or continue in the safety 
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Table 7
Treatment Groups and Schedule of Study Medication during the 
Double-Blind, Double-Dummy Treatment Period
Treatment Group
Schedule of Study Medication
Group A
Ocrelizumab 600 mg regimen
Two IV infusions of ocrelizumab 300 mg separated by 
14 days for the first 24 weeks, followed by single 
IV infusions of ocrelizumab 600 mg every 24 weeks 
thereafter
AND
Placebo Rebif subcutaneous injections, 3weekly.
Group B
Rebif
Rebif subcutaneous injections, 3weekly
AND
Two IV infusions of placebo ocrelizumab 300 mg 
separated by 14 days for the first 24 weeks, followed by 
single IV infusions of placebo ocrelizumab 600 mg 
every 24 weeks thereafter.
The first IV infusion of ocrelizumab or placebo, or the first SC injection of Rebif or 
placebo will be administered on study Day 1.
During the OLE phase screening period, participants will continue to receive blinded 
treatment according to their initial assignment:

Group A:  Rebif placebo SC injections, 3weekly

Group B:  Rebif SC injections, 3weekly
During the OLE phase, all participants will receive ocrelizumab IV infusions every 
24 weeks.  At Cycle 5, participants will receive 2 infusions of 300 mg ocrelizumab IV 
separated by 14 days during the 24-week cycle.  Beginning with Cycle 6, participants will 
receive ocrelizumab 600 mg every 24 weeks.
Please note: 100 mg of methylprednisolone IV will be administered prior to each 
IV infusion of ocrelizumab/ocrelizumab placebo during the double-blind, double-dummy 
treatment period and prior to each IV infusion of ocrelizumab during the OLE phase.  
In the event that the use of methylprednisolone is contraindicated for the participant, use 
of an equivalent dose of an alternative steroid is allowed as premedication.
6.1
OCRELIZUMAB
6.1.1
Preparation and Administration of Ocrelizumab Infusions
Detailed instructions for the preparation of the infusion bags containing the study 
drug will be provided separately in the Dose Preparation Guidelines.
Although ocrelizumab may be administered on an outpatient basis, participants may 
be hospitalized for observation at the discretion of the investigator (in some countries 


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this is the standard procedure).  The study drug infusions should always be 
administered in a hospital or clinic environment under close supervision of the 
investigator or a medically qualified staff member with immediate availability of full 
resuscitation facilities.  Participants receiving ocrelizumab treatment will need to remain 
under observation at the clinic for at least 1 hour after the infusion.  It is anticipated that 
the participant will need to stay at the hospital or clinical site for a full day for the infusion 
visit.
6.1.1.1
Preparation of infusion
Ocrelizumab drug product must be diluted before administration.  Solutions of 
ocrelizumab for IV administration are prepared by dilution of the drug product or 
ocrelizumab-matching placebo into an infusion bag containing 0.9% sodium chloride, to 
a final drug concentration of approximately 1.16 mg/mL.  Specific instructions are 
provided separately in the Dose Preparation Guidelines.  It is important not to use 
evacuated glass containers (to prepare the infusion), which require vented 
administration sets because this causes foaming as air bubbles pass through the 
solution.
Prior to the start of the infusion, please ensure that the content of the bags is at room 
temperature to avoid an infusion reaction due to the administration of the solution at low 
temperatures.
6.1.1.2
Infusion Procedures
Ocrelizumab should be given as a slow IV infusion.  It must not be administered as an 
IV push or bolus.  Well-adjusted infusion pumps should be used to control the infusion 
rate and the study drug should be infused through a dedicated line.
All participants should receive pretreatment before the infusion (see Section 6.1.2).
6.1.1.3
Dual Infusion Cycle (Cycle 1 and OLE Cycle 5)
The first cycle of the double-blind double-dummy treatment period (Cycle 1) and 
OLE phase (Cycle 5) will consist of 2 infusions of 300 mg ocrelizumab IV administered 
14 days apart.  For each infusion it is necessary to prepare a single infusion bag
containing 300 mg ocrelizumab.  Specific instructions will be provided separately in the 
Dose Preparation Guidelines and must be followed exactly.  The infusion should be 
started at a rate of 32 mL/h.  This should be escalated at the rates shown in Table 8.


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Table 8
Infusions of Ocrelizumab 300 mg
Time
(Minutes)
Infusion Rate
(mL/hr)
Maximum Dose per 
Interval (mg)
Cumulative Dose
(mg)
030
32
18.75
18.75
3160
65
37.5
56.25
6190
97
56.25
112.5
91120
129
75
187.5
121150 a
194
112.5
300 a
a Infusion of 300 mg ocrelizumab should be completed at approximately 150 minutes 
(approximately 2.5 hours).
6.1.1.4
Single Infusion Cycles (Cycles 2 - 4, and OLE Cycle 6 Onwards)
Cycles 24 of the double-blind, double-dummy treatment period and Cycle 6 onwards in 
the OLE phase will consist of 1 infusion of 600 mg ocrelizumab IV administered on 
Day 1 of each cycle.  For each cycle it is necessary to prepare a single infusion bag
containing a total of 600 mg ocrelizumab/ocrelizumab placebo.  Specific instructions will 
be provided separately in the Dose Preparation Guidelines and must be followed 
exactly.  The infusion should be started at a rate of 40 mL/hr.  This should be escalated 
at the rates shown in Table 9.
Table 9
Subsequent Infusions of Ocrelizumab 600 mg
Time
(Minutes)
Infusion Rate
(mL/hr)
Maximum Dose per Interval 
(mg)
Cumulative Dose
(mg)
030
40
23.18
23.18
3160
85
49.27
72.45
6190
130
75.36
147.81
91120
169
98.05
245.86
121215 a
200
354.14 b
600.00
a Infusion of 600 mg ocrelizumab should be completed at approximately 215 minutes 
(approximately 3.6 hours).
b This last interval is approximately 95 minutes, delivering a maximum dose of 115.94 mg per 
0.5 hour.
6.1.1.5
Alternative Shorter Infusion of Subsequent 600 mg 
Ocrelizumab Doses
If participants did not experience a serious IRR with any previous ocrelizumab infusion, a 
shorter (2-hour) infusion of 600 mg can be administered for subsequent doses.  
The shorter infusion should be started at a rate of 100 mL/hr.  This should be escalated 
at the rates shown in Table 10.


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Table 10 Alternative Shorter Infusions of Ocrelizumab 600 mg
Time
(Minutes)
Infusion Rate
(mL/hr)
Maximum Dose per Interval 
(mg) a
Cumulative Dose
(mg)
015
100
30
30
1530
200
60
90
3060
250
150
240
60120 b
300
360
600
a Assumes that the infusion bag contains 600 mg ocrelizumab in 500 mL 0.9% sodium 
chloride.  Refer to the Dose Preparation Guidelines for more information. 
b The shorter infusion of 600 mg ocrelizumab should be completed in approximately 
120 minutes (2 hours).
See Section 7.3.1.1 of this protocol and to the current version of the Ocrelizumab IB for 
further details on the alternative shorter infusion option, including safety information.
Because of possible need to vary infusion rates depending on tolerance of the infusion, 
the total infusion time may exceed the time stated.  Unless an infusion reaction occurs 
necessitating discontinuation, the entire content of the infusion bag must be 
administered to the participant.
After completion of the infusion, the IV cannula should remain in situ for at least 1 hour in 
order to be able to administer drugs IV, if necessary in the event of a delayed reaction.  
If no adverse events occur during this period of time, the IV cannula may be removed 
and the participant may be discharged.
The prepared infusion solution of ocrelizumab is physically and chemically stable for 
24 hours at 2–8C and, subsequently, 8 hours at room temperature. The prepared 
infusion solution should be used immediately.  If not used immediately, it can be stored 
for up to 24 hours at 2–8C.  The infusion solution must be completely administered to 
the participant within 32 hours of preparation (not exceeding 24 hours at 2–8°C and 
8 hours at room temperature).
As noted above, the diluted infusion bags should be at room temperature prior to 
administration to the participant.
6.1.2
Prevention and Treatment of Infusion-Related Reactions
Methylprednisolone has been shown to decrease the incidence and the severity of 
infusion reactions.  In participants with RA treated with a similar agent, rituximab, the 
rate and severity of infusion reactions markedly decreased with IV corticosteroid 
premedication (Emery et al. 2006).  A recent integrated analysis of participants with MS 
treated with ocrelizumab revealed that the addition of antihistamines to pretreatment with 
methylprednisolone decreased the incidence of IRRs by 2-fold (OCREVUS USPI).


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To reduce potential infusion reactions, all participants will receive prophylactic treatment 
with 100 mg of methylprednisolone, administered by slow IV infusion, and an oral or IV 
antihistamine (such as diphenhydramine 50 mg or an equivalent dose of an alternative). 
Methylprednisolone administration is to be completed approximately 30 minutes before 
the start of each ocrelizumab infusion; antihistamines should be administered 
3060 minutes prior to the start of an infusion.  In the event that the use of 
methylprednisolone is contraindicated, use of an equivalent dose of alternative steroid 
should be used as premedication prior to the infusion.  Participants administered a 
sedating antihistamine medication for the treatment or prevention of infusion reactions 
should be given appropriate warnings concerning drowsiness and potential impairment 
of the ability to drive or operate machinery.
It is also recommended that the infusion be accompanied by prophylactic treatment with 
an analgesic/antipyretic such as 1 g acetaminophen/paracetamol 3060 minutes prior to 
the start of an infusion to reduce potential infusion reactions.  Participants administered 
a sedating antihistamine for the treatment or prevention of infusion reactions should be 
given appropriate warnings concerning drowsiness and potential impairment of ability to 
drive or operate machinery.
Since transient hypotension may occur during ocrelizumab infusion, the investigator may 
wish to withhold antihypertensive medications 12 hours prior to ocrelizumab infusion.
Infusion-related reactions should be treated symptomatically with oral 1 g 
acetaminophen/paracetamol, and IM or slow IV antihistamine administration, such as 
diphenhydramine (25–100 mg).  Acetaminophen/paracetamol and diphenhydramine 
dosing should be repeated as clinically indicated.  Non-allergic events should be treated 
symptomatically as judged clinically relevant by the investigator.
In participants with associated respiratory symptoms (stridor, wheeze or 
bronchospasm), additional treatment with bronchodilators may be indicated.
One participant with well-controlled asthma at baseline experienced an acute asthma 
attack following their first rituximab infusion.  Physicians should; therefore, monitor 
participants with a history of asthma carefully and institute an appropriate treatment if 
signs and symptoms of asthma are noticed.
After completion of the infusion, the IV cannula should remain in situ for at least 1 hour in 
order to be able to administer drugs IV, if necessary in the event of a delayed reaction.  
If no adverse events occur during this period of time, the IV cannula may be removed 
and the participant may be discharged.
Section 6.1.3 details the reduction, interruption or discontinuation of the infusion in the 
event of an infusion reaction.


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6.1.3
Ocrelizumab Dose Modifications, Interruptions, and Delays
No ocrelizumab dose modifications are foreseen.
Slowing of the infusion rate or interruption of the infusion may be necessary in the event 
of an infusion reaction.  In rare participants, ocrelizumab treatment may need to be 
discontinued.  Guidance is provided below.
6.1.3.1
Handling Infusion Reactions
Handling of IRRs will depend on the intensity of symptoms (see Section 7.1.1.1 for 
grading of intensity of IRRs).
In the event that a participant experiences a (CTCAE Grade 1 or 2; Appendix 3) 
infusion-related event, the infusion rate should be reduced to half the rate being given at 
the time of onset of the event (e.g., from 50–25 mL/hr or from 100–50 mL/hr).  Once the 
event has resolved, the investigator should wait for 30 minutes while delivering the 
infusion at the reduced rate.  If tolerated, the infusion rate may then be increased to the 
next closest rate on the participant’s infusion schedule and the rate increments resumed.
Participants who experience an infusion-related event (CTCAE Grade 3) or flushing, 
fever and throat pain cluster should have their infusion interrupted immediately 
and should receive aggressive symptomatic treatment.  The infusion should be 
re-started only after all the symptoms have disappeared.  The initial infusion rate at 
restart should be half of the infusion rate that was in progress at the time of onset of 
the reaction.
Please note: participants who experience a life-threatening infusion-related event 
(CTCAE Grade 4) during an infusion should have their infusion immediately stopped and 
should receive appropriate treatment (including use of resuscitation medications and 
equipment that must be available and used as clinically indicated).  These participants 
should be withdrawn from treatment and should enter the safety follow-up period.
6.1.4
Criteria for Re-Treatment with Ocrelizumab
Prior to re-treatment with ocrelizumab, participants will be evaluated for the following 
conditions and laboratory abnormalities.  If any of these conditions are present prior to 
re-dosing, further administration of ocrelizumab should be suspended until resolved or 
held indefinitely:

Life-threatening (CTCAE Grade 4) infusion-related event that occurred during a 
previous ocrelizumab infusion

Any significant or uncontrolled medical condition or treatment-emergent, clinically 
significant laboratory abnormality

Active infection (including active TB infection, either new onset or reactivation)
Participants with active TB infection, either new onset or reaction, must suspend 
ocrelizumab treatment for as long as needed to ensure full resolution of the 


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TB infection.  These participants should receive medical care in adherence with 
local/national requirements until complete resolution of the TB infection and should 
be monitored subsequently as per local medical plans.  Upon resolution of the 
TB infection, and based on individual benefitrisk assessments, these participants 
will have the opportunity to restart ocrelizumab treatment if it is considered 
beneficial for them.  Otherwise, the Treating Investigator can decide to permanently 
stop ocrelizumab.

ANC 1.5103/L

CD4 cell count 250/L

Hypogammaglobulinemia IgG 3.3 g/L

Ongoing pregnancy or breastfeeding (for female participants)
In the event of pregnancy, the investigator must counsel the participant as to the 
risks of continuing with the pregnancy and the possible effects on the fetus.  
Given that there are insufficient, well-controlled data from studies testing the use of 
ocrelizumab in pregnant or breastfeeding women, all infusions of ocrelizumab must 
be suspended until the completion of pregnancy and breastfeeding.  Pregnant and 
breastfeeding participants should continue to follow the schedule of activities for the 
OLE; however, no infusions of ocrelizumab will occur.  If there is a concern with the 
ability of a pregnant or breastfeeding participant to perform all scheduled 
assessments, the investigator must contact the Medical Monitor for further 
discussion.  In the OLE period of the study, restart of ocrelizumab treatment 
following pregnancy and breastfeeding will be decided as a result of a thorough 
benefit/risk discussion between the participant and investigator.
Please note: any critical blinded laboratory values for IgG, ANC, and CD4 will be 
provided to the Principal Investigator and the Medical Monitor.  Investigators notified of 
their participant’s critical laboratory test result will be instructed to suspend further 
treatment with study drug until the participant can be further evaluated.  A repeat 
laboratory test may be necessary to confirm the results.  Participants with values below 
these critical values should not be re-treated until the re-treatment criteria are met and 
these laboratory values have normalized.
6.2
REBIF
6.2.1
Dose and Schedule of Rebif
See Table 11 for overview of Rebif dosing regimen.
The first SC injection of Rebif/placebo will be administered on study Day 1.  
Participants will be instructed by a nurse or investigator how to self-administer the 
injections; the first dose of Rebif/placebo will be self-administered under the supervision 
of a nurse or physician.  Thereafter, participants will self-administer their Rebif/placebo 
treatment 3 times weekly.  Rebif/placebo must be administered, if possible, at the same 
time (preferably in the late afternoon or evening) on the same 3 days 
(e.g., Monday, Wednesday, and Friday) at least 48 hours apart.  Participants must be 


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instructed in the use of aseptic techniques when administering Rebif/placebo injections.  
Participant understanding and use of aseptic self-injection techniques and procedures 
must be periodically re-evaluated.
Since Rebif needs to be stored at 28°C, it is recommended to remove the syringe from 
refrigerator at least 30 minutes prior to use.  Participant should be reminded not to heat 
or microwave a syringe.
When starting treatment with Rebif, the dose will be gradually escalated (Table 11).  
The Rebif/placebo initiation package corresponds to the participant needs for the first 
month of treatment.
Table 11 Overview of Rebif Dosing Regimen
Treatment Initiation
Treatment 
Continuation
Dose modification 
(if required)
Week
Weeks 12
Weeks 34
Week 5 onwards
─
Study 
Day
114
1528
29 
At any time Day29
Dose 
of 
Rebif
Rebif 8.8 g
(1 pre-filled 
syringe [0.2 mL] 
containing 
2.4 MIU of 
IFN -1a) SC
3 per week
Rebif 22 g
(1 pre-filled 
syringe [0.5 mL] 
containing 6 MIU 
of IFN -1a) SC
3 per week
Rebif 44 g
(1 pre-filled syringe 
[0.5 mL] containing 
12 MIU of IFN -1a) 
SC
3 per week
Rebif 22 g
(1 pre-filled syringe 
[0.5 mL] containing 
6 MIU of IFN -1a) 
SC
3 per week
Note:  Rebif is provided in a blinded fashion.
Nonsteroidal anti-inflammatory drugs (ibuprofen) or acetaminophen are recommended in 
case of injection site reaction; the investigator should follow the local label for further 
information.
Note: During the OLE phase screening period, administration of Rebif/Rebif placebo SC
3per week should occur.  If during this period, the participant decides not to participate 
in the OLE phase then administration of Rebif/Rebif placebo 3per week should be 
terminated.
6.2.2
Rebif Dose Modifications, Interruptions, and Delays
Rebif/Rebif placebo should be taken 3 a week.  Rebif/Rebif placebo should never be 
taken on 2 consecutive days.  If a participant misses a dose, then the next dose must be 
taken as soon as possible.  The participant should avoid taking Rebif/Rebif placebo on 
the following day.  The participant should return to their regular schedule the following 
week.  If a participant takes more than the prescribed dose or takes it on 2 consecutive 
days, they should inform the investigator immediately.


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The Rebif/Rebif placebo dosage can be modified at the discretion of the 
Principal Investigator due to safety reasons at any time; the Principal Investigator should 
follow information on the local label for further information.
Asymptomatic increases in laboratory parameters of hepatic function have been 
associated with Rebif.


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In case of elevation of liver function tests the following rules will apply:
ALT 10 ULN OR jaundice or other 
clinical symptoms of liver dysfunction
In case of detection of elevated ALT 10 ULN, 
jaundice or other clinical symptoms of liver 
dysfunction the injections of Rebif/Rebif placebo 
must be discontinued permanently.  The monitoring 
of liver function tests should be continued on a 
monthly basis until return to normal baseline levels 
or NCI CTCAE v4.0 Grade 1 toxicity (ALT:  ULN 
3.0 ULN).  A consultation with hepatologist is 
recommended.  Participants should move to safety 
follow-up period.
ALT 5 ULN
In case of detection of elevated ALT 5 ULN
(but below 10 ULN) the injections of Rebif/Rebif 
placebo must be discontinued temporarily.  
Additional blood chemistry panel including AST, 
ALP, GGT, and bilirubin should be performed 
biweekly until no further increase is observed.  
Subsequently, ALT analysis has to be performed 
every month until return to normal baseline levels or 
NCI CTCAE v4.0 Grade 1 toxicity (ALT:  ULN 
3.0 ULN).  A consultation with hepatologist should 
be considered as per investigator judgment.
If causes of toxicity other than possible 
treatment with Rebif are excluded, the 
participant may then be cautiously re-
challenged with Rebif/Rebif placebo 22 g 
provided in a blinded fashion upon request to IxRS.  
The monitoring of liver function tests should 
continue on a monthly basis.  If there is no further 
recurrence of toxicity, participant may continue 
treatment with Rebif/Rebif placebo 44 g provided 
in a blinded fashion upon investigator’s request to 
IxRS.  In case of recurrence of toxicity 
(ALT 3 ULN, or other clinical symptoms of 
liver dysfunction) the injections of Rebif/Rebif 
placebo should be discontinued permanently.  
Participants should move to safety follow-up period.
Please note:  Re-initiation of therapy with Rebif 
following elevation of liver function tests can only be 
considered once.
ALT 3 ULN
In case of detection of elevated ALT 3 ULN
(but below 5 ULN) additional blood chemistry 
panel including AST, ALP, GGT and bilirubin should 
be performed biweekly until no further increase is 
observed.  Subsequently, ALT analysis has to be 
performed every month until return to normal 
baseline levels or NCI CTCAE v4.0 Grade 1 toxicity 
(ALT:  ULN 3.0 ULN).


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6.3
FORMULATION, PACKAGING, AND LABELING
Study drug packaging will be overseen by the Roche clinical trial supplies department 
and bear a label with the identification required by local law, the protocol number, drug 
identification and dosage.
The packaging and labeling of the study medication will be in accordance with Roche 
standards and local regulations.
Upon arrival of investigational products at the site, site personnel should check them for 
damage and verify proper identity, quantity, integrity of seals and temperature 
conditions, and report any deviations or product complaints to the monitor upon 
discovery.
6.3.1
Ocrelizumab
6.3.1.1
Formulation
Ocrelizumab is manufactured as a sterile, clear, colorless, preservative free liquid 
intended for dilution for IV administration.
Ocrelizumab is supplied as a liquid formulation containing 30 mg/mL ocrelizumab in 
20 mM sodium acetate at pH 5.3, with 4% (106 mM) trehalose dihydrate and 
0.02% polysorbate 20.  The drug product is provided as a single-use liquid formulation in 
a 15 cc Type I USP glass vial, fitted with a 20 mm fluoro-resin laminated stopper and an 
aluminum seal with a flip-off plastic cap. The vial contains 300 mg ocrelizumab.  
No preservative is used as each vial is designed for single use.
Ocrelizumab may contain fine translucent and/or reflective particles associated with 
enhanced opalescence.  Do not use the solution if discolored or if the solution contains 
discrete foreign particulate matter.  The infusion solution must be administered with use 
of an infusion set with an in-line, sterile, non-pyrogenic, low-protein-binding filter (pore 
size of 0.2 m or less).
Ocrelizumab-matching placebo is also supplied in 15 cc single-use vials.  Placebo has 
the same composition and configuration as the drug product, but does not contain 
ocrelizumab.
6.3.1.2
Packaging
The hospital units/pharmacy will receive study medication kits for each participant.
For the double-blind treatment in Cycle 1, consisting of two 300 mg infusions 14 days 
apart, the study medication kit will contain 2 single-use liquid vials with ocrelizumab 
(or ocrelizumab placebo).


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For each of the subsequent Cycles 24, consisting of a single 600 mg infusion, 2 kits will 
be dispensed.  Each kit will contain 2 single-use liquid vials with ocrelizumab 
(or ocrelizumab placebo), from which only 3 vials should be used.
For the OLE phase, each study medication kit will contain 1 single-use vial.  
For OLE phase Cycle 5, consisting of two 300 mg infusions 14 days apart, 2 study 
medication kits will be supplied per infusion.  For OLE phase Cycle 6 and each of the 
subsequent cycles consisting of 600 mg infusions, 2 study medication kits (of 300 mg 
ocrelizumab each) will be dispensed.  Detailed instructions are provided separately in 
the Dose Preparation Guidelines.
6.3.1.3
Storage of Ocrelizumab and Placebo Vials for Infusion
Ocrelizumab and placebo vials are stable at 28°C (refrigerated storage).  They should 
not be used beyond the expiration date stamped on the carton.  Expiration dating may 
be extended during the trial; the Sponsor will provide documentation.  Ocrelizumab vials 
should not be frozen or shaken and should be protected from direct sunlight.
The study medication labels will be produced in accordance with the local requirements.
6.3.2
Rebif
6.3.2.1
Formulation and Packaging
Rebif (IFN -1a) will be supplied as a liquid formulation for injection in pre-filled syringes.
The liquid formulation is supplied in syringes containing 0.2 mL or 0.5 mL of solution.  
These commercially available syringes will be provided to the sites by the Sponsor and 
re-labeled as investigational medicinal product.
The placebo to Rebif is provided as a liquid formulation in a pre-filled syringe containing 
0.2 mL or 0.5 mL of 0.9% sodium chloride solution without any active substance.
The study medication kits, which will be used for the initial 4 weeks of treatment, will 
contain 12 pre-filled syringes, either 68.8 g and 622 g OR placebo.  The study 
medication kits that will be used for treatment continuation will contain 12 pre-filled 
syringes 1244 g of IFN -1a or 1222 g of IFN -1a or placebo.
The Rebif and Rebif placebo pre-filled syringes are for SC use only.
Please note: if Rebif dose modification is required due to laboratory abnormalities 
possibly related to the treatment with Rebif, the investigator (the treating physician) will 
need to notify IxRS and the blinded study medication (Rebif placebo or Rebif verum) will 
be dispensed accordingly.  In addition, to ensure participant safety in the study, 
unscheduled visits may be required for additional assessments, monitoring and for 
dispensing study medication.


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The study medication labels will be produced in accordance with the local requirements.  
The strength will be presented as follows: 44 g/22 g/placebo.
6.3.2.2
Storage of Rebif
Rebif/Rebif placebo pre-filled syringes need to be stored in a refrigerator at 28°C, in the 
original package in order to protect from light.  The participant may remove Rebif from 
the refrigerator and store it not above 25°C for one single period of up to 14 days.  
Rebif must then be returned to the refrigerator and used before the expiry date.
6.4
BLINDING AND UNBLINDING
During the double-blind phase of the study, the Participant Randomization List will be 
generated by IxRS with use of a pre-defined randomization specification.  
The Randomization List will not be available at the study center, to the Roche monitors, 
project statisticians or to the Sponsor’s project team.  Unblinding of treatment 
assignment should not occur except in the case of emergency situations, where the 
knowledge of what study medication the participant is receiving is critical for clinical 
management.  Principal Investigators are asked to contact the Roche Medical Monitor, 
prior to unblinding any participant, in order to discuss the medical necessity for 
unblinding.  Any request from the investigator for information about the treatment 
administered to study participants for another purpose must be discussed with Roche.  
Unblinding will be performed by means of an IxRS.  As per regulatory reporting 
requirements, Roche will unblind the identity of the study medication for serious adverse 
events that are considered by the investigator or the Sponsor to be related to study drug, 
that are unexpected as per safety reference document(s), e.g., IB, Core Data Sheet, and
Summary of Product Characteristics, and that are not exempted from unblinding as per 
Section 7.2.2.2.  Details of participants who are unblinded during the study will be 
included in the Clinical Study Report.
In the double-blind phase of the study, unblinding for analysis of biological samples, 
PK data analysis, or ongoing safety monitoring by a Data Monitoring Committee (DMC), 
will be performed according to procedures in place to ensure integrity of the data.
Participant treatment allocation during the double-blind, double-dummy treatment period 
will not be unblinded until the last data point from the last participant is received, as 
required for statistical analysis defined in Section 8.2 and the SAP (see Section 4.1.8).
6.5
ACCOUNTABILITY OF INVESTIGATIONAL MEDICINAL 
PRODUCT AND ASSESSMENT OF COMPLIANCE
6.5.1
Accountability of Investigational Medicinal Product
The investigator is responsible for the control of drugs under investigation.  
Adequate records for the receipt and disposition of the study drug must be maintained.  
Accountability will be assessed by maintaining adequate drug dispensing and return 
records.


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Accurate records must be kept for each study drug provided by the Sponsor.  
These records must contain the following:

Documentation of drug shipments received from the Sponsor (date received and 
quantity)

Disposition of unused study drug not dispensed to participant
A Drug–Dispensing Log must be kept current and should contain the following 
information:

The identification of the participant to whom the study medication was dispensed

The date(s) and quantity of the study medication dispensed to the participant

The date(s) and quantity of the study medication returned by the participant
All records and drug supplies must be available for inspection/accountability by the study 
monitor at every monitoring visit.
6.5.2
Assessment of Compliance
Participant compliance will be assessed by maintaining adequate study drug dispensing 
records.  The investigator is responsible for ensuring that dosing is administered in 
compliance with the protocol.  Delegation of this task must be clearly documented and 
approved by the investigator.
The study pharmacist should keep all ocrelizumab/ocrelizumab placebo vials to measure 
compliance.  All participants will be asked to return on regular intervals all used and 
unused Rebif/Rebif placebo containers to the site as a measure of compliance.
6.6
DESTRUCTION OF THE INVESTIGATIONAL MEDICINAL 
PRODUCT/COMPARATOR
Local or institutional regulations may require immediate destruction of used IMP for 
safety reasons.  In these cases, it may be acceptable for investigational site staff to 
destroy dispensed IMP before a monitoring inspection provided that source document 
verification is performed on the remaining inventory and reconciled against the 
documentation of quantity shipped, dispensed, returned and destroyed.  
Written authorization must be obtained from the Sponsor at study start up before 
destruction.
Written documentation of destruction must contain the following:

Identity (batch numbers or medication numbers) of IMP and comparators destroyed

Quantity of IMP destroyed

Date of destruction

Method of destruction

Name and signature of responsible person who destroyed the IMP


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Wherever possible, preferably drug should be destroyed locally on site according to their 
local policies and procedures once drug accountability has been completed by the 
monitor.
7.
SAFETY INSTRUCTIONS AND GUIDANCE
7.1
ADVERSE EVENTS AND LABORATORY ABNORMALITIES
7.1.1
Clinical Adverse Events
According to the International Conference of Harmonisation (ICH), an adverse event is 
any untoward medical occurrence in a participant or clinical investigation participant
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment.  An adverse event can; therefore, be any unfavorable 
and unintended sign, including an abnormal laboratory finding, symptom, or disease 
temporally associated with the use of a (investigational) medicinal product, whether or 
not considered related to the medicinal (investigational) product.  Preexisting conditions 
which worsen during a study are to be reported as adverse events.
In the eCRF, adverse events will be reported at each visit.
Clinical relapses will be recorded only on a pre-specified eCRF “MS relapse” eForm.
Infusion-related reactions will be recorded only on a pre-specified eCRF 
“Infusion-Related Reaction” eForm.
B cell depletion is the expected outcome of ocrelizumab treatment and is not an adverse 
event.  However, participants may be at risk for infections and particular attention should 
be directed toward early identification and treatment of infections.  During the study, 
investigators are requested to promptly investigate participants reporting signs or 
symptoms of infection, to take appropriate specimens for identification of the pathogen 
and to treat infections aggressively (see Section 7.3.1).  Prior to enrollment into the 
study, it is recommended that the investigators review and, if warranted, update 
participant’s immunizations in accordance with country medical immunization guidelines 
(see Section 5.5.3).
7.1.1.1
Intensity of Clinical Adverse Events
Adverse events will be graded according to CTCAE, v4 and is provided to the 
investigator in a separate handout entitled “Common Terminology Criteria for Adverse 
Events v4.0”- see Appendix 3.
Adverse events not listed by the CTCAE and IRRs as a comprehensive entity will be 
graded with use of the following criteria:

Grade 1:  discomfort noticed but no disruption of normal daily activity

Grade 2:  discomfort sufficient to reduce or affect normal daily activity

Grade 3:  inability to work or perform normal daily activity


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
Grade 4:  represents an immediate threat to life
Any Grade 4 adverse event, either by CTCAE criteria or the additional criteria listed in 
Section 7.1.1.3, should be reported as an serious adverse event.
7.1.1.2
DrugAdverse Event Relationship
Relationship of the adverse event to the treatment should always be assessed by the 
investigator.  The causality relationship of study drug to the adverse event will be 
assessed by the investigator as either: Yes or No.  See Appendix 1 for more details.
7.1.1.3
Serious Adverse Events (Immediately Reportable to Sponsor)
A serious adverse event is any experience that suggests a significant hazard, 
contraindication, side effect or precaution.  It is any adverse event that, at any dose, 
fulfils at least 1 of the following criteria:

Is fatal; (results in death; please note: death is an outcome, not an event)
The term “sudden death” should only be used when the cause is of a cardiac origin
as per standard definition.  The terms “death” and “sudden death” are clearly distinct 
and must not be used interchangeably.

Is life-threatening (please note: the term “Life-Threatening” refers to an event in 
which the participant was at immediate risk of death at the time of the event; it does 
not refer to an event which could hypothetically have caused a death had it been 
more severe)

Required in-patient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is medically significant or requires intervention to prevent one or other of the 
outcomes listed above
The following are not considered as a serious adverse event:

Elective hospitalizations or surgical procedures that are a result of a participant’s 
preexisting condition(s) that have not worsened since receiving trial medication. 
Examples may include, but are not limited to, cholecystectomy for gallstones, and 
diagnostic testing.  Such events should still be recorded as medical procedures in 
the Concomitant Procedures/Treatments eCRF.

Hospitalization to receive trial medication such as infusions of ocrelizumab unless 
this is prolonged (more than 24 hours)

Hospitalization following an MS relapse as long as the reason for hospitalization is 
to receive standard treatment with IV methylprednisolone (or with another equivalent 
corticosteroid; see Section 5.5.2)
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF. Generally, only 1 such event should be reported.  


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If the cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the Adverse Event eCRF.  If the cause of 
death later becomes available (e.g., after autopsy), "unexplained death" should be 
replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
For a list of serious ADRs that are considered expected, refer to the current version of 
the Ocrelizumab IB.
The study will comply with all local regulatory requirements and will adhere to the full 
requirements of the ICH Guideline for Clinical Safety Data Management, Definitions and 
Standards for Expedited Reporting, Topic E2 (see Appendix 2).
7.1.1.4
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; 
see Section 7.2.2 for reporting instructions). Company-mandated adverse events of 
special interest include the following:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s law (see Section 7.1.3.1)

Suspected transmission of an infectious agent by the study drug, as defined below:
–
Any organism, virus, or infectious particle (e.g., prion protein-transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent
Transmission of an infectious agent may be suspected from clinical symptoms or 
laboratory findings that indicate an infection in a participant exposed to a medicinal 
product. This term applies only when a contamination of the study drug is suspected.
7.1.2
Treatment and Follow-Up of Adverse Events
Adverse events should be followed up until they have stabilized or have returned to 
baseline status (in the event of an exacerbation of a preexisting condition).  This is 
especially important for those events where the reported causal relationship to study 
medication(s) is “related”.  If a clear explanation is established, it should be recorded on 
the eCRF.
If after study completion or withdrawal, return to baseline status or stabilization cannot 
be established an explanation should be recorded on the eCRF.
7.1.3
Laboratory Test Abnormalities
Laboratory test results will appear on electronically produced laboratory reports 
submitted directly from the central laboratory.


 
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Any treatment-emergent abnormal laboratory result Zhich is clinically significant, 
ie, meeting 1 or more of the folloZing conditions, should be recorded as a single 
diagnosis on the adverse event eForm in the eCRF 
 
Accompanied by clinical symptoms 
 
Leading to a change in study medication (eg, dose modification, interruption or 
permanent discontinuation) 
 
ReTuiring a change in concomitant therapy (eg, addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment) 
 
Any laboratory result abnormality fulfilling the criteria for a serious adverse event should 
be reported as such, in addition to being recorded as an adverse event in the eCRF 
... 
Follow-8p of Abnormal Laboratory Test 9alues 
In the event of medically significant unexplained abnormal laboratory test values, the 
tests should be repeated and folloZed up until they have returned to the normal range 
and/or an adeTuate explanation of the abnormality is found  If a clear explanation is 
established it should be recorded on the eCRF 
B cell depletion is a pharmacodynamic effect and is not an adverse event 
During the double-blind, dummy-dummy treatment period, blinded laboratory values for 
IgG, ANC and CD Zill be provided to the investigator and the Medical Monitor  
Investigators notified of their participant¶s critical laboratory test result Zill be instructed 
to suspend further treatment Zith study drug until the participant can be further 
evaluated  A repeat laboratory test may be necessary to confirm the results  
Participants Zith values beloZ these critical values should not be re-treated until the 
re-treatment criteria are met (see Section 61) and these laboratory values have 
normalized  During the OLE phase from Cycle 6 onZard, these laboratory values Zill 
not be blinded 
... 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (! 3 u 8LN) in combination Zith either an elevated 
total bilirubin (! 2 u 8LN) or clinical Maundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver inMury  
Therefore, investigators must report as an adverse event the occurrence of either of the 
folloZing 
 
Treatment-emergent ALT or AST ! 3 u 8LN in combination Zith total bilirubin 
! 2 u 8LN 
 
Treatment-emergent ALT or AST ! 3 u 8LN in combination Zith clinical Maundice 
 
The most appropriate diagnosis or (if a diaPgnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 7.1.1) 


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and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or a non-serious adverse event of special 
interest (see Section 7.1.1.2 and Section 7.1.1.3).
7.2
HANDLING OF SAFETY PARAMETERS
7.2.1
Reporting of Adverse Events 
All adverse events will be documented in the eCRF.
New or worsening neurological symptoms not considered MS-related should be 
recorded on an adverse event page and the Medical Monitor should be informed.
7.2.2
Reporting of Serious Adverse Events
7.2.2.1
Immediate Reporting to the Sponsor
Any clinical adverse event or abnormal laboratory test value that is serious (as defined in 
Section 7.1.1.3), or adverse events of special interest (as defined in Section 7.1.1.4),
which occur during the course of the study, regardless of the treatment group, must be 
reported to the Sponsor within 24 hours of the investigator becoming aware of the event 
(expedited reporting).  In addition, for fatal and life-threatening events, the Roche 
Medical Monitor should be contacted immediately.  Contact numbers for the Roche 
Medical Monitor (including afterhours cover) will be provided to the site before any 
participants are screened.
After the participant signs the Informed Consent Form, but prior to initiation of study 
medication, only serious adverse events caused by a protocol-mandated intervention will 
be collected (e.g., serious adverse events related to MRI examination).  After first dose 
of study medication, all serious adverse events must be reported.
Related serious adverse events MUST be collected and reported regardless of the time 
elapsed from the last study drug administration, even if the study has been closed.
Unrelated serious adverse events must be collected and reported during the study 
through the end of the safety follow-up period, which is up to 48 weeks after the last 
infusion.  The investigator must complete the serious adverse event Reporting Form in 
the eCRF.  Relevant follow-up information should be submitted as soon as it becomes 
available.  Only if a technical failure prevents the ability to report a serious adverse event 
in the eCRF, then the paper serious adverse event Reporting Form provided by the 
Sponsor must be completed and faxed to the number provided.
A death occurring during the study or information related to such occurrence that comes 
to the attention of the investigator during the study must be reported immediately to the 
Sponsor, whether considered treatment-related or not.


 
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Of specific importance is the prompt reporting of serious infections  In particular, PML 
should be reported as a serious adverse event (Zith all available information) Zith 
immediate notification of the Medical Monitor 
This study adheres to the definition and reporting reTuirements of ICH Guideline for 
Clinical Safety Data Management, Definitions, and Standards for Expedited Reporting, 
Topic E2 (see Appendix 2) 
... 
(mergency Medical Contacts 
Medical Monitor Contact Information 
Medical Monitor/ 
Roche Medical Responsible: 
 M.D. 
Mobile Telephone No.: 
E-mail: 
 
To ensure the safety of the study participants, an Emergency Medical Call Center Help 
Desk Zill access the Roche Medical Emergency List, escalate emergency medical calls, 
provide medical translation services (if necessary), connect the investigator Zith a 
Roche Medical Monitor, and track all calls  The Emergency Medical Call Center Help 
Desk Zill be available 2 hours per day,  days per Zeek  Toll-free numbers for the 
Help Desk and Medical Monitor contact information Zill be distributed to all investigators 
(see ³Protocol Administrative and Contact Information and List of Investigators´) 
... 
(xpedited Reporting to Health Authorities Investigators 
Institutional Review Boards and (thics Committees  
The Sponsor Zill promptly evaluate all reported serious adverse events against 
cumulative product experience to identify and expeditiously communicate possible neZ 
safety findings to investigators, IRBs, ECs, and relevant health authorities based on 
applicable legislation 
Reporting reTuirements Zill be based on the investigator
s assessment of causality and 
seriousness, Zith alloZance for upgrading by the Sponsor as needed  To determine 
reporting reTuirements for single adverse event cases, the Sponsor Zill also assess the 
expectedness of the event on the basis of the Ocrelizumab IB and the E8 Summary of 
Product Characteristics for IFN -1a 
In principle, adverse events Zhich are serious, related and unexpected Zill be reported 
in an expedited manner Zithin 1 days (non-fatal/non-life-threatening) or  days (fatal or 
life-threatening) 
Only those adverse events Tualifying for expedited reporting occurring in participants on 
active treatment Zill be sent in an expedited timeframe to health authorities  
This reTuires unblinding of participant treatment allocation  Investigators, IRBs, and ECs 
Zill receive blinded reports unless local regulations reTuire that unblinded expedited 
reports are sent 


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In the double-blind phase of this study, the relation to study medication for certain types 
of adverse events cannot be assessed based on single case evaluation.  Therefore, in 
order to prevent unnecessary unblinding of study participants during the double-blind 
phase of the study, the following events are exempted from expedited reporting:

Neoplasms benign, malignant, and unspecified (including cysts and polyps)

Infections and infestations with the exception of opportunistic infections 
(including PML and reactivation of viral infections)
The DMC will review adverse events at periodic meetings and assess their relation to 
study medication based on review of aggregate unblinded safety information until the 
primary analysis is performed.  Following unblinding after the 96-week period, 
independent Data Monitoring Committee (iDMC) involvement in safety monitoring 
throughout the OLE phase is no longer needed.
7.2.3
Pregnancy and Lactation
In the OLE phase of the study, female participants should take all appropriate 
precautions to avoid becoming pregnant during this study. Women of childbearing 
potential must use the method of contraception defined by the protocol (see Section 5.4) 
for the duration of the trial and for 6 months after receiving their last infusion of 
ocrelizumab.  Regular pregnancy tests will be performed during the study.
Reproductive toxicology studies of ocrelizumab conducted in cynomolgus monkeys are 
described in the Ocrelizumab IB.  Studies of the effect of ocrelizumab on human 
reproduction have not been performed.  It is not known whether ocrelizumab can cause 
fetal harm when administered to pregnant women or whether it can affect reproductive 
capacity.  However, since IgG molecules such as ocrelizumab are known to cross the 
placenta, ocrelizumab may cause fetal CD20 B-cell depletion.  Because pregnancy 
induces a natural state of immunosuppression, it is unknown whether pregnancy in 
combination with ocrelizumab exposure may cause a more profound state of 
immunosuppression (Branch 1992). It is also unknown whether ocrelizumab is excreted 
in breast milk and what effect this might have on the breastfeeding infant.  However, it 
should be noted that immunoglobulins are found in breast milk.
A female participant must be instructed to immediately inform the investigator if she 
becomes pregnant during the study (including the safety follow-up period).  In the event 
of pregnancy, the investigator must counsel the participant as to the risks of continuing 
with the pregnancy and the possible effects on the fetus.  Given that there are 
insufficient, well-controlled data from studies testing the use of ocrelizumab in pregnant 
or breastfeeding women, all infusions of ocrelizumab must be suspended until the end of 
pregnancy and breastfeeding.
Pregnant and breastfeeding participants should continue to follow the schedule of 
activities for the OLE; however, no infusions will occur.  If there is a concern with the 


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ability of a pregnant or breastfeeding participant to perform all scheduled assessments, 
or if an assessment is contraindicated during pregnancy, the investigator must contact 
the Medical Monitor for further discussion. Restart of ocrelizumab treatment following 
pregnancy and breastfeeding will be decided as a result of a thorough benefitrisk 
discussion between the participant and investigator. Participants who have already 
permanently discontinued from the study because of pregnancy (or for any other reason) 
may not be re-enrolled in the study.
The investigator should report all pregnancies within 24 hours to the Sponsor by means 
of an eCRF Pregnancy Reporting Form. The site should continue to monitor the 
participant’s pregnancy and enter the following information in the eCRF pregnancy 
Reporting Form: the outcome of the pregnancy (including spontaneous or voluntary 
abortions), the details of the birth, the presence or absence of birth defects or congenital 
abnormalities, and any other maternal or newborn complications. Babies born to 
mothers participating in this study should have an assessment of their lymphocyte 
counts and be carefully followed until these are within the normal range for the age of 
the infant.
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 7.2.2).
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 7.2.2).  A therapeutic 
or elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
For pregnancies occurring in female participants who have been exposed to ocrelizumab 
at any time during pregnancy or within 6 months prior to conception, additional
pregnancy outcome information and the health status of the child will be followed until 
the child is 1 year of age.  Data collection is voluntary only; it does not include any 
interventions or invasive procedures.  The data will be collected on a paper Pregnancy 
Outcome and Infant Health Information on First Year of Life questionnaire that will be 
submitted to health authorities and IRB/ECs for their approval, along with the infant data 
release consent form.
For more information on the Infant Health Questionnaire, please refer to the latest 
version of the Infant Health Questionnaire Guidance document.


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7.3
WARNINGS AND PRECAUTIONS
7.3.1
Ocrelizumab
Participants should be informed of the risks associated with taking ocrelizumab.  
Below are listed specific major risks of which the participants should be made aware.  
For the most recent information regarding identified and potential risks associated with 
ocrelizumab, please see the current version of the Ocrelizumab IB.
7.3.1.1
Identified Risks and Adverse Drug Reactions Associated with 
Ocrelizumab Use
Infusion-Related Reactions
All CD20-depleting agents administered via the IV route, including ocrelizumab, have 
been associated with acute IRRs. Following the approved administration regimen 
(which includes the use of premedication prior to treatment with ocrelizumab in order to 
reduce frequency and severity of IRRs), symptoms of IRRs may occur during any 
ocrelizumab infusion but have been more frequently reported during the first infusion.  
Physicians should alert participants that IRRs can occur within 24 hours of an infusion.  
Across the RMS and PPMS trials, symptoms associated with IRRs included, but were 
not limited to, pruritus, rash, urticaria, erythema, throat irritation, oropharyngeal pain, 
dyspnea, pharyngeal or laryngeal edema, flushing, hypotension, pyrexia, fatigue, 
headache, dizziness, nausea, and tachycardia.  Some of these events have been severe 
enough to warrant interruption or discontinuation of the infusion.  Symptoms are often 
reversible if the infusion is interrupted and/or participants receive additional treatment 
with an antihistaminic, acetaminophen, epinephrine or an IV corticosteroid.  
See Sections 6.1.2 and 6.1.3 for further information.
Participants should be observed for at least 1 hour after the completion of the infusion 
for any symptom of IRR and should be informed about the possibility of delayed
post-infusion symptoms and instructed to contact their study physician if they develop 
such symptoms.
Hypotension, as a symptom of IRR, may occur during ocrelizumab infusion.
Therefore, withholding of antihypertensive treatments should be considered for 12 hours 
prior to and throughout each ocrelizumab infusion.
Alternative Shorter Infusion of Subsequent Doses
In Study MA30143 (ENSEMBLE Plus) designed to characterize the safety profile of 
shorter ocrelizumab infusions in participants with RRMS, no differences were found in 
the frequency and severity of IRRs associated with shorter (2-hour) infusions compared 
with longer (3.5-hour) conventional infusions.  For further details, refer to the current 
version of the Ocrelizumab IB.
Infections
Infection is an identified risk associated with ocrelizumab treatment, predominantly 
involving mild to moderate respiratory tract infections. Non-disseminated herpes 


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virusassociated infections, mostly mild to moderate, were also reported more frequently 
with ocrelizumab (approximately 5%6%, simplex and zoster) than with comparators 
(approximately 3%).
During the controlled period of the pivotal trials, the proportion of participants with 
serious infections in RMS was lower in the ocrelizumab group (1.3%) than in the 
IFN -1-a group (2.9%); in PPMS, the proportion of participants with serious infections 
was similar in both groups: 6.7% in the placebo group compared with 6.2% in the 
ocrelizumab group.
Serious opportunistic and fatal infections have occurred in participants with lupus and 
RA treated with ocrelizumab in Phase III clinical trials. Data from completed studies 
regarding infection risks with ocrelizumab treatment in these participant populations are 
provided in the Ocrelizumab IB.
No opportunistic infections were reported for any participant with MS treated with 
ocrelizumab during the controlled period of the pivotal trials.
In interventional clinical studies, there were no reports of hepatitis B reactivation in 
participants with MS treated with ocrelizumab, but it had been reported for 1 participant 
with RA treated with ocrelizumab. Hepatitis B virus screening should be performed in all 
participants before initiation of treatment with ocrelizumab as per local guidelines.  
Participants with active HBV should not be treated with ocrelizumab. Participants with 
positive serology should consult liver disease experts before start of treatment and 
should be monitored and managed following local medical standards to prevent hepatitis 
B reactivation. Ocrelizumab administration should be delayed for participants with active 
infection until the infection is resolved.
For PML, see Section 7.3.1.2.
Delayed Return of Peripheral B Cells
Treatment with ocrelizumab leads to rapid depletion of CD19B cells in blood by 
14 days post-treatment (first timepoint of assessment) and is an expected 
pharmacologic effect. This was sustained throughout the treatment period. The longest 
follow-up time after the last ocrelizumab infusion is from 51 participants in Study 
WA21493 and indicates that the median time to B-cell repletion (returned to baseline or 
LLN, whichever occurred first) of B cells was 72 weeks (range: 27175 weeks).
Decrease in Immunoglobulins
Treatment with ocrelizumab resulted in a decrease in total Igs over the controlled period 
of the studies, mainly driven by reduction in IgM.  The proportion of participants with 
decrease in Igs below LLN increased over time and with successive dosing.  Based on 
additional participant exposure, in cases of continuous decrease over time, a higher risk 
of serious infection cannot be ruled out (see below).


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Serious Infections Related to Decrease in Immunoglobulins (Particularly in 
Participants Previously Exposed to Immunosuppressive or 
Immunomodulary Drugs or with Preexisting Hypogammaglobulinemia)
Based on additional participant exposure, an apparent association between sustained 
decrease in Igs and serious infections with ocrelizumab was observed and was most 
apparent with IgG.  There was no difference in the pattern (type, latency, duration, 
outcome) of the serious infections reported in this subset of participants compared with
the overall serious infections profile.  In addition, risk factors for a subset of participants 
at higher risk of serious infections could not be identified.
Impaired Response to Vaccination
The degree of impairment of B celldependent humoral response to neo-antigens and 
polysaccharide antigens and its clinical relevance are currently unknown in participants 
with MS.
After treatment with ocrelizumab over 2 years in pivotal clinical trials, the proportion of 
participants with positive antibody titers against S. pneumoniae, mumps, rubella, and 
varicella were generally similar to the proportions at baseline.
Physicians should review the immunization status of participants being considered for 
treatment with ocrelizumab.  Participants who require vaccination should complete it at 
least 6 weeks prior to initiation of ocrelizumab.
In the randomized open-label Study BN29739, the humoral responses to tetanus toxoid 
(TT), 23-valent pneumococcal polysaccharide (23-PPV), keyhole limpet hemocyanin 
(KLH) neoantigen, and seasonal influenza vaccines were decreased in participants with 
RMS treated with ocrelizumab (compared with those participants not treated with 
ocrelizumab) at all timepoints measured.  Nevertheless, participants with RMS who 
received ocrelizumab and were peripherally B-cell depleted were able to mount humoral 
responses, albeit decreased, to clinically relevant vaccines (TT, 23-PPV, influenza) and 
the neoantigen KLH.  The results of the study confirm the current recommendation that 
participants should complete local vaccination requirements 6 weeks prior to initiation of 
ocrelizumab to obtain full effectiveness of the vaccines.  In addition, for seasonal 
influenza vaccines, it is still recommended to vaccinate participants receiving 
ocrelizumab, as a humoral response to the vaccine, even if attenuated, can be expected.
Due to the potential depletion of B cells in neonates and infants of mothers who have 
been exposed to ocrelizumab during pregnancy, it is recommended that vaccination of 
neonates and infants with live or live-attenuated vaccines should be delayed until B-cell 
levels have recovered.  Therefore, measuring CD19-positive B cell levels in neonates 
and infants prior to vaccination is recommended.


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The safety of immunization with live or live-attenuated viral vaccines, following 
ocrelizumab therapy has not been studied, and vaccination with live-attenuated or live 
vaccines is not recommended while B cells are depleted.
7.3.1.2
Potential Risks Associated with Ocrelizumab Use
Malignancies, Including Breast Cancer
An increase of malignancy with ocrelizumab may exist.  Participants should follow 
standard breast cancer screening guidelines.
Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy is an important potential risk for 
ocrelizumab.  It has been reported in participants receiving ocrelizumab but only in 
participants where other contributory factors were present, such as prior 
immunosuppressive treatment (e.g., natalizumab or fingolimod).  Physicians should be 
vigilant for early signs and symptoms of PML, which can include any new onset or 
worsening of neurological signs or symptoms, as these can be similar to an MS relapse.  
If PML is suspected, dosing with ocrelizumab must be withheld.  Evaluation of PML, 
including MRI, confirmatory CSF testing for JCV DNA, and repeat neurological 
assessments, should be considered.  If PML is confirmed, ocrelizumab must be 
discontinued permanently.  More information on PML can be found in Section 7.3.5. 
Please see the current version of the Ocrelizumab IB for more details regarding PML risk 
and see Section 7.3.5.1 for guidance on diagnosing PML.
Neutropenia
In the controlled treatment period, decreased neutrophils were observed in 12% and 
15% of participants with MS treated with ocrelizumab, in PPMS and RMS, respectively. 
Most events were mild to moderate in severity.  Approximately 1% of the participants 
had Grade 3 or 4 neutropenia, and no temporal association with infections was 
identified.
Hypersensitivity Reactions
No hypersensitivity reactions to ocrelizumab were reported in the controlled clinical trials. 
Hypersensitivity may be difficult to distinguish from IRRs in terms of symptoms.  
A hypersensitivity reaction may present during any infusion, although not typically during 
the first infusion. For subsequent infusions, more severe symptoms than previously 
experienced, or new severe symptoms, should prompt consideration of a potential 
hypersensitivity reaction. If a hypersensitivity reaction is suspected during an infusion, 
the infusion must be stopped immediately and permanently. Participants with known 
Inge-mediated hypersensitivity to ocrelizumab must not be treated.
7.3.2
Rebif
Participants should be informed of the risks associated with taking Rebif.  The most 
frequent Rebif adverse reactions of which the participants should be made aware have 
been summarized in Section 2.1.5.


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Depression and suicide ideation are known to occur in increased frequency in the MS 
and in association with IFN use.  Therefore, all participants should be advised to 
immediately report any symptoms of depression and/or suicidal ideation to investigator.  
Participants exhibiting depression should be monitored closely and treated appropriately.  
Cessation of double-blind treatment should be considered.
Injection site necrosis has been reported in participants using Rebif.  To minimize the 
risk of injection site necrosis participants should be advised to:

Use an aseptic injection technique

Rotate the injection sites with each dose
If the participant experiences any break in the skin, which may be associated with 
swelling or drainage of fluid from the injection site, the participant should be advised to 
consult with their physician before continuing injections with Rebif/Rebif placebo.  If the 
participant has multiple lesions, injections should be discontinued until healing has 
occurred.  Participants with single lesions may continue provided that the necrosis is not 
too extensive.
Rebif, like other IFN , has a potential for causing severe liver injury including acute 
hepatic failure.  The mechanism for the rare symptomatic hepatic dysfunction is not 
known.  No specific risk factors have been identified.  Please see Section 6.2.2 for 
additional guidelines.
7.3.3
Corticosteroids
The adverse reactions of corticosteroids may result from unwanted glucocorticoid 
actions or from inhibition of the hypothalamic-adrenal axis.  See the local prescribing 
information.
7.3.4
Antihistamines
The adverse reactions depend on the sedating properties of the antihistamine and 
include, but are not limited to, nausea, drowsiness, headaches, dry mouth, and allergic 
reactions such as rash.  See the local prescribing information.
7.3.5
Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy is a potentially fatal neurological condition 
linked to reactivation of a polyomavirus (JCV) and active viral replication in the brain.  
Polyomavirus infection is acquired in childhood and up to 80% of adults demonstrate 
serological evidence of past infection.  Reactivation of JCV replication with transient 
viremia or viruria unassociated with clinical symptoms may occur spontaneously in 
healthy persons.  Less frequently, CNS symptoms associated with active viral replication 
in brain tissue is observed.  The clinical syndrome is significantly more frequent among 
immune suppressed participants.


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Physicians should consider the diagnosis of PML in any participant presenting with new 
and/or progressive neurological deficits localized to the cerebral cortex, such as cortical 
symptoms/signs, behavioral and neuropsychological alteration, retrochiasmal visual 
defects, hemiparesis, cerebellar symptoms/signs (e.g., gait abnormalities, limb 
incoordination), at each visit.
If PML is considered, a neurological consultation should be obtained and treatment 
suspended until PML has been ruled out.  If PML is confirmed in a participant receiving 
ocrelizumab, no further infusions should be administered and the participant will be 
withdrawn from treatment (see Section 5.6).  No known interventions can reliably 
prevent PML or adequately treat PML, if it occurs.
It is not known whether the risk of PML is altered by anti-CD20 treatment given as 
monotherapy.  See Section 7.3.5.1 for guidance on the diagnosis of PML.
Progressive multifocal leukoencephalopathy should be reported as a serious adverse 
event (with all available information) with immediate notification of the Medical Monitor.  
Study drug should be withheld and participants with confirmed PML should enter the 
safety follow-up phase of the study.
There is no known treatment or cure for PML.  Treatment considerations are discussed 
in the medical literature (Calabrese et al. 2007).
Detailed information regarding PML risk with ocrelizumab treatment can be found in the 
current version of the Ocrelizumab IB.
7.3.5.1
Guidance for Diagnosis of Progressive Multifocal 
Leukoencephalopathy
The following diagnostic algorithm framework (Figure 2) will be implemented in this 
study.
In the eCRF, the investigator will record the presence or absence of neurological deficits 
localized to the cerebral cortex (e.g., cortical symptoms/signs, behavioral and 
neuropsychological alteration, retrochiasmal visual defects, hemiparesis), cerebellar 
symptoms/signs (e.g., gait abnormalities, limb incoordination), at each visit.  Presence of 
such neurological findings will be recorded as adverse events.  If a diagnosis for the 
deficits is identified, the symptoms should be replaced by the diagnosis in the adverse 
event eCRF.
In addition to the neurological evaluation at regular visits, participants will undergo a 
telephone interview between the study visits by site personnel familiar with the 
participant(s).  The purpose of this interview is to identify new or worsening neurological 
symptoms that warrant an unscheduled visit (Appendix 4). Partners or caregivers of 
study participants, if applicable, will be informed on symptoms and signs that may be 


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suggestive of PML and should be instructed to contact the site, should any such signs or 
symptoms appear.
In the event that new or worsening neurological symptoms are considered during the 
telephone interview, a neurological evaluation will be conducted.  Should a non-MS 
etiology, such as PML, be considered, further assessments should be done 
(see Figure 2).
The following clinical guidance is provided:
Treatment of Relapse and Other Neurological Symptoms

As in all MS studies, new or recurrent neurological symptoms occurring in study 
participants should prompt careful clinical evaluation

Given the occurrence of PML in immunocompromised participants with other 
anti-CD20 and MS DMTs, PML should be considered in participants who develop 
worsening neurological signs or symptoms

There are no pathognomonic signs or symptoms that distinguish MS from PML, but 
there are certain clinical features that may help differentiate between the 
two conditions (see Table 12)

In addition to PML and MS, other CNS conditions (e.g., stroke, migraine, etc.) 
should be considered when evaluating a participant with new neurological changes

Relapses should be managed according to the study protocol

Corticosteroid treatment should only be considered for cases in which PML is 
unlikely on clinical grounds and when the severity of the relapse warrants such 
treatment.  Lack of response to corticosteroids should trigger further investigation.
Action Steps if PML Is Suspected
If the clinical presentation is suggestive of PML, further investigations should include 
brain MRI evaluation as soon as possible.  If MRI evaluation reveals lesions suspicious 
for PML (see Figure 2) a lumbar puncture with evaluation of the CSF for the detection of 
JCV DNA should be undertaken.  A diagnosis of PML can potentially be made by 
evaluating clinical and MRI findings plus the identification of JCV in the CSF.
Please note:  In the event that PML is suspected, an additional plasma, urine, as well as 
a CSF sample should be obtained for JCV analysis.  Cerebrospinal fluid samples will be 
analyzed upon receipt with high-sensitivity test and the results will be provided directly to 
the investigational site and to the Sponsor.  The additional plasma and urine samples 
will be stored together with the routine JCV samples.  For details, please refer to the 
most up-to-date Laboratory Manual providing storage conditions and shipment 
instructions.
MRI Assessment 

Although there are no pathognomonic findings that differentiate PML from MS, a 
brain MRI scan that includes fluid-attenuated inversion recovery (FLAIR) and 


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T2-weighted and T1-weighted sequences, with and without Gd, should be 
performed to assess participants with neurological changes suggestive of PML 
(Figure 2)

Comparison with a baseline scan may assist with interpretation of the findings on 
the newly acquired MRI (see Table 13 for differences in lesion characteristics that 
may help differentiate between PML and MS)
CSF Assessment
The detection of JCV DNA in the CSF of a participant with clinical and MRI features 
suggestive of PML establishes the diagnosis of PML.  If JCV DNA is not detected in CSF 
and if clinical suspicion of PML remains high, a repeat lumbar puncture should be 
performed.  If diagnosis remains uncertain and suspicion of PML remains high, a brain 
biopsy may be considered to establish a definitive diagnosis.


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Figure 2
Diagnostic Algorithm Framework for PML
Source:  Berger et al. 2013.
CSFcerebrospinal fluid; FLAIRfluid-attenuated inversion recovery; JCVJohn Cunningham 
virus; MRImagnetic resonance imaging; PCRpolymerase chain reaction; PML progressive 
multifocal leukoencephalopathy; PRESposterior reversible encephalopathy syndrome; 
VZVvaricella zoster virus.


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Table 12 Clinical Features to Distinguish between MS Relapse and PML
MS Relapse
PML
Onset
Acute
Subacute
Evolution

Over hours to days

Normally stabilizes

Resolves spontaneously 
or with treatment

Over weeks

Progressive
Clinical presentation

Diplopia

Paresthesia

Paraparesis

Optic neuritis

Myelopathy

Cortical signs and symptoms

Behavioral and 
neuropsychological 
alterations 

Retrochiasmal visual deficits

Hemiparesis

Cerebellar symptoms/signs 
(e.g., gait abnormalities, limb 
incoordination)
Source:  Kappos et al. 2007.
MSmultiple sclerosis; PMLprogressive multifocal leukoencephalopathy.


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Table 13 MRI Lesion Characteristics Typical of PML and MS
Feature
MS (relapse)
PML
Location of new lesions
Mostly focal; affect entire 
brain and spinal cord, in 
white and possibly grey 
matter
Diffuse lesions, mainly subcortical 
and rarely periventricular, located 
almost exclusively in white matter, 
although occasional extension to 
grey matter has been seen; 
posterior fossa frequently involved 
(cerebellum)
Borders
Sharp edges; mostly round 
or finger-like in shape 
(especially periventricular 
lesions), confluent with 
other lesions; U-fibers may 
be involved
Ill-defined edges; irregular in 
shape; confined to white matter; 
sparing grey matter; pushing 
against the cerebral cortex; U-
fibers destroyed
Mode of extension
Initially focal; lesions 
enlarge within days or 
weeks and later decrease in 
size within months
Lesions are diffuse and 
asymmetric, extending 
homogeneously; no confluence 
with other lesions; confined to 
white matter tracks, sparing the 
cortex; continuous progression
Mass effect
Acute lesions show some 
mass effect
No mass effect even in large 
lesions (but lesion slightly abuts 
cerebral cortex)
On T2-weighted sequence
Acute lesions: 
hyperintense center, 
isointense ring, discrete 
hyperintensity outside the 
ring structure
Subacute and chronic 
lesions:  
hyperintense with no ring 
structure
Diffuse hyperintensity, slightly 
increased intensity of newly 
involved areas compared with old 
areas, little irregular signal 
intensity of lesions
On T1-weighted sequence
Acute lesions:
densely hypointense 
(large lesions) or isointense 
(small lesions); increasing 
signal intensity over time in 
80%; decreasing signal 
intensity (axonal loss) in 
about 20% 
Slightly hypointense at onset, with 
signal intensity decreasing over 
time and along the affected area; 
no reversion of signal intensity
On FLAIR sequence
Hyperintense, sharply 
delineated
Hyperintensity more obvious; true 
extension of abnormality more 
clearly visible than in T2-weighted 
images


 
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Table  
MRI Lesion Characteristics Typical of MS and 3ML (cont.) 
Feature 
MS (relapse) 
3ML 
With enhancement 
 Acute lesions  
dense homogeneous 
enhancement, sharp 
edges 
 Subacute lesions  
ring enhancement 
 Chronic lesions  
no enhancement 
8sually no enhancement, even in 
large lesions in participants Zith 
HIV, some peripheral 
enhancement is possible, 
especially under therapy 
Atrophy 
Focal atrophy possible due 
to focal Zhite matter 
degeneration no 
progression 
No focal atrophy 
Source  <ousry et al 2006 
MS   multiple sclerosis PML   progressive multifocal leukoencephalopathy 
 
. 
STATISTICAL CO1SI'(RATIO1S A1' A1AL<TICAL 3LA1 
Full details of all statistical issues and planned statistical analyses for the double-blind 
portion of the study Zere specified in a separate SAP Zhich Zas finalized prior to the 
interim database lock and unblinding of the study database  A separate SAP for the 
OLE Zill be finalized prior to the final study database lock 
. 
ST8'< (1'3OI1TS 
.. 
3rimary (fficacy (ndpoint 
The primary efficacy endpoint is annualized protocol-defined relapse rate by 2 years 
(96 Zeeks) 
Protocol-defined relapse is defined as the occurrence of neZ or Zorsening neurological 
symptoms attributable to MS  Symptoms must persist for !2 hours and should not be 
attributable to confounding clinical factors (eg, fever, infection, inMury, adverse reactions 
to medications) and immediately preceded by a stable or improving neurological state for 
least 30 days  The neZ or Zorsening neurological symptoms must be accompanied by 
obMective neurological Zorsening consistent Zith an increase of at least half a step on 
the EDSS scale, or 2 points on one of the appropriate FSS, or 1 point on 2 or more of 
the appropriate FSS  The change must affect the selected FSS 
(ie, pyramidal, ambulation, cerebellar, brainstem, sensory, or visual)  Episodic spasms, 
sexual dysfunction, fatigue, mood change or bladder or boZel urgency or incontinence  
 
 


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will not suffice to establish a relapse.  Please note: Sexual dysfunction and Fatigue will 
not be scored.
Adjudication of protocol-defined relapses will be performed by the Sponsor based on 
pre-specified criteria, applied to data collected by investigator, in a blinded fashion.
8.1.2
Secondary Efficacy Endpoints
The key secondary efficacy endpoints are:

The time to onset of confirmed disability progression for at least 12 weeks with the 
initial event of neurological worsening occurring during the 96-week, double-blind, 
double-dummy, treatment period (see Section 5.10.2.2 for the definition of 
confirmed disability progression)

The total number of T1 Gd-enhancing lesions as detected by brain MRI at 
Weeks 24, 48, and 96

The total number of new, and/or enlarging T2 hyperintense lesions as detected by 
brain MRI at Weeks 24, 48, and 96

The proportion of participants who have confirmed disability improvement for at 
least 12 weeks, with the initial event of neurological improvement occurring during 
the 96-week double-blind, double-dummy treatment period

The time to onset of confirmed disability progression for at least 24 weeks with the. 
initial event of neurological worsening occurring during the 96-week, double-blind, 
double-dummy, treatment period (see Section 5.10.2.2 for the definition of 
confirmed disability progression)

The total number of new T1-hypointense lesions (chronic black holes) at Weeks 24, 
48, and 96

The change in MSFCS score from baseline to Week 96

The percentage change in brain volume as detected by brain MRI from Week 24 to 
Week 96

The change in SF-36 PCS Score from baseline to Week 96

The proportion of participants who have NEDA by Week 96
8.1.3
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints in this study may include, but may not be limited to:

The change in low-contrast visual acuity from baseline to Weeks 48 and 96

The change in the SDMT from baseline to Weeks 48 and 96

The proportion of relapse-free participants by 96 weeks

The change in total T2 hyperintense lesion volume as detected by brain MRI from 
baseline to Week 96

The ARR, based on all clinical at the end of the 96-week comparative treatment 
period (protocol-defined relapses are a subset of all clinical relapses)


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
The ARR of relapses requiring IV steroid therapy

The ARR of severe relapses

The percentage change in brain volume as detected by brain MRI from baseline to 
Week 96

The change in MSFCS score from baseline to Week 48

The cumulative change in EDSS scores, measured in AUC by Week 96

The change in EDSS from baseline to Week 96

The change in Timed 25-Foot Walk from baseline to Week 96

The change in 9-HPT from baseline to Week 96

The change in PASAT from baseline to Weeks 48 and 96

The time to onset of sustained 20% increase in 9-HPT for at least 12 weeks

The time to onset of sustained 20% increase in T25FWT for at least 12 weeks

The change in fatigue, as measured by the MFIS total score from baseline to 
Week 96

The change from baseline in participant-reported depressive symptoms, as 
measured by the CES-D, from baseline to Week 96

Analyses of EQ-5D, collected at baseline, Week 48, and Week 96

The change in Karnofsky Performance Status Scale from baseline to Week 96

The percentage change in cortical grey-matter volume from baseline to Week 96

The percentage change in white matter volume from baseline to Week 96

The proportion of participants who have disability improvement confirmed for at 
least 24 weeks, with the initial event of neurological improvement occurring during 
the 96-week double-blind, double-dummy treatment period

The proportion of participants who have disability improvement sustained for at least 
12 weeks and sustained until the end of the 96-week, double-blind, double-dummy 
treatment period, with the initial event of neurological improvement occurring during 
the 96-week, double-blind, double-dummy treatment period

The duration of the confirmed disability improvement

The proportion of participants who at Week 96 have improved, stable or worsened 
disability, compared with baseline

The change in Quality of Life, as measured by the SF-36 version 2 MCS Score from 
baseline to Week 96

To evaluate the long-term effects of ocrelizumab on clinical and MRI parameters of 
disease activity and progression during the OLE phase of the study

To evaluate the long-term safety of ocrelizumab treatment during the OLE phase of 
the study

To evaluate the effects of switching from Rebif to ocrelizumab treatment


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8.1.4
Safety
Safety will be assessed through regular neurological and physical examinations, vital 
signs, ECG, and the occurrence of adverse events, as per the schedule of activities.  
In addition, the following will be examined:

Non-MS pathology in all available MRI scans

C-SSRS

Standard hematology, chemistry, and urinalysis assessments

Circulating B cell total and subsets, T cells, natural killer cells and other leukocytes

Plasma immunoglobulins

HAHA: in any case of anaphylaxis, anaphylactoid reaction, or serious or severe 
hypersensitivity reaction, HAHA and ocrelizumab concentration samples should be
collected as close as possible to the event and then at 4 and 16 weeks postdose

Antibody titers for mumps, rubella, varicella, and Streptococcus pneumoniae

MS relapses classified as serious

Serial pregnancy tests (serum/urine -hCG) will be performed in women of 
childbearing potential

JCV plasma/urine sampling only if deemed necessary
8.2
STATISTICAL AND ANALYTICAL METHODS
Prior to unblinding the treatment groups, a SAP will be produced that will contain full 
details of all planned analyses.  An outline of the planned analyses is described below.
After the Week 96 visit of the last participant randomized, approximately 12 weeks may 
be needed to allow the confirmation of the last event of the 12-week confirmed disability 
progression.  Therefore, the clinical cutoff date will occur approximately 12 weeks after 
the last participant’s Week 96 visit when the status is clarified for each participant.  
Database lock and unblinding of the Sponsor will occur several weeks after the clinical 
cutoff in order to clarify all outstanding queries.  The sites and EDSS raters will remain 
blinded until approximately 24 weeks after the Week 96 visit of the last participant
randomized to allow the confirmation of the last 24-week confirmed disability progression 
event, in case an updated analysis of this endpoint is requested at a later point.
The time to onset of confirmed disability progression for at least 12 weeks during the 
96-week comparative treatment period, the proportion of participants who have 
confirmed disability improvement for at least 12 weeks with the initial event of 
neurological improvement occurring during the 96-week double-blind, double-dummy 
treatment period, and the time to onset of confirmed disability progression for at least 
24 weeks during the 96-week comparative treatment period will be analyzed with use of
pooled data across the 2 identical studies running as a part of the Phase III program, 
with respect to ocrelizumab group versus Rebif group.


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All eligible participants will be randomized to treatment stratified by region 
(United States vs. ROW) and baseline EDSS (4.0 vs. 4.0).  All analyses will also be 
stratified by region (United States vs. ROW) and baseline EDSS (4.0 vs. 4.0).
Some efficacy analyses will be undertaken for some subgroups, as agreed with 
regulatory authorities.  Details of these subgroup analyses are presented in the SAP.
All analyses, summaries and listings will be performed with use of SAS® software 
(Version 9.2 or higher in a UNIX environment).
8.2.1
Primary Efficacy Analysis
The primary efficacy analysis for this trial will compare annualized protocol-defined 
relapse rate by 96 weeks between ocrelizumab group and Rebif group.  The annualized 
relapse rates by 96 weeks will be analyzed with use of a negative binomial model, 
adjusting for region (United States vs. ROW) and baseline EDSS (4.0 vs. 4.0).  
The adjusted ARR and the 2-sided 95% CIs for the relapse rates will be presented along 
with the p-value.
Other sensitivity analyses may also be performed for the primary efficacy endpoint 
(and documented in the SAP).
8.2.2
Secondary Efficacy Analyses
The statistical testing strategy for all secondary efficacy endpoints, the testing hierarchy 
and the rationale for this hierarchical order of secondary endpoints is fully explained in 
the SAP.
Secondary efficacy endpoints will be tested in hierarchal order, all at 0.05 level.  
The first secondary efficacy endpoint will be tested if and only if the primary endpoint has 
reached the significant level at 0.05 (e.g., P-value 0.05).  With the exception of the 
3 secondary efficacy endpoints, which will be analyzed at the pooled level 
(see Section 8.2), all secondary efficacy endpoints will be tested if and only if the 
secondary endpoint listed ahead of it has reached the significance level at 0.05.
Additional pooled analyses are also described in a separate SAP (called the pooled 
SAP). This document describes solely those analyses that will be performed on the 
2 studies combined.
8.2.2.1
The Time to Onset of Confirmed Disability Progression for 
at least 12 Weeks during the 96-Week Comparative Treatment 
Period
Time to confirmed disability progression (12 week confirmation) is defined as the time 
from baseline to the first disability progression, which is confirmed at the next regularly 
scheduled visit 84 days after the initial disability progression.  Disability progression is 
defined as an increase of 1.0 point from baseline EDSS, if the baseline EDSS is 


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between 0 and 5.5 points (inclusive), or an increase of 0.5 points, if the baseline EDSS 
is 5.5 points.  Please note that the inclusion criterion of EDSS (05.5) only applies to 
screening EDSS.  It is still possible that a participant’s baseline EDSS (derived based on 
both screening and day 1 EDSS results) is 5.5.  The non-confirmatory EDSS 
assessments (if any) between the initial and confirmation of disability progression should 
be at least as high as the minimum change required for progression.  All initial disability 
progression events up to Week 96 with corresponding confirmation visits at the next 
scheduled visit (see schedule of activities in Section 1.3) will be taken into account for 
the statistical analysis irrespective of whether or not the confirmation visit occurred 
during the treatment phase or after study drug discontinuation, or during the OLE phase.  
Thus, participants who prematurely discontinue study drug treatment should be kept in 
the study, and every effort should be made to follow-up their EDSS status at the next 
scheduled visit.  Participants who according to the above definition did not have 
confirmed disability progression by Week 96 visit, time of early discontinuation of 
treatment, or loss to follow-up will be censored at the date of their last EDSS 
assessment.
Data from the 2 studies with respect to ocrelizumab group vs Rebif group will be pooled 
for analysis of this endpoint.  To assess the validity of pooling data across the 2 RMS 
studies, demographic and baseline characteristics will be compared by trials.  
The treatment effect (hazard ratio and CI) for confirmed disability progression within 
each trial will be compared between the 2 trials.  In interpreting the trial comparisons 
with a view toward assessing the validity of the pooled dataset, the primary interest is in 
confirming that the treatment effect is qualitatively similar across the 2 studies – positive 
treatment effects (the estimated hazard to have confirmed disability progression in 
participants treated with ocrelizumab is numerically smaller than that in participants 
treated with Rebif) are shown in both studies.  If the results from the 2 studies are not 
qualitatively similar (e.g., positive treatment effect is only shown in one study), data will 
not be pooled.  Further details regarding the assessment of poolability are provided in 
the SAP.
Time to confirmed disability progression for ocrelizumab group and Rebif group 
(across the studies) will be compared with use of a 2-sided log-rank test stratifying by 
region (United States vs. ROW), baseline EDSS (4.0 vs. 4.0).  The proportion of 
participants with confirmed disability progression will be estimated with use of
Kaplan-Meier methodology.  The overall hazard ratio will be estimated with use of a 
stratified Cox regression model with the same stratification factors used in the stratified 
log-rank test above.  More details are provided in the SAP for the study.
8.2.2.2
Total Number of T1 Gadolinium-Enhanced Lesions as Detected 
by Brain MRI at Weeks 24, 48, and 96
The total number of T1 Gd-enhanced lesions will be calculated as the sum of the 
individual number of T1 Gd-enhanced lesions at Weeks 24, 48 and 96.  Data from other 
unscheduled assessments will not be included in this summary or analysis.


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A negative binomial model will be used to compare the difference between ocrelizumab 
and Rebif groups.
8.2.2.3
The Total Number of New and/or Enlarging T2 Hyperintense 
Lesions as Detected by Brain Magnetic Resonance Imaging at 
Weeks 24, 48, and 96
The same approach will be used for the statistical analysis as for the total number of T1 
Gd-enhanced lesions.
8.2.2.4
Proportion of Participants who have Disability Improvement 
Confirmed for At Least 12 Weeks
This endpoint will be analyzed only for the subgroup of participants with a baseline 
EDSS score 2.0.  Exactly the same approach to data derivation will be used for 
disability improvement as for disability progression (see Section 8.2.2.1, although note 
that, here, the endpoint is a binary improved/not improved variable, rather than a 
time-to-event endpoint).  In particular, the same approach to the timing of the 
confirmation of disability improvement will be applied as for disability progression.  
The baseline EDSS score is the average of the EDSS score at the screening period and 
the EDSS score at the baseline visit, without rounding.  For participants with a baseline 
EDSS score 2 and 5.5, disability improvement is defined as a reduction in EDSS 
score 1.0 compared with baseline EDSS score.  For participants with a baseline EDSS 
score 5.5, disability improvement is defined as a reduction in EDSS score of 0.5.  
All participants without disability improvement will be counted as not improved, 
independent of follow-up time.
Data from the 2 studies with respect to ocrelizumab group versus Rebif group will be 
pooled for analysis of this endpoint.
The proportions in treatment groups will be compared with use of the 
Cochran-Mantel-Haenszel (CMH) test stratified by geographical region 
(United States vs. ROW) and baseline EDSS score (4.0 vs. 4.0).
8.2.2.5
The Time to Onset of Confirmed Disability Progression for 
At Least 24 Weeks During the 96-Week Comparative Treatment 
Period
Time to confirmed disability progression between ocrelizumab group and Rebif group 
with use of a 24-week confirmation window for disability progression will be compared 
with use of the same analysis method for time to confirmed disability progression using a 
12-week confirmation window.  Time to confirmed disability progression 
(24-week confirmation) is defined as the time from baseline (Day 1) to the first disability 
progression, which is confirmed at the next regularly scheduled visit 161 days after the 
initial disability progression.  All initial disability progression events up to Week 96 with 
corresponding confirmation visits at the next schedule visit (see schedule of activities in 
Section 1.3) will be taken into account for the statistical analysis.  The same analysis 


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principles as described in Section 8.2.2.1 will be applied to the 24-week disability 
endpoint.
Data from the 2 studies with respect to ocrelizumab group vs. Rebif group will be pooled 
for analysis of this endpoint.
8.2.2.6
Total Number of New T1-Hypo-Intense Lesions (Chronic Black 
Holes) at Weeks 24, 48, and 96
The same approach will be used for the statistical analysis as for the total number of T1 
Gd-enhanced lesions.
8.2.2.7
The Change in MSFCS Score from Baseline to Week 96
The change in MSFCS from baseline to Week 96 will be compared between ocrelizumab 
group and Rebif group with use of a Mixed-Effect Model Repeated Measures (MMRM) 
analysis, adjusting for baseline MSFCS, region (United States vs. ROW), and baseline 
EDSS (4.0 vs. 4.0).
8.2.2.8
The Percentage Change in Brain Volume as Detected by Brain 
Magnetic Resonance Imaging Scan from Week 24 to Week 96
The change in brain volume as detected by brain MRI from week 24 to Week 96 will be 
compared between ocrelizumab group and Rebif group with use of an MMRM analysis.  
Baseline covariates here will be as follows:  brain volume at Week 24, baseline 
Gd lesion (present or not), region (United States vs. ROW), and baseline EDSS score 
(4.0 vs. 4.0).
8.2.2.9
Change in Quality of Life As Measured by the Short Form-36 
Version 2 Physical Component Summary Score from Baseline 
to Week 96
The change in quality of life, as measured by the SF-36 PCS score from baseline to 
Week 96 will be compared between ocrelizumab group and Rebif group with use of a 
MMRM analysis.  Baseline covariates here will be as follows:  baseline PCS score, 
region (United States vs. ROW), and baseline EDSS (4.0 vs. 4.0).
8.2.2.10
Proportion of Participants Who Have No Evidence of Disease 
Activity by Week 96
This endpoint will be defined only for those participants with a baseline EDSS score 
2.0.  All available data during the 96-week treatment period will be used for the 
analysis.  Participants who complete the 96-week treatment period will be considered as 
having evidence of disease activity if at least one protocol-defined relapse, a confirmed 
disability progression (CDP) event having occurred or at least one MRI scan showing 
MRI activity (defined as Gd-enhancing T1 lesions, or new or enlarging T2 lesions) was 
reported during the 96-week treatment period, otherwise the participant will be 
considered as having NEDA.  Participants who discontinue treatment early with at least 
one event before early discontinuation will be considered as having evidence of disease 
activity. 


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Even if an event was not reported before early discontinuation, the participant will be 
considered as having evidence of disease activity if the reason for early discontinuation 
is lack of efficacy or death; otherwise, it will be considered a missing observation.
The proportions within treatment groups will be compared with use of the CMH 2 test 
stratified by region (United States vs. ROW) and baseline EDSS (4.0 vs. 4.0).
8.2.3
Exploratory Analyses
The exploratory endpoints will be summarized with use of tables, listings and graphs, 
where appropriate.  Full details of the derivations and analyses of exploratory endpoints 
will be provided in the SAP.
8.2.4
Sample Size
The sample size for this study has been estimated based on data from previous RRMS 
trials, with the use of 2-sided tests with an experiment-wise 0.05.  The ARR among 
participants receiving ocrelizumab at 96 weeks is predicted to be 0.165 
(standard deviation of approximately 0.60), as compared with 0.33 (standard deviation of 
approximately 0.80) among participants receiving the control treatment, Rebif 
(this represents a RR of 50% on ocrelizumab compared with the active comparator).  
For the ARR, a t-test has been used to determine the sample size between ocrelizumab 
and the control arm.  The sample size of 400 participants per arm provides 84% power, 
maintaining the type I error rate of 0.05, and assuming a dropout rate of 20% 
approximately (assuming RR among participant dropout is 25%).
For confirmed disability progression, a 2-group test of equal exponential survival with 
exponential dropout is used to determine the sample size.  Assuming the 2-year 
confirmed disability progression rate is 18% for the Rebif arm and 12.6% for the 
ocrelizumab arm (this represents a RR of 30% on ocrelizumab compared with the active 
comparator), and assuming a dropout rate of 20 percent over 2 years approximately, the 
sample size of 400 participants arm will provide 80% power, maintaining the type I error 
rate of 0.05 based on the pooled analysis of 2 RMS trials (800 participants treated with 
ocrelizumab 600 mg and 800 participants treated with Rebif).
8.2.5
Hypothesis Testing
The hypotheses to be tested are:

H0 (null hypothesis): there is no statistically significant difference in annualized 
protocol-defined relapse rate at 2 years between ocrelizumab group and Rebif group

H1 (alternative hypothesis): there is a statistically significant difference in 
protocol-defined ARR at 2 years between ocrelizumab group and Rebif group
Protocol-defined ARR at 2 years between the ocrelizumab group and Rebif group will be 
compared with use of a negative binomial model adjusting region 
(United States vs. ROW) and baseline EDSS (4.0 vs. 4.0).  If the test result for 


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comparing 600 mg ocrelizumab and Rebif groups is statistically significant at 0.05 
level (2-sided test), we will conclude that the 600 mg ocrelizumab group demonstrated a 
superior effect of reducing protocol-defined ARR, when compared with the Rebif group.
Similar hypotheses will also be tested for the secondary efficacy parameters.  
Methods for handling multiplicity issues related to secondary endpoints will be described 
in the SAP.
8.2.6
Analysis Populations
One participant population will be defined for the purpose of the safety analysis and 
2 populations for the efficacy analysis.  All efficacy analyses will be performed with use 
of the ITT population.  The per protocol (PP) population will be used for all primary 
efficacy analyses in order to evaluate the influence of major protocol violators and as a 
sensitivity check to the ITT analysis.
8.2.6.1
Safety Population
This population will be used for all summaries of safety data.  The safety population will 
include all participants who received any study drug.  Randomized participants that 
receive incorrect therapy from that intended will be summarized in the group according 
to the therapy actually received.  Participants who are not randomized, but who receive 
study drug will be included in the safety population and summarized according to the 
therapy actually received.
8.2.6.2
Intent-to-Treat Population
All randomized participants will be included in the intent–to-treat population.  
Participants who prematurely withdraw from the study for any reason and for whom an 
assessment is not performed for whatever reason will still be included in the 
ITT analysis.  Participants who receive an incorrect therapy from that which is intended 
will be summarized according to their randomized treatment.
8.2.6.3
Per Protocol Population
The PP population will include all participants in the ITT population adhering to the 
protocol.  Participants may be excluded if they significantly violate the 
inclusion/exclusion criteria or deviate from the study plan.  Specific reasons for 
warranting exclusion will be agreed and documented in the SAP prior to unblinding of 
the treatment groups.  Only those participants with violations that are deemed to 
potentially affect the efficacy of study treatment will be excluded from the PP population.  
Participants who receive an incorrect therapy from that intended will be excluded from 
the PP population.
8.2.7
Interim Analysis
No formal efficacy interim analyses are planned.


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8.2.8
Safety Data Analysis
All safety parameters will be summarized and presented in tables based on the safety 
population.  The safety data will be listed and summarized at determined cutoff points, 
e.g., with use of data for each participant up to Week 96, using all available data at the 
Week 96 database lock for the primary analysis.
All adverse events will be coded and tabulated by System Organ Class and 
Preferred Term for individual events within each System Organ Class, and will be 
presented in descending frequency.  Adverse events will also be tabulated by severity 
and relationship to the study medication.  Serious adverse events will be summarized 
separately.  Results of C-SSRS will be summarized by treatment group.
Non-MS pathology reported by local safety radiologist will be summarized by treatment 
group.
Associated laboratory parameters such as hepatic function, renal function and 
hematology values will be grouped and presented together.  Correlation between low 
IgG and IgM and infections will be presented separately.  Marked abnormalities will also 
be flagged.  Marked abnormalities will be tabulated for each laboratory test by treatment 
group.
Analysis of HAHA to ocrelizumab will be summarized graphically and descriptively.  
Correlation between presence of HAHA and IRR/B-cell depletion will be presented 
descriptively.
The results of vital sign, physical examination and ECG will be included in individual 
participant listings.  Change from baseline in vital signs will be summarized by groups.
Type I IFN neutralizing antibody data will be summarized in listings and additional 
analysis will be performed as appropriate.
An external, iDMC will periodically review safety data throughout the study until the 
primary analysis is performed.  Following unblinding after the 96-week period, iDMC 
involvement in safety monitoring throughout the OLE phase is no longer needed.  
Analyses required for the DMC data review will be performed as described in the DMC 
Charter and DMC data handling plan.
8.2.9
Safety Follow-Up Period
Data from this period will be analyzed to provide information on the maintenance effect 
and the potential withdrawal effect of ocrelizumab.  In addition, data will be analyzed to 
provide information concerning the long-term safety of ocrelizumab.  Data will be 
summarized and tables and listings will be produced.


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8.2.10
Open-Label Extension Phase
Data from this period of the study will be analyzed in order to characterize the long-term 
safety and efficacy of participants treated with ocrelizumab beyond the double-blind, 
double-dummy treatment period of the study.  The data will be summarized according to 
the randomized treatment groups of the double-blind, double-dummy treatment period of 
the study.  Details of the statistical analyses will be provided in a separate SAP.
8.2.11
Other Analyses
8.2.11.1
Pharmacokinetic Analysis
Pharmacokinetic Parameters
Ocrelizumab serum concentration-time data will be modeled with use of a population 
approach.  The primary population PK parameters (clearances and volumes) for 
ocrelizumab will be estimated by means of Nonlinear Mixed Effects Modeling 
(NONMEM) analysis of the sparse PK data.  Clearances with associated interparticipant
variability may be characterized by a saturable and non-saturable clearance as well as 
an intercompartmental clearance depending on the final structural model.  Volumes with 
associated interparticipant variability may be characterized by central and peripheral 
volumes depending on the final structural model.  Exposure (AUC) to ocrelizumab will be 
estimated.  The selection of other parameters will depend on the final PK model used for 
this analysis.
Pharmacokinetic Analysis
Nonlinear mixed-effects modeling (with software NONMEM; Beal et al. 1992) will be 
used to analyze the sparse sampling dose-concentration-time data of ocrelizumab.  
Participants who have measurable concentrations of ocrelizumab will be included in the 
PK analysis unless major protocol deviations or unavailability of information 
(e.g., exact blood sampling time) occurred which may interfere with PK evaluation.  
The PK data of this study may be pooled with more extensive data from other studies.  
Population PK parameters (clearances and volumes) will be estimated and the influence 
of covariates, such as age, sex, weight, HAHA, and baseline CD19 lymphocytes, on
these parameters will be investigated.
Details of the mixed-effects modeling analyses will be described in a Modeling and 
Simulation Analysis Plan and results will be reported separately.
8.2.11.2
Pharmacodynamic Analysis
The relationship between individual ocrelizumab exposure and selected safety and 
efficacy parameters will be analyzed and explored, in order to characterize the 
exposure/dose response curve of ocrelizumab.  This may include but is not limited to 
ARR, T1 and T2 lesions at Week 96, IRRs, infections, and other adverse event or safety 
parameters of interest.  Other exploratory analyses may be performed to assess the 
possible relationship between PD markers (e.g., CD19 count, PK, and clinical response).


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8.2.11.3
Roche Clinical Repository/Protein Biomarker Samples
Additional blood samples for serum and/or plasma analyses will be taken for research 
purposes subject to discretionary approval from each center’s IRB/EC and the 
participant’s specific written consent.  These samples will be used to identify dynamic 
biomarkers to help us better understand the pathogenesis of RMS and response to 
treatment with ocrelizumab.  Such future biomarkers have yet to be determined but may 
include circulating biochemical markers in blood including cytokines as well as peripheral 
blood gene expression patterns.  Exploratory statistical data analyses may include 
assessments for possible relationships between these biomarker levels, PK and clinical 
response.
8.2.11.4
Research Biosample Repository
All statistical analyses of biosample testing results will be conducted as exploratory and 
may include, but may not be limited to, examining possible relationships between 
disease progression biomarker levels and clinical response.
9.
DATA COLLECTION, MANAGEMENT AND QUALITY 
ASSURANCE
The overall procedures for quality assurance of clinical study data are described in the 
Sponsor’s (or designee) Standard Operational Procedures.
Data for this study will be recorded via an Electronic Data Capture (EDC) system with 
use of eCRFs.  It will be transcribed by the site from the paper source documents onto 
the eCRF.  In addition, EDSS, MSFC, C-SSRS, Karnofsky Performance Status Scale 
and PROs will be collected according to the protocol schedule of activities, and the data 
will be entered into the clinical database.
Accurate and reliable data collection will be assured by verification and cross-check of 
the eCRFs against the investigator’s records by the study monitor (source document 
verification), and the maintenance of a drug–dispensing log by the investigator.
A comprehensive validation check program utilizing front-end checks in the 
eCRF/electronic interface and backend checks in the data base will verify the data and 
discrepancies will be generated accordingly.  These are transferred electronically to the 
site for resolution by the investigator.
Throughout the study the Study Management Team (SMT) will review data according to 
the EDC Cleaning Process as described in the Data Management Plan.
9.1
ASSIGNMENT OF PREFERRED TERMS AND ORIGINAL 
TERMINOLOGY
For classification purposes, preferred terms will be assigned by the Sponsor to the 
original terms entered on the eCRF, with use of the most up-to-date version of the 
MedDRA terminology for adverse events and diseases and the International 


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Non-proprietary Name (INN) Drug Terms and Procedures Dictionary for treatments and 
surgical and medical procedures.
10.
STUDY COMMITTEES
10.1
STEERING COMMITTEE
An external Steering Committee will provide general guidance, assist with liaison to 
investigators and oversee any external communication of the results of the study.
10.2
DATA MONITORING COMMITTEE
An external iDMC will be chartered to review safety data throughout the study and make 
recommendations regarding continuation, termination, or modification of the study.  
During the double-blind, double-dummy phase of the study, regularly scheduled safety 
data reviews will occur at least 3 times per year after the first participant is enrolled.  
The DMC will not continue safety monitoring during the OLE phase.
Any safety event that requires unblinding of study treatment allocation will be 
immediately reported to the DMC and to the health authorities in an expedited safety 
report.  The DMC may request and review any additional reports outside of the planned 
analyses at any time if deemed necessary to ensure the safety of participants.  
The safety evaluations will be conducted on parameters specified within the 
DMC Charter and may vary depending on the requirements and requests of the DMC.
The details of the DMC roles and responsibilities, scope of work and the logistics of the 
DMC activities will be outlined in a DMC Charter.  The purpose of the DMC interim 
analyses is primarily safety evaluation, and the study may be stopped or amended 
because of significant safety concerns.


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11.
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PART II: ETHICS AND GENERAL STUDY ADMINISTRATION
12.
ETHICAL ASPECTS
12.1
LOCAL REGULATIONS/DECLARATION OF HELSINKI
The investigator will ensure that this study is conducted in full conformance with the 
principles of the “Declaration of Helsinki” or with the laws and regulations of the country 
in which the research is conducted, whichever affords the greater protection to the 
individual.  The study must fully adhere to the principles outlined in “Guideline for Good 
Clinical Practice” ICH Tripartite Guideline or with local law if it affords greater protection 
to the participant.  For studies conducted in the E.U./EEA countries, the investigator will 
ensure compliance with the E.U. Clinical Trial Directive [2001/20/EC].  For studies 
conducted in the U.S. or under U.S. Investigational New Drug Application, the 
investigator will additionally ensure adherence to the basic principles of “Good Clinical 
Practice” as outlined in the current version of 21 Code of Federal Regulations (CFR), 
Subchapter D, Part 312, “Responsibilities of Sponsors and Investigators”, Part 50, 
“Protection of Human Subjects”, and Part 56, “Institutional Review Boards”.
In other countries where a “Guideline for Good Clinical Practice” exists, Roche and the 
investigators will strictly ensure adherence to the stated provisions.
12.2
INFORMED CONSENT
12.2.1
Study Informed Consent
It is the responsibility of the investigator, or a person designated by the investigator 
(if acceptable by local regulations], to obtain signed informed consent for the 
double-blind, double-dummy treatment period and the OLE phase of the study from each 
participant prior to participating in either the double-blind, double-dummy treatment 
period or the OLE phase of this study after adequate explanation of the aims, methods, 
anticipated benefits, and potential hazards of the study.
The investigator or designee must also explain that the participants are completely free 
to refuse to enter any period of the study or to withdraw from it at any time, for any 
reason.  
The eCRFs for this study contain a section for documenting participant informed 
consent, and this must be completed appropriately.  If new safety information results in 
significant changes in the risk/benefit assessment, the consent form should be reviewed 
and updated if necessary.  All participants (including those already being treated) should 
be informed of the new information, given a copy of the revised form and give their 
consent to continue in the study.
For the participant not qualified or incapable of giving legal consent, written consent 
must be obtained from the legally acceptable representative.  In the case where both the
participant and his/her legally acceptable representative are unable to read, an impartial 


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witness should be present during the entire informed consent discussion.  After the 
participant and representative have orally consented to participation in the trial, the 
witness’ signature on the form will attest that the information in the consent form was 
accurately explained and understood.

For U.S. Investigational New Drug (IND) studies: in a life-threatening situation 
where a participant is unconscious or otherwise unable to communicate, the 
emergency is such that there is not enough time to obtain consent from the 
participant's legally acceptable representative, and there is no other or better 
treatment available, it is permissible to treat the participant under protocol with 
consent of both the investigator and another physician not involved in the study, with 
appropriate documentation submitted to the IRB within 5 days.  If this collaboration 
is not immediately possible, there must be a written evaluation by a physician 
independent of the study and the appropriate documentation be submitted to the 
IRB within 5 days of treating the participant.  In addition, the participant or his/her 
legally acceptable representative should be informed about the trial as soon as 
possible and consent to continue, giving written consent as described above.

For non-U.S. IND studies: in a life-threatening situation where a participant is 
unconscious or otherwise unable to communicate, the emergency is such that there 
is not enough time to obtain consent from the participant's legally acceptable 
representative, and there is no other or better treatment available, it is permissible to 
treat the participant under protocol with consent of the investigator, with appropriate 
documentation that the EC had approved the procedures used to enroll participants 
in such situations.  In addition, the participant or his/her legally acceptable 
representative should be informed about the trial as soon as possible and consent 
to continue, giving written consent as described above.
12.2.2
RBR Informed Consent
The Informed Consent Form (ICF) will contain a separate section that addresses 
participation in the RBR.  For details on the RBR consent, see Section 5.12.5. 
12.2.3
Death or Loss of Competence of Participant who has Donated 
a Specimen(s) that is Stored in the RCR
In case the ICF and/or the study protocol do not provide any specific provisions for death 
or loss of competence, specimen and data will continue to be used as part of RCR 
research.
In the event of the death of a participant of a Roche Clinical Trial or Experimental 
Medicine Research study or if a participant is legally incompetent at the time of the 
specimen and data procurement, or becomes legally incompetent thereafter, applicable 
provisions as stated for such situations in the respective ICF and/or the study protocol 
shall become effective and be followed accordingly.


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Additional procurement of assent from legally incompetent persons and minors shall 
take place according to local laws and international best practice, as it applies to the 
specific case.
12.3
INDEPENDENT ETHICS COMMITTEES AND INSTITUTIONAL 
REVIEW BOARD
The protocol, informed consent and any accompanying material provided to the 
participant in the U.S. will be submitted by the investigator to an IRB for review.  
For European Economic Area (EEA) member states, the Sponsor will submit to the 
Competent Authority and EC, the protocol and any accompanying material provided to 
the participant.  In both the United States and EEA member states, the accompanying 
material may include participant information sheets, descriptions of the study used to 
obtain informed consent and terms of any compensation given to the participant as well 
as advertisements for the trial.
An approval letter or certificate (specifying the protocol number and title) from the 
IRB/EC must be obtained before study initiation by the investigator specifying the date 
on which the committee met and granted the approval.  This applies whenever 
subsequent amendments/modifications are made to the protocol.
Any modifications made to the protocol, informed consent or material provided to the 
participant after receipt of the IRB/EC approval must also be submitted by the 
investigator in the U.S. and by the Sponsor in the EEA member states in accordance 
with local procedures and regulatory requirements.
When no local review board exists, the investigator is expected to submit the protocol to 
a regional committee.  If no regional committee exists, Roche will assist the investigator 
in submitting the protocol to the European Ethics Review Committee.
Roche shall also submit an Annual Safety Report once a year to the EC and Competent 
Authorities (CAs) according to local regulatory requirements and timelines of each 
country participating in the study.  In the U.S. Roche submits an IND Annual Report to 
the FDA according to local regulatory requirements and timelines.
13.
CONDITIONS FOR MODIFYING THE PROTOCOL
Requests from investigators to modify the protocol to ongoing studies will be considered 
only by consultation between an appropriate representative of the Sponsor and the 
investigator (investigator representative[s] in the case of a multicenter trial).  
Protocol modifications must be prepared by a representative of the Sponsor and initially 
reviewed and approved by the Clinical Science Leader and Biostatistician.
All protocol modifications must be submitted to the appropriate Independent IRB or EC for 
information and approval in accordance with local requirements, and to Regulatory 
Agencies if required.  Approval must be obtained before any changes can be 


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implemented, except for changes necessary to eliminate an immediate hazard to trial 
participants, or when the change(s) involves only logistical or administrative aspects of the 
trial (e.g., change in monitor[s], change of telephone number[s]).
14.
CONDITIONS FOR TERMINATING THE STUDY
Both the Sponsor and the investigator reserve the right to terminate the study at any 
time.  Should this be necessary, both parties will arrange the procedures on an individual 
study basis after review and consultation.  In terminating the study, Roche and the 
investigator will assure that adequate consideration is given to the protection of the 
participants’ interests.  The appropriate IRB/EC and Regulatory Agencies should be 
informed accordingly.
15.
STUDY DOCUMENTATION, CASE REPORT FORMS, AND 
RECORD KEEPING
15.1
INVESTIGATOR'S FILES/RETENTION OF DOCUMENTS
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be subsequently verified.  
These documents should be classified into two different separate categories 
(1) Investigator's Study File, and (2) participant clinical source documents.
The investigator's Study File will contain the protocol/amendments, eCRF and schedule 
of activities, IRB/EC and governmental approval with correspondence, sample informed 
consent, drug records, staff curriculum vitae and authorization forms and other 
appropriate documents/correspondence, etc.  In addition, at the end of the study the 
investigator will receive the participant data, which includes an audit trail containing a 
complete record of all changes to data, query resolution correspondence and reasons 
for changes, in human readable format on compact disc which also has to be kept with 
the Investigator’s Study File.
Participant clinical source documents (usually defined by the project in advance to 
record key efficacy/safety parameters independent of the eCRFs) would include 
participant hospital/clinic records, physician's and nurse's notes, appointment book, 
original laboratory reports, ECG, EEG, X-ray, pathology and special assessment reports, 
signed informed consent forms, consultant letters, and participant screening and 
enrollment logs.
The investigator must keep the two categories of documents as described above 
(including the archival compact disc) on file for at least 15 years after completion or 
discontinuation of the study.  After that period of time the documents may be destroyed, 
subject to local regulations.
Should the investigator wish to assign the study records to another party or move them 
to another location, Roche must be notified in advance.


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If the investigator cannot guarantee this archiving requirement at the investigational site 
for any or all of the documents, special arrangements must be made between the 
investigator and Roche to store these in a sealed container(s) outside of the site so that 
they can be returned sealed to the investigator in case of a regulatory audit.  
Where source documents are required for the continued care of the participant, 
appropriate copies should be made for storing outside of the site.
International Council for Harmonisation Good Clinical Practice (GCP) guidelines require 
that investigators maintain information in the study participant’s records which 
corroborate data collected on the eCRF(s).  Completed eCRF will be transferred to 
Sponsor.
15.2
SOURCE DOCUMENTS AND BACKGROUND DATA
The investigator shall supply the Sponsor on request with any required background data 
from the study documentation or clinic records.  This is particularly important when 
errors in data transcription are suspected.  In case of special problems and/or 
governmental queries or requests for audit inspections, it is also necessary to have 
access to the complete study records, provided that participant confidentiality is 
protected.
15.3
AUDITS AND INSPECTIONS
The investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from the Roche Pharma Development 
Quality Assurance Unit or its designees, or to health authority inspectors after 
appropriate notification.  The verification of the eCRF data must be by direct inspection 
of source documents.
15.4
ELECTRONIC CASE REPORT FORMS
Data for this study will be captured via an EDC system by with use of eCRFs.  An audit 
trail will maintain a record of initial entries and changes made; reasons for change; time 
and date of entry; and user name of person authorizing entry or change.  
The investigator must update eCRF and connect on a regular basis.
For each participant enrolled, an eCRF must be completed and electronically signed by 
the Principal Investigator or authorized delegate from the study staff.  This also applies 
to records for those participants who fail to complete the study (even during a 
pre-randomization screening period if an eCRF was initiated).  If a participant withdraws 
from the study, the reason must be noted on the eCRF.  If a participant is withdrawn 
from the study because of a treatment-limiting adverse events, thorough efforts should 
be made to clearly document the outcome.
The investigator should ensure the accuracy, completeness and timeliness of the data 
reported to the Sponsor in the eCRFs and in all required reports.


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15.5
FINANCIAL DISCLOSURE
The investigator(s) will provide the Sponsor with sufficient accurate financial information 
(Form PD35) to allow the Sponsor to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities.  The investigator is 
responsible to promptly update any information provided to the Sponsor if relevant 
changes occur in the course of the investigation and for 1 year following the completion 
of the study (last participant, last visit).
16.
MONITORING THE STUDY
It is understood that the responsible Roche monitor (or designee) will contact and visit 
the investigator regularly and will be allowed, on request, to inspect the various records 
of the trial (eCRFs and other pertinent data) provided that participant confidentiality is 
maintained in accord with local requirements.
It will be the monitor's responsibility to inspect the eCRFs at regular intervals throughout 
the study, to verify the adherence to the protocol and the completeness, consistency and 
accuracy of the data being entered on them.  The monitor must verify that the participant
received the study drug assigned by the randomization center (by controlling the written 
confirmation of the randomization by IxRS).  The monitor should have access to 
laboratory test reports and other participant records needed to verify the entries in the 
eCRF.  The investigator (or deputy) agrees to cooperate with the monitor to ensure that 
any problems detected in the course of these monitoring visits are resolved.
Roche Clinical Repository specimens will at all times be tracked in a manner consistent 
with GCP, by a quality controlled, auditable and validated Laboratory Information 
Management System, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in the study protocol and ICF, 
respectively.  Roche monitors and auditors will have direct access to appropriate parts of 
records relating to participants participating in this study for the purposes of verifying the 
data provided to Roche.  The site will permit monitoring, audits, IRB/EC review, and 
regulatory inspections by providing direct access to source data and documents related 
to the RCR Research Project.
17.
CONFIDENTIALITY OF TRIAL DOCUMENTS AND PARTICIPANT
RECORDS
The investigator must assure that participants’ anonymity will be maintained and that 
their identities are protected from unauthorized parties.  On Case Report Forms (CRFs)
or other documents submitted to the Sponsor, participants should not be identified by 
their names, but by an identification code.  The investigator should keep a Participant
Identification Log showing codes, names and addresses.  The investigator should 
maintain documents not for submission to Roche, e.g., participants' written consent 
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The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in-line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Roche personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Roche personnel.
Data derived from RCR specimen analysis on individual participants will not be provided 
to study investigators, except where explicitly stipulated in a study protocol (e.g., if the 
result is an enrollment criterion).  Exceptions may be granted (e.g., if biomarker data 
would be linked to safety issues).  The aggregate results of any research conducted with 
use of RCR specimens will be available in accordance with the effective Roche policy on 
study data publication.
Any inventions and resulting patents, improvements and/or know-how originating from 
the use of data will become and remain the exclusive and unburdened property of the 
Sponsor, except where agreed otherwise.


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Appendix 1
Adverse Event Categories for Determining Relationship to 
Test Drug
The causality relationship of study drug to the adverse event will be assessed by the 
investigator as either: Yes or No.
If there is a reasonable suspected causal relationship to the study medication, i.e., there 
are facts (evidence) or arguments to suggest a causal relationship, drug-event 
relationship should be assessed as Yes.
The following criteria should be considered in order to assess the relationship as 
Yes:

Reasonable temporal association with drug administration

It may or may not have been produced by the participant’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the 
participant

Known response pattern to suspected drug

Disappears or decreases on cessation or reduction in dose

Reappears on rechallenge
The following criteria should be considered in order to assess the relationship as 
No:

It does not follow a reasonable temporal sequence from administration of the drug

It may readily have been produced by the participant’s clinical state, environmental 
or toxic factors, or other modes of therapy administered to the participant

It does not follow a known pattern of response to the suspected drug

It does not reappear or worsen when the drug is readministered


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Appendix 2
ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2
A serious adverse event is any experience that suggests a significant hazard, 
contraindication, side effect or precaution.  It is any adverse event that at any dose fulfills 
at least one of the following criteria:

Is fatal (results in death)
NOTE: death is an outcome, not an event.

Is life-threatening (NOTE: the term "life-threatening" refers to an event in which the 
participant was at immediate risk of death at the time of the event; it does not refer 
to an event which could hypothetically have caused a death had it been more 
severe)

Requires in-patient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is medically significant or requires intervention to prevent one or other of the 
outcomes listed above
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting to the Sponsor is appropriate in other situations, such as important medical 
events that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the participant or may require intervention to prevent one of the 
outcomes listed in the definitions above.  These situations should also usually be 
considered serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse.
An unexpected adverse event is one in which the nature or severity is not consistent with 
the applicable product information.
Causality is initially assessed by the investigator.  For serious adverse events, possible 
causes of the event are indicated by selecting 1 or more options (check all that apply):

Preexisting/Underlying disease specify

Study treatment specify the drug(s) related to the event

Other treatment (concomitant or previous) specify

Protocol-related procedure

Other (e.g., accident, new or intercurrent illness) – specify


Appendix 2
ICH Guidelines for Clinical Safety Data Management, Definitions and 
Standards for Expedited Reporting, Topic E2 (cont.)
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The term severe is a measure of intensity, thus a severe adverse event is not 
necessarily serious.  For example, nausea of several hours' duration may be rated as 
severe, but may not be clinically serious.
A serious adverse event occurring during the study or which comes to the attention of 
the investigator within 15 days after stopping the treatment or during the protocol-defined 
follow-up period, if this is longer, whether considered treatment-related or not, must be 
reported.  In addition, a serious adverse event that occurs after this time, if considered 
related to test “drug”, should be reported.
Such preliminary reports will be followed by detailed descriptions later, which will include 
copies of hospital case reports, autopsy reports and other documents when requested 
and applicable.
For serious adverse events, the following must be assessed and recorded on the 
adverse events electronic form (eForm) of the electronic Case Report Form (eCRF): 
intensity, relationship to test substance, action taken, and outcome to date.
The investigator must notify the Institutional Review Board/Ethics Committee of a 
serious adverse event in writing as soon as is practical and in accordance with 
international and local laws and regulations.
24 HOUR MEDICAL COVERAGE
Identification of a contact for 24 Hour Medical Coverage is mandatory to be compliant 
with worldwide regulatory agencies and to ensure the safety of study participants.
An Emergency Medical Call Center Help Desk will access the Roche Medical 
Emergency List, escalate emergency medical calls, provide medical translation service 
(if necessary), connect the investigator with the Roche medical contact for this study and 
track all calls.  The Emergency Medical Call Center Help Desk will be manned 24 hours 
7 days a week.  Toll-free numbers will be distributed to all investigators running Roche 
Pharma Development clinical trials.  The Help Desk will be used for medical 
emergencies outside regular business hours, or when the regular Clinical Science 
Leader cannot be reached.


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Appendix 3
Common Terminology Criteria (CTCAE)
In the present study, toxicities will be graded according to the Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.0.
The CTCAE v4.0 can be found in the Roche handout entitled: “Common Terminology 
Criteria for Adverse Events v4.0” or via the following website: https://ctep.cancer.gov.


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Appendix 4
Telephone Interviews
The purpose of this interview is to identify and collect information on any changes in the 
participant’s health status that warrant an unscheduled visit (including new or worsening 
neurological symptoms).  Telephone interviews should be performed by study personnel 
every 4 weeks between clinic visits.
Please ask the following questions and record participant’s answers during the 
Telephone Interview:
Questions
No
Yes
1.  Since your last visit or telephone interview, have you had any new or 
worsening medical problems (such as sudden changes in your thinking, 
alterations in your behavior, visual disturbances, extremity weakness, 
limb coordination problems, or gait abnormalities) that have persisted 
over more than one day?
2.  Since your last visit or telephone interview, have you had any signs of an 
infection?
3.  Since your last visit or telephone interview, have you had any other new 
or worsening medical problems or conditions (including pregnancy)?
4.  Since your last visit or telephone interview, have you taken any new 
medicines (including medicines to treat cancer or MS, any other new 
medicines that weaken your immune system, or steroid medicines other 
than for the treatment of a recent relapse)?
If the participant answered Yes to any question, contact the Treating Investigator and 
review the participant’s answers.  The investigator can determine if an unscheduled visit 
is required.
Please report all relevant information in the electronic Case Report Form as well.
Record any pertinent comments made by the participant during the interview:
________________________________________________________________
________________________________________________________________
________________________________________________________________
NAME:______________________________ Date:______________________________
Name of person completing the telephone interview


Appendix 4 
Telephone Interviews (Cont.) 
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Below is a sample list of medications that can weaken the immune system.  
This list does not include all drugs that can suppress the immune system. 
Approved MS therapies: 
 
Glatiramer acetate (Copaxone®) 
 
Interferon -1a (Rebif®, AVONEX®) 
 
Interferon -1b (Betaseron®) 
 
Mitoxantrone (Novantrone®) 
 
Natalizumab (Tysabri®) 
 
Fingolimod (Gilenya®) – if relevant 
 
Immunosuppressants/Antineoplastics: 
 
Azathioprine (Imuran®, Azasan®) 
 
Cladribine (Leustatin®) 
 
Cyclophosphamide (Cytoxan®, Neosar®) 
 
Cyclosporine (Sandimmune®, Neoral®) 
 
Fludarabine phosphate (Fludara®) 
 
Leflunomide (Arava®) 
 
Mercaptopurine (Purinethol®) 
 
Methotrexate (Methotrex®, Rheumatrex®, Trexall®) 
 
Mycophenolate mofetil (CellCept®) 
 
Pemetrexed (Alimta®) 
 
Additional Immunomodulators and Immunosuppressants: 
 
Other interferons (Actimmune®, Infergen®, Intron® A, 
Pegasys®, PEG-Intron®, Rebetron®, Roferon®-A) 
 
Adalimumab (Humira®) 
 
Alefacept (Amevive®) 
 
Alemtuzumab (Campath®) 
 
Anakinra (Kineret®) 
 
Daclizumab (Zenapax®) 
 
Etanercept (Enbrel®) 
 
Infliximab (Remicade®) 
 
Intravenous immunoglobulin (IVIG) 
 
Ofatumumab (Arzerra®) 


Appendix 4 
Telephone Interviews (Cont.) 
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 
Rituximab (Rituxan/MabThera®) 
 
Trastuzumab (Herceptin®) 
 


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Appendix 5 Modified Fatigue Impact Scale (MFIS)


Appendix 5
Modified Fatigue Impact Scale (MFIS) (Cont.)
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Appendix 5
Modified Fatigue Impact Scale (MFIS) (Cont.)
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Appendix 6
The Center for Epidemiologic Studies Depression Scale 
(CES-D)


Appendix 6
The Center for Epidemiologic Studies Depression Scale (CES-D) (Cont.)
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Appendix 7
The Short Form-36 (SF-36) Health Survey


Appendix 7
The Short Form-36 (SF-36) Health Survey (Cont.)
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Appendix 7
The Short Form-36 (SF-36) Health Survey
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Appendix 7
The Short Form-36 (SF-36) Health Survey
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Appendix 7
The Short Form-36 (SF-36) Health Survey
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Appendix 7
The Short Form-36 (SF-36) Health Survey
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Appendix 8
Optical Coherence Tomography Exploratory Substudy
INTRODUCTION
Optical coherence tomography (OCT) is a noninvasive imaging tool capable of sensitive, 
reproducible and rapid measurements of structural architecture of the retina and retinal 
nerve fiber layer (Frohman et al. 2008).  Optical coherence tomography can be of 
particular interest in multiple sclerosis (MS), because optic neuritis is often the pivotal 
event in establishing the diagnosis of MS.  Optic nerve dysfunction is characterized by 
optic disc pallor and loss of contrast sensitivity, and visual field defects, which may occur 
subclinically in many participants.  It is estimated that nearly 20% of all participants with 
MS present initially with optic neuritis, and an additional 30%100% will have optic 
neuritis at some point in their disease course (Sergott et al. 2007).  The OCT outcome 
measures such as retinal nerve fiber layer (RNFL) thickness and macular volumes have 
been shown to correlate with clinical measures of vision loss and may facilitate 
visualization of any process of neurodegeneration or repair as part of natural history of 
MS or as a consequence of neuroprotective interventions (Costello et al. 2008).
This substudy is part of 3 ongoing Phase III studies that serve to evaluate the 
neuroprotective effect of ocrelizumab in MS as measured by RNFL thickness and 
macular volume in both eyes of participants who participate in the confirmatory pivotal 
studies in participants with relapsing multiple sclerosis (RMS; Studies WA21092 and 
WA21093) or participants with primary progressive multiple sclerosis 
(PPMS; Study WA25046).
In July 2017, Roche determined that sufficient data had been collected from the 
OCT substudy.  During 2017 and 2018, participating participants will be discontinued 
from the OCT substudy but may continue in the open-label extension (OLE).
OBJECTIVES
EFFICACY OBJECTIVES
The primary efficacy objectives for this substudy are as follows:

To evaluate the neuroprotective effect of ocrelizumab therapy as measured by 
macular volume and RNFL over time

To characterize the time-course of changes in RNFL that imply axonal loss in 
participants with both RMS and PPMS with or without ocrelizumab treatment
The secondary efficacy objectives for this study are as follows:

In the case of RMS participants (Studies WA21092 and WA21093), the study will 
assess whether ocrelizumab 600 mg has superior neuroprotective effect compared 
with Rebif® as measured by RNFL thickness


Appendix 8
Optical Coherence Tomography Exploratory Substudy (Cont.)
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
In the case of PPMS participants (Study WA25046), the study will assess whether 
ocrelizumab 600 mg has superior neuroprotective effect compared with placebo as 
measured by RNFL thickness
SAFETY OBJECTIVES
The safety objectives for this study are as follows:

To evaluate the ophthalmological safety of ocrelizumab therapy in participants with 
MS, focusing on serious adverse events
EXPLORATORY OBJECTIVES
The exploratory objectives for this study are as follows:

To evaluate if OCT outcomes can serve as a reliable and predictive measure of 
response to ocrelizumab therapy in MS participants or progression to a more severe 
disease state

To evaluate the relationship of OCT outcomes with outcomes from ocrelizumab 
Phase III pivotal studies, such as
–
Change in brain volume as measured by brain MRI

Confirmed disability progression

T2 lesion volume

Number of T1 gadolinium (Gd)-enhanced lesions

Change in Multiple Sclerosis Functional Composite Scale (MSFCS) score
STUDY DESIGN
DESCRIPTION OF STUDY
Overview
The current substudy is an add-on, multicenter, longitudinal study to the ongoing 
Phase III ocrelizumab Studies WA21092, WA21093, and WA25046 to evaluate the 
neuroprotective effects of ocrelizumab treatment as measured by OCT.  
Optical coherence tomography will be performed in parallel to the ocrelizumab pivotal 
Phase III studies.
Participants can be enrolled at any time during the first 48 weeks after enrollment in the 
main pivotal studies.  However, all attempts should be made to enroll the participant at 
the time of screening of the main pivotal study.  Participants will undergo an 
ophthalmological examination prior to first OCT scan and at the end of the study.  
Participants will also undergo at least 3 OCT scans at 24-week intervals (see schedule 
of activities of this substudy, Appendix 9).
For participants participating in Studies WA21092 and WA21093:

The participant should undergo OCT measurement every 24 weeks after the first 
OCT Visit (Visit 1 of the OCT substudy).  If the participant is enrolled into the 


Appendix 8
Optical Coherence Tomography Exploratory Substudy (Cont.)
Ocrelizumab—F. Hoffmann-La Roche Ltd
175/Protocol WA21093J, Version 10
OCT substudy at baseline of the main study, the following visits should occur:
Visit 1 (Week 0; occurring at the baseline visit of the main study), Visit 2 
(Week 24 occurring at Visit 5 of the main study), Visit 3 (Week 48; occurring at 
Visit 7 of the main study), Visit 4 (Week 72; occurring at Visit 9 of the main study) 
and Visit 5 (Week 96; occurring at Visit 11 of the main study).  If the participant is 
enrolled after baseline of the main study, OCT visits should occur every 24 weeks 
after the first OCT Visit (Visit 1, Week 0).
For participants participating in Study WA25046:

The participant should undergo OCT measurement every 24 weeks after the first 
OCT Visit (Visit 1 of the OCT substudy).  If the participant is enrolled into the 
OCT substudy at baseline of the main study, the following visits should occur: 
Visit 1 (Week 0; occurring at the baseline visit of the main study), Visit 2 
(Week 24, occurring at Visit 5 of the main study), Visit 3 (Week 48, occurring at 
Visit 8 of the main study), Visit 4 (Week 72, occurring at Visit 11 of the main study), 
Visit 5 (Week 96, occurring at Visit 14 of the main study), and Visit 6 
(Week 120, occurring at Visit 17 of the main study).  If the participant is enrolled 
after baseline of the main study, OCT visits should occur every 24 weeks after the 
first OCT Visit (Visit 1, Week 0).
If the participant is withdrawn from study treatment in the main protocol, an OCT Visit 
should occur if it has not been performed during the previous 4 weeks.  
Participants should then have an OCT measurement at the end of the safety follow-up of 
the main protocol.
If a participant decides to participate in the OLE phase of the main protocol, 
OCT measurements should continue to occur every 24 weeks during the OLE phase.
A schedule of activities is provided in Appendix 9 of this substudy.
Image Review
A masked, central OCT reading center will review and analyze OCT images.  
The procedures will be detailed in an Imaging Review Charter.
END OF STUDY
In July 2017, Roche determined that sufficient data had been collected from the 
OCT substudy.  During 2017 and 2018, participating participants will be discontinued 
from the OCT substudy but may continue in the OLE.
OUTCOME MEASURES 
Efficacy Outcome Measures
The efficacy outcome measures for this study are as follows:

Overall and quadrant RNFL thickness measured by OCT

Macular volume maps as measured by OCT


Appendix 8
Optical Coherence Tomography Exploratory Substudy (Cont.)
Ocrelizumab—F. Hoffmann-La Roche Ltd
176/Protocol WA21093J, Version 10
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence, nature, and severity of ophthalmological adverse events
Materials and Methods 
Participants
Adult participants who fulfill eligibility criteria for one of the main Phase III ocrelizumab 
pivotal studies (i.e., Studies WA21092, WA21093, or WA25046) and the eligibility criteria 
outlined in the following inclusion and exclusion sections of this substudy can be enrolled 
into the study.
Inclusion Criteria
Participants must meet the following criteria for study entry:

Able and willing to provide written informed consent and comply with the study 
protocol

Be a participant in one of the following studies: WA21092, WA21093, or WA25046
Exclusion Criteria
Participants who meet any of the following criteria will be excluded from study entry:

Medical history of macular degeneration, retinopathy, glaucoma, amblyopia, 
diabetes, or any other documented cause of vision loss

Inability to undergo reliable OCT testing

More than 48 weeks have lapsed since randomization
STUDY ASSESSMENTS
Screening and Baseline Examination and Eligibility Screening Form
All participants must sign and date the most current Institutional Review Board/Ethics 
Committee-approved written informed consent before any study specific assessments or 
procedures are performed.
Consenting participants must also have signed the informed consent and be eligible for 
the main pivotal Phase III study.  Participants will receive an ophthalmological and eye 
examination to be evaluated for eligibility to participate in this substudy.  If the participant
is eligible, this ophthalmological examination will be considered the baseline 
ophthalmological measure (OCT Visit 1).
An Eligibility Screening Form documenting the investigator’s assessment of each 
screened participant with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the investigator.
It should be stated in the medical record that the participant is participating in this clinical 
study.


Appendix 8
Optical Coherence Tomography Exploratory Substudy (Cont.)
Ocrelizumab—F. Hoffmann-La Roche Ltd
177/Protocol WA21093J, Version 10
Once a participant has fulfilled all eligibility criteria, he or she will undergo 
OCT according to the schedule of activities (Appendix 9 of this substudy).
Procedure in Case of Delayed Dosing Visit, Relapse or Unscheduled Visits, 
and Withdrawal Visits in the Main Phase III Ocrelizumab Pivotal Studies
The main ocrelizumab pivotal studies have mechanisms set up regarding delayed 
dosing visits, unscheduled visits due to relapse, and withdrawal visits.
Optical coherence tomography measurements should occur at initially scheduled times 
and should not be rescheduled due to delayed dosing schedule or unscheduled visit due 
to relapse.  In case there is a relapse during an OCT scheduled visit, the investigator 
should document all ocular symptoms, including ocular neuritis, in the eCRF as well as 
communicate them to the Principal Investigator of the main study. If a participant suffers 
a relapse with symptoms acute optic neuritis during the month before OCT study, a 
second OCT must be performed 1 month later to account for the effect of papilledema.
If the participant is withdrawn from study treatment in the main protocol, an OCT Visit 
should occur if it has not been performed during the previous 4 weeks.  
Participants should then have an OCT measurement every 24 weeks until the end of the 
safety follow-up of the main protocol.
It is possible that the participant withdraws from only the OCT Exploratory substudy. 
In this case, an OCT Visit should occur if it has not been performed during the previous 
4 weeks.
Description of Study Assessments
Medical History and Demographic Data
Medical history and demographic data will be captured in main study in which the 
participant is enrolled.  Further medical history includes clinically significant diseases 
that may cause vision loss of the affected eye that have been documented by the 
ophthalmologist.
Ophthalmological and Eye Examination
The presence of any visual abnormalities will be established in a full eye examination.  
This will include an examination performed by an ophthalmologist during Visit 1 
(Week 0) and completion/withdrawal visit.  This will include best corrected visual acuity 
evaluation (with Early Treatment Diabetic Retinopathy Study standardized eye chart); 
color vision test (Hardy Rand Rittler pseudoisochormatic plate); visual field 
measurement; intraocular pressure; slitlamp examination to examine the anterior parts 
(cornea, lens, and sclera); and a dilated ophthalmoscopic examination of retina, optic 
nerve, retinal blood vessels, and macula.  The eye chart chosen for a participant must 
be consistently used throughout the study as well as the use of corrective lenses during 
the ophthalmological exam.


Appendix 8
Optical Coherence Tomography Exploratory Substudy (Cont.)
Ocrelizumab—F. Hoffmann-La Roche Ltd
178/Protocol WA21093J, Version 10
Visual Evoked Potential
Visual evoked potential (VEP) is a sensitive test of visual pathway function and a marker 
of optic nerve involvement in MS, and it has been used as a diagnostic tool for RMS and 
PPMS (Polman et al. 2005).  It can be used to supplement information provided by a 
clinical examination to provide objective evidence of a second lesion provided that the 
only clinically expressed lesion did not affect the visual pathways.  Visual evoked 
potential measurement should occur during OCT Visit 1 (Week 0).  If available at the 
center, multifocal VEP will be performed instead of full-field VEP.
Note:  In the rare cases that the selected site cannot deliver VEP data for any reason, 
VEP measurements will not be necessary after discussion with the Sponsor.  
However, all efforts should be made to collect VEP data during Visit 1 (Week 0).
Optical Coherence Tomography
Optical coherence tomography images will be acquired in all participants as detailed in 
the schedule of activities (Appendix 9 of this substudy).  In addition, an OCT scan will be 
performed in participants withdrawn from the main study treatment if it has not been 
performed within the previous 4 weeks.
All OCT images will be performed by certified personnel.  The following time windows 
apply: 

OCT Visit 1 (Week 0) should occur prior to baseline visit of the primary study 
and at Visit 2 (Week 24), Visit 3 (Week 48), Visit 4 (Week 72), and Visit 5 
(Week 96)

In case the participant is enrolled after the baseline visit of main study, OCT Visit 1 
should occur at time of enrollment into the substudy.  All further OCT scans should 
occur every 24 weeks thereafter.

If a participant enrolls into the OLE phase of the main study, OCT assessments 
should continue to occur every 24 weeks.
During OCT Visit 1 (Week 0), the OCT scan should be performed twice in order to 
control for test-retest reliability.
Optical coherence tomography images will be read by a centralized reading center.  
The reading will be performed in a masked fashion in the absence of clinical information.  
Further details on the OCT protocols and standardization of machines are described in a 
separate Independent Review Charter (IRC).
Procedure in Case of Ocular Neuritis or Relapse
If the participant presents with optic neuritis, the affected eye should be documented.  
The participant should also be referred to the Principal Investigator of the main study for 
examination. If the participant suffers a relapse with symptoms of acute optic neuritis 
during the month before an OCT scan, a second OCT scan must be performed 1 month 
later to account for the effect of papilledema.


Appendix 8
Optical Coherence Tomography Exploratory Substudy (Cont.)
Ocrelizumab—F. Hoffmann-La Roche Ltd
179/Protocol WA21093J, Version 10
Assessment of Safety
Safety Plan
Any adverse event regarding ocular findings should be reported to the 
Principal Investigator of the main study in which the participant is participating, as well as 
the Sponsor.  Please see protocol Section 7 regarding the procedures related to 
reporting of adverse events and serious adverse events.
Statistical Considerations and Analysis Plan
Full details of all statistical issues and planned statistical analyses will be specified in the 
IRC charter.
Sample Size
A total of approximately 300 participants will be enrolled in this substudy.
EFFICACY ANALYSES
The purpose of this study is to estimate the neuroprotective effect of ocrelizumab 
treatment in participants with MS relative to Rebif in the case of Studies WA21092 and 
WA21093 and relative to placebo in the case of Study WA25046.  Point and interval 
estimates of the decrease of RNFL thickness and macular volume will be obtained.
Primary Efficacy Endpoint
The primary efficacy endpoint is the decrease in RNFL thickness over time during the 
duration of the main study.
Secondary and Exploratory Efficacy Endpoints
Secondary and exploratory endpoints are:

Determination of macular volume over time during the duration of the study

Exploratory correlation analyses to determine the predictive value of OCT measures 
(RNFL thickness and macular volume) with outcomes measured in the main study, 
such as (but not restricted to): 
–
Change in brain volume as measured by brain MRI
–
Confirmed disability progression
–
T2 lesion volume
–
Number of T1 Gd-enhanced lesions
–
Change in MSFCS score
SAFETY ANALYSES
No safety analyses are planned for this substudy.  Any safety event noted during this 
substudy will be forward to the Principal Investigator of the main study.  See Section 7 of 
the main protocol.


Appendix 8
Optical Coherence Tomography Exploratory Substudy (Cont.)
Ocrelizumab—F. Hoffmann-La Roche Ltd
180/Protocol WA21093J, Version 10
REFERENCES
Costello F, Hodge W, Pan YI, et al. Tracking retinal nerve fiber layer loss after optic 
neuritis: a prospective study using optical coherence tomography. Mult Scler 
2008;14:893905.
Frohman, EM, Fujimoto JG, Frohman TC, et al. Optical coherence tomography: a 
window into the mechanisms of multiple sclerosis. Nat Clin Prac 2008;4:66475.
Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 
2005 revisions to the "McDonald Criteria". Ann Neurol 2005;58:8406.
Sergott RC, Frohman E, Glanzman R, et al. The role of optical coherence tomography in 
multiple sclerosis: expert panel consensus. J Neurol Sci 2007;263:314.


Ocrelizumab—F. Hoffmann-La Roche Ltd
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Appendix 9 Optical Coherence Tomography Exploratory Substudy Schedule of Activities
Treatment Period a
Open-Label 
Extension Phase 
(for OPERA study) e
Completion Visit
Safety 
Follow-Up
Withdrawal 
Visit a
Visit
1
2
3
4
5
Week (window in days)
0
24 
(14)
48
(14)
72
(14)
96
(14)
Informed consent
x
Ophthalmological and 
Eye Examination
x
x
x
Visual Evoked Potential
x
Medical History
x
Baseline Conditions
x
OCTb
x
x
x
x
x
x
x
xc
x
Adverse events d
x
x
x
x
x
x
x
x
x
OCToptical coherence tomography; OLEopen-label extension.
a Treatment period is variable, as it depends on the time of enrollment within the main study.
b In cases where the initially submitted OCT Visit scan is inadequate/not evaluable by Bern Photographic Reading Center, the site should make all 
efforts to request the participant to come back to site to perform a new OCT scan.
c Safety follow-up: OCT assessment should continue every 24 weeks counting after last OCT assessment visit.
d Any adverse events should be reported to the Principal Investigator of the study.
e If a participant enrolls in the OLE phase of the main study, OCT assessments should occur every 24 weeks.


Ocrelizumab—F. Hoffmann-La Roche Ltd
182/Protocol WA21093J, Version 10
Appendix 10 Abbreviations
Abbreviation or Term
Definition
23-PPV
23-valent pneumococcal polysaccharide
9HPT
9-Hole Peg Test
ADA
anti-drug antibody (also known as human anti-human antibody
[HAHA])
ADCC
antibody-dependent cellular cytotoxicity
ARR
annualized relapse rate
AUC
area under the concentration-time curve
BCG
Bacille Calmette-Guérin
CAs
Competent Authorities
CD
cluster of differentiation
CDC
complement-dependent cytotoxicity
CDP
confirmed disability progression
cDNA
complementary DNA
CDR3
third complementarity determining region
CES-D
Center for Epidemiologic Studies Depression Scale
CFR
Code of Federal Regulations
CMH
Cochran Mantel Haenszel
CRF
Case Report Form
CSF
cerebrospinal fluid
C-SSRS
Columbia-Suicide Severity Rating Scale
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee
DMT
disease-modifying therapy
EC
Ethics Committee
EEA
European Economic Area
eCRF
electronic Case Report Form
EDC
electronic data capture
EDSS
Expanded Disability Status Scale
eForm
Electronic form
ePRO
electronic participant-reported outcomes
ESF
Eligibility Screening Form
FACS
fluorescence-activated cell sorting
FDA
(U.S.) Food and Drug Administration
FLAIR
fluid-attenuated inversion recovery
FSH
follicle-stimulating hormone


Appendix 10
Abbreviations (Cont).
Ocrelizumab—F. Hoffmann-La Roche Ltd
183/Protocol WA21093J, Version 10
Abbreviation or Term
Definition
FSS
Functional Systems Scale
GCP
Good Clinical Practice
Gd
gadolinium
GGT
gamma glutamyl transferase
HAHA
human anti-human antibody (also known as anti-drug antibody 
[ADA])
HAM
human T-lymphotropic virus type 1 associated myelopathy
HBsAg
hepatitis B surface antigen
HBcAb
hepatitis B core antibody
HepCAb
hepatitis C antibody
HDHF
high-dose high-frequency
hCG
human chorionic gonadotropin
HTLV-1
human T lymphotropic virus type 1
IB
Investigator's Brochure
ICF
Informed Consent Form
ICH
International Council on Harmonisation
iDMC
independent Data Monitoring Committee
IFN
interferon
IM
intramuscular
IMP
Investigational Medicinal Product
IND
Investigational New Drug
INN
International Non proprietary Name
IRB
Institutional Review Board
IRR
infusion-related reaction
ITT
intent-to-treat
IxRS
interactive voice or web-based response system
JCV
John Cunningham virus
KFS
Kurtzke Functional Systems
KLH
keyhole limpet haemocyanin
LLN
lower limit of normal
MCS
mental component summary
MFIS
Modified Fatigue Impact Scale
MMRM
Mixed-Effect Model Repeated Measures
MRI
magnetic resonance imaging
MS
multiple sclerosis
MSFCS
Multiple Sclerosis Functional Composite Scale
MTX
methotrexate


Appendix 10
Abbreviations (Cont).
Ocrelizumab—F. Hoffmann-La Roche Ltd
184/Protocol WA21093J, Version 10
Abbreviation or Term
Definition
NEDA
no evidence of disease activity
NONMEM
Nonlinear Mixed Effects Modelling
OCB
oligoclonal band
OCT
optical coherence tomography
OLE
open-label extension
PASAT
Paced Auditory Serial Addition Test
PCR
polymerase chain reaction
PCS
Physical Component Summary
PML
progressive multifocal leukoencephalopathy
PP
per protocol (population)
PPMS
primary progressive multiple sclerosis
PRO
participant-reported outcome
PY
participant-year
RA
rheumatoid arthritis
RBR
Research Biosample Repository
RCR
Roche Clinical Repository
RMS
relapsing multiple sclerosis
RRMS
relapsing-remitting multiple sclerosis
RNFL
retinal nerve fiber layer
ROW
Rest of World
RPR
rapid plasma reagin
RR
relative reduction
RRMS
relapsing-remitting multiple sclerosis
S1P
sphingosine-1 phosphate
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SDMT
Symbol Digit Modalities Test
SF-36
Short Form-36 Health Survey
SMT
Study Management Team
SPMS
secondary progressive multiple sclerosis
T25FWT
Timed 25-Foor Walk Test
TB
tuberculosis
TT
tetanus toxoid
ULN
upper limit of normal
USPI
U.S. Package Insert
VH4
variable heavy 4
VLA-4
-4 -1 integrin

SAP_001.pdf: 
 
Official Title: 
A Randomized, Double-Blind, Double-Dummy, Parallel-Group Study 
to Evaluate the Efficacy And Safety of Ocrelizumab in Comparison to 
Interferon Beta-1a (Rebif®) in Patients With Relapsing Multiple 
Sclerosis 
NCT Number: 
NCT01412333 
Document Date: 
SAP Version 5: 20 March 2023 
 
 
 
 


STATISTICAL ANALYSIS PLAN AMENDMENT APPROVAL 
 
 
CONFIDENTIAL 
 
This is a F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WA21092 and WA21093 
 
 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A RANDOMIZED, DOUBLE-BLIND, DOUBLE-
DUMMY, PARALLEL-GROUP STUDY TO 
EVALUATE THE EFFICACY AND SAFETY 
OF OCRELIZUMAB IN COMPARISON TO 
INTERFERON BETA-1A (REBIF®) IN PATIENTS 
WITH RELAPSING MULTIPLE SCLEROSIS 
PROTOCOL NUMBERS: 
WA21092 and WA21093 
STUDY DRUG: 
Ocrelizumab (RO4964913) 
VERSION NUMBER: 
5 
IND NUMBER: 
100,593 
EUDRACT NUMBERS: 
2010-020337-99 and 2010-020315-36 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY: 
, Ph.D. 
, M.Sc. 
DATE FINAL: 
8 March 2011 
DATES AMENDED: 
Version 2:  14 January 2014 
Version 3:  3 September 2014 
Version 4:  14 May 2015 
Version 5:  See electronic date stamp on the last 
page of the document. 


Ocrelizumab—F. Hoffmann-La Roche Ltd 
2/Statistical Analysis Plan WA21092 and WA21093 
STATISTICAL ANALYSIS PLAN AMENDMENT 
RATIONALE 
January 2014 
Study WA21093 number for pooling was not included in the first version.  Several 
exploratory and sensitivity analyses have been removed in order to focus on the 
analyses to be performed for the regulatory submission.  The hierarchy of the secondary 
efficacy endpoints has been modified.  Efficacy analyses in some subgroups have been 
added for EU regulatory purposes.  The intent-to-treat population includes all patients 
randomized to adhere to the standard definition. 
August 2014 
This Statistical Analysis Plan (SAP) was amended to implement EMA Scientific Advice 
and to increase statistical rigor (for example, replacing ranked ANCOVA analysis with 
Mixed-Effect Model Repeated Measures analysis (MMRM) in relevant analyses).  This 
SAP has also been updated to align with the amended study protocols.  In both the 
protocols and this SAP, the secondary and exploratory efficacy endpoints have been 
extensively modified to reflect the latest clinical and scientific thinking in the field of MS, 
and also to increase rigor (for example, the proportion of relapse-free patients was 
changed from a secondary to an exploratory efficacy endpoint, since it is closely related 
to the primary efficacy endpoint, hence adds only limited value to our understanding of 
efficacy). 
More details have been added to specify the calculation of the baseline Expanded 
Disability Status Scale (EDSS) value. The average value of the screening EDSS score 
and the value at the baseline visit used as reference for the analyses of increase or 
decrease EDSS score (i.e., the Confirmed Disability Progression, Confirmed Disability 
Improvement (CDI), and mean change of EDSS over time).  However, for the 
stratification, the value is rounded up to the next EDSS score (e.g., 3.75 is rounded up to 
4. and 3.25 is rounded up to 3.5), in order to present a valid score for the baseline 
characteristics and randomization scheme.  The definition of the confirmed disability 
progression has been slightly modified to take into account the existence of a baseline 
EDSS of 5.75, with no impact to the identification of the progression.  The definition of 
the Confirmed Disability Improvement has been added.  In order to simplify the definition 
of the safety population and adhere to the standard, the safety population now includes 
all patients who received any study drug. 
This Statistical Analysis Plan covers analyses performed at the level of each individual 
study.  The scope of this statistical analysis plan includes: 
• 
All data collected in the 96-week comparative treatment phase 
• 
All data collected in the Open-Label Extension (OLE) phase up to the date of clinical 
cutoff applied for the analysis of the 96-week comparative treatment phase 


Ocrelizumab—F. Hoffmann-La Roche Ltd 
3/Statistical Analysis Plan WA21092 and WA21093 
• 
All data collected in the Safety Follow-Up (SFU) phase up to the date of clinical 
cutoff applied for the analysis of the 96-week comparative treatment phase 
Note that substudies conducted at certain selected sites, such as the substudy collecting 
Optical Coherence Tomography (OCT) scans, are not within the scope of this statistical 
analysis plan.  These analyses will be planned, executed, and reported separately. 
Analyses performed upon data from both studies combined are described in a separate 
analysis plan (i.e., the “Pooled SAP”). 
It is planned that this statistical analysis plan will be reviewed, to include the SAS code 
for primary and secondary analysis per FDA request, once more before the first of the 
two study database locks for the primary analysis, to ensure it remains fit for purpose 
and provides sufficient detail. 
Protocol synopsis and schedule of assessment have been removed from the SAP and 
are available in the protocols. 
Additional minor changes have been made to improve clarity and consistency. 
May 2015 
Updates made at this time include the following major aspects.  The rationale for the 
updates is to provide full and complete information on these important aspects prior to 
database lock: 
• 
Subgroup analyses for EU planning purposes have been removed; these are now 
covered in the pooled SAP. 
• 
Detailed updates have been made to the safety analysis section. 
• 
SAS code has been included for statistical models for primary and secondary 
analyses. 
• 
Derivation of protocol-defined relapses has been added. 
• 
Reasons for patient exclusion from the per-protocol population have been added. 
• 
Sensitivity analyses have been added to describe alternative analyses when 
negative binomial models do not fit appropriately 
• 
Methods have been added to handle MSFC values outside of normal ranges 
Additional minor changes have been made to improve clarity and consistency. 
Jan 2022 
This SAP is updated to describe the modification to the pre-specified analyses during the 
double-blind phase, as well as the analyses to be performed on data from the open-label 
extension (OLE) period.  The OLE differed from the double-blind phase of the study with 
respect to the objectives and the data collected.  As a result, the statistical analysis plan 
required modification.  Moreover, several modifications were made based on the 


Ocrelizumab—F. Hoffmann-La Roche Ltd 
4/Statistical Analysis Plan WA21092 and WA21093 
availability of the data.  A list of these modifications can be found below.  A table is also 
added to display the status of each reporting event. 
Updated Analysis: 
Some analyses that were pre-specified for the double blind period were modified after 
unblinding and are summarized below: 
• 
The pre-specified exploratory analyses of T2 hyperintense lesion volume, the timed 
25-foot walk (T25-FW) and nine-hole peg test (9-HPT) utilizing the change from 
baseline (see SAP version 4 May 2015 Sections 4.4.3.2, 4.4.3.7 and 4.4.3.8 
respectively) did not meet assumptions of normality and so were adapted post-hoc 
to use a logarithmic transformation of the scores, hence the ratio of post-baseline to 
baseline scores are reported. 
The pre-specified exploratory analysis of ARR for severe relapses (SAP version 4 May 
2015 Section 2.2.3) was not conducted due to the low number of severe relapses 
observed during the study (two severe relapses in the IFN group and zero in the OCR 
group). 
Additional Exploratory Analysis: 
• 
ARR by year 
• 
Annualized change in Non-enhancing T1 lesion volume radius 
• 
Time to Onset of Confirmed Disability Progression for at least 48 Weeks  
• 
Time to 24-week confirmed Expanded Disability Status Scale score ≥ 6.0 (time to 
requiring a walking-aid) 
• 
Time to 48-week confirmed Expanded Disability Status Scale score ≥ 6.0 (time to 
requiring a walking-aid) 
• 
Time to Onset of Composite Confirmed Disability Progression (EDSS or T25-FW or 
9-HPT) for at least 12 Weeks 
• 
Time to Onset of Composite Confirmed Disability Progression (EDSS or T25-FW or 
9-HPT) for at least 24 Weeks 
The analyses of EuroQoL EQ-5D questionnaire collected at baseline, Week 48 and 
Week 96 during the double-blind phase and yearly during the OLE phase were not 
conducted at the time of the Primary Analysis and will be reported descriptively in the 
final CSRs. 
Protocol Updates:  
Due to various protocol amendments, SAP is updated to reflect changes or updates 
made in the protocol amendments. Below are some of such changes; 


Ocrelizumab—F. Hoffmann-La Roche Ltd 
5/Statistical Analysis Plan WA21092 and WA21093 
• 
OLE treatment phase is extended till 31 Dec 2022 to allow additional long-term 
efficacy and safety data. Study can be ended by 31 Dec 2022 and an option is 
introduced for all ongoing participants of OPERA studies to enroll into a new open-
label extension study (MN43964) prior to or following the closure of Study 
WA21092/WA21093, latest by End of 2022. 
• 
PK/HAHA collection has been stopped since Dec 2019. 
• 
Ocrelizumab must be suspended in the event of an active TB infection or if a female 
patient is pregnant or breastfeeding in OLE period. Ocrelizumab infusions may be 
restarted at the discretion of the Investigator and based on individual benefit-risk 
assessments, but only upon resolution of the active TB infection or after completion 
of pregnancy and breastfeeding. 
• 
Patients starting other DMT or commercial ocrelizumab will discontinue from the 
study completely and will not enter safety follow-up. 
Additional minor changes have been made to improve clarity and consistency. 


Ocrelizumab—F. Hoffmann-La Roche Ltd 
6/Statistical Analysis Plan WA21092 and WA21093 
 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE ............................. 2 
1. 
BACKGROUND ............................................................................ 11 
2. 
WA21092 AND WA21093 STUDY DESIGN ................................. 11 
2.1 
Protocol Synopsis .................................................................... 15 
2.2 
Outcome Measures ................................................................. 15 
2.2.1 
Primary Efficacy Outcome Measure ........................................ 15 
2.2.2 
Exploratory Efficacy Outcome Measures ................................. 15 
2.2.3 
Pharmacokinetic Analysis:  Objectives and Outcome 
Measures ................................................................................. 16 
2.2.4 
Pharmacodynamic Outcome Measure ..................................... 17 
2.2.5 
Safety Outcome Measures ...................................................... 17 
2.3 
Determination of Sample Size ................................................. 17 
2.4 
Analysis Timing ........................................................................ 18 
3. 
STUDY CONDUCT ....................................................................... 18 
3.1 
Randomization ......................................................................... 18 
3.2 
Independent Review Facility .................................................... 19 
3.3 
Expanded Disability Status Scale Cleaning Process ............... 19 
3.4 
Data Monitoring ....................................................................... 19 
4. 
STATISTICAL METHODS ............................................................ 19 
4.1 
Analysis Populations ................................................................ 19 
4.1.1 
Intent-to-Treat Population ........................................................ 20 
4.1.2 
Per-Protocol Population ........................................................... 20 
4.1.3 
Pharmacokinetic Evaluable Population .................................... 21 
4.1.4 
Safety Population ..................................................................... 21 
4.1.5 
OLE Intent-to-Treat Population ................................................ 21 
4.1.6 
OLE Safety Population ............................................................ 22 
4.2 
Analysis of Study Conduct ....................................................... 22 
4.3 
Analysis of Treatment Group Comparability ............................ 22 
4.3.1 
Demography ............................................................................ 23 
4.3.2 
Baseline Disease Characteristics ............................................ 23 


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4.3.3 
Multiple Sclerosis Disease History ........................................... 24 
4.3.4 
Non-MS Disease History ......................................................... 24 
4.3.5 
Prior Treatments for Multiple Sclerosis .................................... 24 
4.3.6 
Baseline Magnetic Resonance Imaging Data .......................... 25 
4.3.7 
OLE Baseline ........................................................................... 25 
4.4 
Efficacy Analysis ...................................................................... 25 
4.4.1 
Primary Efficacy Endpoint, Annualized Protocol-Defined 
Relapse Rate by 2 Years (96 weeks) ...................................... 26 
4.4.2 
Secondary Efficacy Endpoints ................................................. 30 
4.4.2.1 
Rationale for Hierarchy of Secondary Efficacy Endpoints ........ 30 
4.4.2.2 
Statistical Testing Strategy for Secondary Efficacy 
Endpoints ................................................................................. 32 
4.4.2.3 
Time to Onset of Confirmed Disability Progression for at 
Least 12 Weeks with the Initial Event of Neurological 
Worsening Occurring during the 96-Week, Double-Blind, 
Double-Dummy Treatment Period ........................................... 35 
4.4.2.4 
Total Number of T1 Gadolinium−Enhanced Lesions as 
Detected by Brain Magnetic Resonance Imaging at 
Weeks 24, 48, and 96 .............................................................. 38 
4.4.2.5 
Total Number of New and/or Enlarging T2 Hyperintense 
Lesions as Detected by Brain Magnetic Resonance 
Imaging at Weeks 24, 48, and 96 ............................................ 39 
4.4.2.6 
Proportion of Patients Who Have Confirmed Disability 
Improvement Sustained for at Least 12 Weeks with the 
Initial Event of Neurological Improvement Occurring during 
the 96-Week, Double-Blind, Double-Dummy Treatment 
Period ...................................................................................... 40 
4.4.2.7 
Time to Onset of Confirmed Disability Progression for at 
Least 24 Weeks with the Initial Event of Neurological 
Worsening Occurring during the 96-Week, Double-Blind, 
Double-Dummy Treatment Period ........................................... 41 
4.4.2.8 
Total Number of New T1-Hypo-Intense Lesions (Chronic 
Black Holes) at Weeks 24, 48, and 96 ..................................... 42 
4.4.2.9 
Change in Multiple Sclerosis Functional Composite Scale 
Score from Baseline to Week 96 ............................................. 43 
4.4.2.10 
Percentage Change in Brain Volume as Detected by Brain 
Magnetic Resonance Imaging Scan from Week 24 to 
Week 96 .................................................................................. 46 


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4.4.2.11 
Change in Quality of Life, as Measured by the Short Form 
36 Version 2 Physical Component Summary Score from 
Baseline to Week 96 ................................................................ 47 
4.4.2.12 
Proportion of Patients Who Have No Evidence of Disease 
Activity by Week 96 ................................................................. 48 
4.4.3 
Exploratory Efficacy Endpoints ................................................ 49 
4.4.3.1 
Proportion of Relapse-Free Patients by 96 Weeks .................. 49 
4.4.3.2 
Percentage Change in Total T2 Lesion Volume as 
Detected by Brain Magnetic Resonance Imaging from 
Baseline to Week 96 ................................................................ 49 
4.4.3.3 
Annualized Relapse Rate, Based on All Clinical Relapses 
at the End of the 96-Week Comparative Treatment Period ..... 50 
4.4.3.4 
Annualized Protocol-Defined Relapse Rate by 2 Years 
(96 weeks) for Relapses Requiring Intravenous Steroid 
Therapy ................................................................................... 50 
4.4.3.5 
Percentage Change in Brain Volume as Detected by Brain 
Magnetic Resonance Imaging from Baseline to Week 96 ....... 50 
4.4.3.6 
Time to Onset of Confirmed Disability Progression for at 
Least 48 Weeks with the Initial Event of Neurological 
Worsening Occurring during the 96-Week, Double-Blind, 
Double-Dummy Treatment Period ........................................... 50 
4.4.3.7 
Time to Confirmed EDSS ≥ 6 for at least 24 weeks during 
96-Week, Double-Blind, Double-Dummy Treatment Period .... 51 
4.4.3.8 
Time to Confirmed EDSS ≥ 6 for at least 48 weeks during 
96-Week, Double-Blind, Double-Dummy Treatment Period .... 52 
4.4.3.9 
Ratio in Timed 25-Foot Walk relative to Baseline 
at Week 96............................................................................... 52 
4.4.3.10 
Ratio in 9-Hole Peg Test relative to Baseline at Week 96 ....... 53 
4.4.3.11 
Change in PASAT from Baseline to Week 96 .......................... 54 
4.4.3.12 
Change in Fatigue, as Measured by the Modified Fatigue 
Impact Scale Total Score from Baseline to Week 96 ............... 54 
4.4.3.13 
Change in Patient-Reported Depressive Symptoms, as 
Measured by the Center for Epidemiologic Studies 
Depression Scale, from Baseline to Week 96 .......................... 55 
4.4.3.14 
Change in Karnofsky Performance Status Score from 
Baseline to Week 96 ................................................................ 56 
4.4.3.15 
Percentage Change in Cortical Grey Matter Volume as 
Detected by Brain MRI from Baseline to Week 96 ................... 56 


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4.4.3.16 
Percentage Change in White Matter Volume as Detected 
by Brain MRI from Baseline to Week 96 .................................. 57 
4.4.3.17 
Proportion of Patients who Have Disability Improvement 
Sustained for At Least 24 Weeks with the Initial Event of 
Neurological Improvement Occurring during the 96-Week, 
Double-Blind, Double-Dummy Treatment Period ..................... 57 
4.4.3.18 
Proportion of Patients Who have Disability Improvement 
Sustained for at Least 12 Weeks and Sustained until the 
End of the 96-Week, Double-Blind, Double-Dummy 
Treatment Period, with the Initial Event of Neurological 
Improvement Occurring during the 96-Week, Double-Blind, 
Double-Dummy Treatment Period ........................................... 57 
4.4.3.19 
Duration of Confirmed Disability Improvement......................... 58 
4.4.3.20 
Proportion of Patients Who at Week 96 Have Improved, 
Stable or Worsened Disability, Compared with Baseline ......... 58 
4.4.3.21 
Change in EDSS Score from Baseline to Week 96 ................. 58 
4.4.3.22 
Change in Quality of Life, as Measured by the Short Form 
36 Version 2 Mental Component Summary Score from 
Baseline to Week 96 ................................................................ 59 
4.4.3.23 
Ratio in Total T2 Lesion Volume as Detected by Brain MRI 
Scans relative to Baseline at Week 96 .................................... 59 
4.4.3.24 
Ratio in Total T1 Lesion Volume as Detected by Brain MRI 
Scans relative to Baseline at Week 96 .................................... 60 
4.4.3.25 
Time to Onset of Composite Confirmed Disability 
Progression (cCDP) for at Least 12 Weeks and at Least 24 
Weeks ...................................................................................... 60 
4.4.3.26 
Change in EuroQoL 5 Dimension 3 Levels (EQ-5D-3L) 
VAS and Index from Baseline to Week 48 and Week 96 ......... 60 
4.4.3.27 
NfL ........................................................................................... 61 
4.4.4 
Subgroup Analyses .................................................................. 61 
4.4.4.1 
Efficacy Data from the Safety Follow-Up Phase ...................... 62 
4.5 
Pharmacokinetic and Pharmacodynamic Analyses ................. 62 
4.5.1 
Pharmacokinetic Analyses ....................................................... 62 
4.5.2 
Pharmacodynamic Analyses .................................................... 62 
4.6 
Safety Analyses ....................................................................... 63 
4.6.1 
Exposure of Study Medication ................................................. 63 
4.6.2 
Columbia-Suicide Severity Rating Scale ................................. 64 
4.6.3 
Adverse Events ........................................................................ 64 


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4.6.3.1 
Selected Adverse Events ......................................................... 66 
4.6.4 
Magnetic Resonance Imaging Data ......................................... 67 
4.6.5 
Laboratory Data ....................................................................... 67 
4.6.6 
Vital Signs ................................................................................ 68 
4.6.7 
Safety by Treatment and Period .............................................. 68 
4.6.8 
Double-Blind Period ................................................................. 69 
4.6.9 
OLE Period .............................................................................. 69 
4.6.10 
Type I Interferon-Neutralizing Antibody Data ........................... 69 
4.6.11 
COVID-19 analyses: ................................................................ 69 
4.7 
Missing Data ............................................................................ 69 
4.8 
Interim Analyses ...................................................................... 69 
5. 
REFERENCES.............................................................................. 70 
 
 
LIST OF TABLES 
Table 1 
Overview of Dosing Regimen in the Double-Blind, Double-
Dummy Treatment Period ........................................................... 13 
Table 2 
Overview of Dosing Regimen in the OLE Phase Screening 
Period and the OLE Phase ......................................................... 14 
Table 3 
Center for Epidemiologic Studies Depression Scale ................... 55 
 
 
LIST OF FIGURES 
Figure 1 
Hierarchical Order of Key Efficacy Endpoints ............................. 35 
 
 
 
LIST OF APPENDICES 
Appendix 1 
Standard Operating Procedure “EDSS Assessment Check 
for the Roche Trials WA25046, WA21092, and WA21093” ........ 71 
 
 
 


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11/Statistical Analysis Plan WA21092 and WA21093 
1. 
BACKGROUND 
Studies WA21092 and WA21093 are two Phase III studies with identical study design.  
This Statistical Analysis Plan (SAP) describes the analyses that will be performed for 
each study independently.  The analyses will be conducted in exactly the same way for 
both studies; therefore, only one SAP has been written to be applied to both studies.  
The analysis of some secondary efficacy endpoints will necessitate the pooling of data 
from both studies in order to have sufficient statistical power to detect relevant treatment 
differences.  Analyses of pooled data are described separately in the “Pooled SAP.” 
Study WA21493 is an ongoing double-blind, double-dummy, parallel-group, Phase II 
study of the efficacy and safety of ocrelizumab compared with interferon beta-1a 
intramuscular (IM) (Avonex) in patients with relapsing remitting multiple sclerosis 
(RRMS).  The study was unblinded in November 2009 and has an open-label phase that 
is ongoing.  After 24 weeks of treatment, both doses of ocrelizumab (600 mg and 
2000 mg) demonstrated a strong effect with a highly statistically significant reduction 
versus placebo in signs of paraclinical disease activity as measured by the number of 
gadolinium (Gd)−enhancing brain lesions in magnetic resonance imaging (MRI), the 
primary endpoint of the study, at Weeks 12, 16, 20, and 24.  Compared with placebo, 
this represents a relative reduction in the number of lesions of 89% and 96%, for the 
600-mg and 2000-mg ocrelizumab groups respectively.  In addition, a statistically 
significant reduction in the annualized relapse rate (ARR) was observed with both 
ocrelizumab doses compared with placebo.  Moreover, both ocrelizumab doses were 
superior to the active comparator, Avonex, for both the MRI primary endpoint and the 
ARR. 
Although Study WA21493 (which enrolled approximately 50 patients per arm) 
demonstrated significant treatment effects in both MRI and ARR endpoints at 
Week 24 versus Avonex, the sample size required to demonstrate a statistically 
significant difference in disability progression between ocrelizumab and an active 
comparator is estimated to be much greater (i.e., approximately 800 patients per arm).  
To demonstrate significant treatment benefit of ocrelizumab in disability progression, the 
Sponsor plans to pool data from two Phase III studies (WA21092 and WA21093), which 
both include approximately 400 patients per treatment arm (ocrelizumab or interferon 
beta-1a 44 μg subcutaneous [SC] [Rebif]), have identical inclusion and exclusion criteria, 
and were implemented concurrently. 
2. 
WA21092 AND WA21093 STUDY DESIGN 
The primary objective of Studies WA21092 and WA21093 is to assess whether the 
efficacy of ocrelizumab 600 mg (given as dual infusions of 300 mg on Days 1 and 15 of 
the first 24-week Dose and as a single infusion of 600 mg on Day 1 of each 24-week 
Dose thereafter) intravenously every 24 weeks is superior to interferon beta-1a 44 µg SC 
as measured by the annualized protocol-defined relapse rate (see Section 4.4.1 for the 


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12/Statistical Analysis Plan WA21092 and WA21093 
efinition of protocol-defined relapse) by 2 years (96 weeks) in patients with relapsing 
forms of multiple sclerosis (RMS). 
The studies consist of the following periods:  
Screening: 
Consenting patients entered a screening period to be evaluated for eligibility.  The 
screening period lasted approximately 2 weeks, but it may have been prolonged for up 
to 8 weeks for relevant clinical, administrative, or operational reasons. 
Treatment Period: 
Double-blind, double-dummy, 96-week comparative treatment period 
Eligible patients were randomized via an Interactive Voice and Web Response System 
(IxRS) into one of two treatment groups:  ocrelizumab 600 mg regimen (Group A) or 
interferon beta-1a 44 µg SC (Group B). 
 
Open-Label Extension Phase  
Patients who complete the 96-week treatment period may become eligible for the open-
label extension (OLE) phase of the study.   
All patients will continue their treatment in the open-label ocrelizumab phase until 31 
December 2022, as per the protocol. All patients will discontinue ongoing open-label 
extension phase and move into a new extension trial (OLERO) on or before 31 
December 2022.   
Safety Follow-Up Period: 
Patients who discontinue treatment for any reason during the following periods will be 
entered into the Safety Follow-Up Period: 
• 
During or after completion of the 96-week, double-blind, double-dummy treatment 
period 
• 
During the OLE Phase Screening Period 
• 
During the OLE Phase 
• 
Patients who choose not to enter the OLE Phase or are not eligible for the OLE 
Phase after completing the 96-week, double-blind, double-dummy treatment period  
Patients who start treatment with other DMT or commercial ocrelizumab will discontinue 
from the study completely and will not enter or continue in the Safety Follow-Up Period. 
All patients ongoing in SFU at study completion should move to OLERO by 
31 December 2022. 
Table 1 and Table 2 give an overview of the study design and dosing regimen during the 
double-blind double-dummy treatment period and OLE, respectively.


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13/Statistical Analysis Plan WA21092 and WA21093 
Table 1 
Overview of Dosing Regimen in the Double-Blind, Double-Dummy Treatment Period 
Study Medication 
Double-Blind, Double-Dummy Treatment Period a, b 
1st Dose c 
(Weeks 1−24) 
2nd Dose c 
(Weeks 24−48) 
3rd Dose c 
(Weeks 48−72) 
4th Dose c 
(Weeks 72−96) 
Day 1 
Day 15 
Week 24 
Week 48 
Week 72 
A:  Ocrelizumab 
600 mg regimen 
300 mg IV 
300 mg IV 
600 mg IV 
600 mg IV 
600 mg IV 
B:  Interferon beta-1a 
44 μg SC regimen d 
Interferon beta-1a 
44 μg SC 3 times per 
week 
→ 
→ 
→ 
→ 
IV = intravenous; SC = subcutaneous. 
Note:  100 mg of methylprednisolone IV will be administered in both treatment arms prior to each infusion of ocrelizumab/ocrelizumab placebo. 
a 
The double-blind, double-dummy, treatment period consists of 96 weeks of treatment (four Doses). 
b 
The first Dose consists of two 300-mg ocrelizumab IV infusions separated by 14 days.  Doses 2−4 consist of a single IV infusion of 600-mg 
ocrelizumab. 
c 
Prior to each infusion, a clinical evaluation will be performed to ensure that the patient remains eligible for treatment. 
d 
Refer to the protocol for detailed interferon beta-1a 44 μg SC dosing regimen. 


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14/Statistical Analysis Plan WA21092 and WA21093 
Table 2 
Overview of Dosing Regimen in the OLE Phase Screening Period and the OLE Phase 
Study Medication 
OLE Phase 
Screening Period 
OLE Phase a 
5th Dose b, c,d 
6th Dose b, c, d 
7th Dose b, c, d 
Nth Dose b, c, d 
Day 1 Infusion 
Day 15 Infusion 
Ocrelizumab 
600 mg regimen 
NA e 
300 mg IV 
300 mg IV 
600 mg IV 
600 mg IV 
600 mg IV 
Interferon beta-1a 
44 μg SC regimen 
Interferon beta-1a 
44 μg SC 3 times  
per weekf 
NA g 
NA g 
NA g 
NA g 
NA g 
IV = intravenous; N =  “nth” Dose; NA = not applicable; OLE = open-label extension; SC = subcutaneous.  
Note:  100 mg of methylprednisolone IV will be administered prior to each infusion of ocrelizumab. 
To keep the blinding, all patients will receive the first dose of ocrelizumab in the open-label phase in a split form, even if they had been treated with 
ocrelizumab in the previous blinded phase 
a 
The OLE Phase can terminate at any moment.  
b 
The assessments requested for N represent the typical schedule of assessments. 
c 
Prior to each infusion, a clinical evaluation will be performed to ensure that the patient remains eligible for treatment.  
d 
The first Dose of the OLE Phase consists of two 300-mg ocrelizumab IV Infusions that are to be separated by 14 days.  Dose 6 onward 
consists of a single IV infusion of 600 mg ocrelizumab. 
e 
During the OLE Phase Screening Period there will be no administration of ocrelizumab.  
f 
Refer to the protocol for detailed interferon beta-1a 44 μg SC dosing regimen. 
g 
During the OLE, there will be no administration of interferon beta-1a 44 μg SC; patients previously assigned to interferon beta-1a 44 μg SC 
receive ocrelizumab.


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15/Statistical Analysis Plan WA21092 and WA21093 
2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis and the Schedule of Assessments are included in the protocols. 
2.2 
OUTCOME MEASURES 
2.2.1 
Primary Efficacy Outcome Measure 
The primary efficacy endpoint is the annualized protocol-defined relapse rate at 2 years 
(96-weeks). 
Secondary Efficacy Outcome Measures 
The secondary efficacy endpoints are as follows: 
• 
The time to onset of confirmed disability progression (CDP) for at least 12-weeks, 
with the initial event of neurological worsening occurring during the 96-week, 
double-blind, double-dummy treatment period 
• 
The total number of T1 Gd-enhancing lesions as detected by brain MRI at 
Weeks 24, 48, and 96 
• 
The total number of new and/or enlarging T2 hyperintense lesions as detected by 
brain MRI at Weeks 24, 48, and 96 
• 
The proportion of patients who have confirmed disability improvement for at least 
12 weeks, with the initial event of neurological improvement occurring during the 96-
week, double-blind, double-dummy treatment period 
• 
The time to onset of confirmed disability progression for at least 24 weeks, with the 
initial event of neurological worsening occurring during the 96-week, double-blind, 
double-dummy treatment period  
• 
The total number of new T1−hypo-intense lesions (chronic black holes) at 
Weeks 24, 48, and 96 
• 
The change in Multiple Sclerosis Functional Composite Scale (MSFCS) score from 
baseline to Week 96 
• 
The percentage change in brain volume as detected by brain MRI from Week 24 to 
Week 96 
• 
The change in SF-36 Physical Component Summary (PCS) Score from baseline to 
Week 96 
• 
The proportion of patients who have no evidence of disease activity (NEDA) by 
Week 96 
 
2.2.2 
Exploratory Efficacy Outcome Measures 
The exploratory efficacy endpoints are as follows: 
• 
In addition to below specified exploratory outcomes, specific primary, secondary and 
exploratory efficacy analysis will be repeated combined and separately for double 
blind and open label period 
• 
The proportion of relapse-free patients by Week 96 


 
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16/Statistical Analysis Plan WA21092 and WA21093 
• 
The percentage change in total T2 hyperintense lesion volume as detected by brain 
MRI from baseline to Week 96 
• 
The ARR, based on all clinical relapses at the end of the 96-week comparative 
treatment period (protocol-defined relapses are a subset of all clinical relapses) 
• 
The ARR of relapses requiring IV steroids therapy 
• 
The percentage change in brain volume as detected by brain MRI from baseline to 
Week 96  
• 
The change in timed 25-foot walk from baseline to Week 96 
• 
The change in 9-hole peg test from baseline to Week 96 
• 
The change in fatigue, as measured by the Modified Fatigue Impact Scale (MFIS) 
total score from baseline to Week 96 
• 
The change from baseline in patient-reported depressive symptoms, as measured 
by the Center for Epidemiologic Studies Depression Scale (CES-D), from baseline 
to Week 96 
• 
The change in Karnofsky Performance Status Scale from baseline to Week 96 
• 
The percentage change in cortical gray matter volume from baseline to Week 96 
• 
The percentage change in white matter volume from baseline to Week 96 
• 
The proportion of patients who have confirmed disability improvement for at least 
24 weeks, with the initial event of neurological improvement occurring during the 96-
week, double-blind, double-dummy treatment period 
• 
The proportion of patients who have disability improvement sustained for at least 
12 weeks and sustained until the end of the 96-week, double-blind, double-dummy 
treatment period, with the initial event of neurological improvement occurring during 
the 96-week, double-blind, double-dummy treatment period 
• 
The duration of the confirmed disability improvement 
• 
The proportion of patients who at Week 96 have improved, stable, or worsened 
disability, compared to baseline 
• 
The change in Expanded Disability Status Scale (EDSS) Score from baseline to 
Week 96 
• 
The change in Quality of Life, as measured by the Short Form 36 Version 2 (SF-
36 v2) Mental Component Summary Score from baseline to Week 96 
• 
The change in EQ-5D-3L Index and visual analogue scale (VAS) from baseline to 
Week 48 and Week 96 
 
2.2.3 
Pharmacokinetic Analysis:  Objectives and Outcome Measures 
The pharmacokinetic (PK) endpoints are as follows: 
• 
Develop a population PK model to describe the pharmacokinetics of ocrelizumab in 
patients with MS and to estimate inter- and intra-patient variability 
• 
Determine individual post hoc estimates to derive PK exposure measures 


 
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17/Statistical Analysis Plan WA21092 and WA21093 
• 
Explore and quantify the potential influence of covariates contributing to the 
interpatient variability in PK parameters 
• 
Explore the relationship between ocrelizumab exposure and selected efficacy 
endpoints (e.g., annualized relapse rate) 
• 
Explore the relationship between ocrelizumab exposure and appropriate safety 
parameters 
 
2.2.4 
Pharmacodynamic Outcome Measure 
The pharmacodynamics (PD) endpoint is the CD19 count, as a PD marker. 
2.2.5 
Safety Outcome Measures 
Safety will be assessed through regular neurological and physical examinations, vital 
signs, ECGs, and the occurrence of adverse events.  In addition, the following will be 
examined: 
• 
Non-MS pathology at all available MRI scans 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
Standard hematology, chemistry, and urinalysis assessments 
• 
Circulating B-cell total and subsets, T cells, natural killer cells, and other leukocytes 
• 
Plasma immunoglobulins 
• 
Anti-drug antibodies (ADAs), also called human anti-human antibodies (HAHAs) 
• 
Antibody titers for mumps, rubella, varicella, and Streptococcus pneumonia 
• 
MS relapses classified as serious 
 
2.3 
DETERMINATION OF SAMPLE SIZE 
The sample size for this study was estimated on the basis of data from previous RRMS 
trials, with use of two-sided tests with an experiment-wise alpha of 0.05.  The ARR at 
96 weeks in patients receiving ocrelizumab is predicted to be 0.165 (SD of 
approximately 0.60), compared with 0.33 (SD of approximately 0.80) in patients 
receiving the control treatment (interferon beta-1a 44 µg SC); this represents a relative 
reduction of approximately 50% with ocrelizumab treatment compared with the active 
comparator.  For the ARR, a t-test was used to determine the sample size between 
ocrelizumab and interferon beta-1a 44 µg SC.  The sample size of 400 patients per 
treatment group provides 84% power, maintaining the type I error rate of 0.05 and with 
the assumption of a dropout rate of approximately 20% (with the assumption that relative 
reduction among patient dropout is 25%).  
For confirmed disability progression, a two group test of equal exponential survival with 
exponential dropout was used to determine the sample size.  Assuming the 2-year 
confirmed disability progression rate is 18% for the interferon beta-1a 44 µg SC arm and 
12.6% for the ocrelizumab arm (this represents a relative reduction of 30% on 
ocrelizumab compared to the active comparator), and assuming a dropout rate of 20% 
over 2 years approximately, the sample size of 400 per arm will provide 80% power, 


 
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maintaining the type I error rate of 0.05 based on the pooled analysis of two RMS 
studies (800 patients treated with ocrelizumab 600 mg and 800 patients treated with 
interferon beta-1a 44 µg SC). 
2.4 
ANALYSIS TIMING 
After the 96-week visit of the last randomized patient, approximately 12-weeks may be 
needed to allow the confirmation of the latest event of the 12-week confirmed disability 
progression.  Therefore, the clinical cutoff date will be approximately 12-weeks after the 
last patient’s 96-week visit when the status is clarified for each patient.  Database lock 
and unblinding of the Sponsor will occur several weeks after the clinical cutoff to clarify 
all outstanding queries. 
The sites and EDSS raters will remain blind until approximately 24-weeks after the 96-
week visit of the last patient randomized, to allow the confirmation of the last 24-week 
confirmed disability progression, in case an updated analysis of this endpoint is 
requested at a later point. 
The following reporting events are done / planned for this study: 
Report 
Clinical cutoff date 
Status 
Primary CSR 
Opera 1: 10 April 2015 
Opera 2: 12 May 2015 
Completed 
Pooled safety analyses for 
safety monitoring and 
Publication of updated interim 
results 
Yearly data cut has been 
performed since 
February 2017 to conduct 
interim analyses used for 
publication purposes 
Completed until 2021 and 
planned for subsequent years 
until the end of the study 
Interim CSR (Time to 
milestone analysis) 
03 January 2020 
Completed 
Final CSR 
After the last patient last visit 
of the open label extension 
phase or Safety Follow-up 
Phase (31 Decemeber 2022) 
Planned 
CSR = clinical study report 
 
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION 
Patients were randomized into two groups (Group A or Group B) in a 1:1 ratio.  An 
independent IxRS provider conducted randomization (with use of blocked randomization 
with a block size of 4) and holds the treatment assignment code.  Patients were stratified 
by geographical region (United States vs. rest of world [ROW]) and baseline EDSS 
score (< 4.0 and ≥ 4.0).  (Note:  If both screening EDSS and randomization EDSS scores 
were collected, the average of both values will be considered as baseline EDSS score 
for all analyses and for the stratification factor, unless otherwise specified.) 


 
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The patient randomization list was generated by the IxRS with use of a pre-defined 
randomization specification.  The randomization list will not be available to the study 
center, study monitors, project statisticians, or the Sponsor’s project team.  Unblinding of 
individual patients should not occur except in the case of emergency situations.  Any 
request from the investigator for information about the treatment administered to study 
patients for another purpose must be discussed with the Sponsor.  Unblinding will be 
performed by means of the IxRS.  In accordance with regulatory reporting requirements, 
the Sponsor will unblind the identity of the study medication for all unexpected serious 
adverse events that are considered by the investigator to be related to study drug per 
safety reference document(s), (e.g., Investigator’s Brochure, Core Data Sheet, and 
Summary of Product Characteristics).  Details of patients who are unblinded during the 
study will be included in the Clinical Study Report. 
3.2 
INDEPENDENT REVIEW FACILITY 
MRI scans will be read by a centralized reading center.  The centralized reading center 
is blinded to the treatment assignment, and the reading is performed in the absence of 
clinical information.  Further details on scanning acquisition sequences; methods, 
handling, and transmission of the scans; certification of site MRI radiologist/technicians; 
and the procedures for the blinded analysis of the scans at the central reading center are 
described in a separate MRI technical manual. 
3.3 
EXPANDED DISABILITY STATUS SCALE CLEANING PROCESS 
EDSS assessments are performed by a qualified examining investigator (a person other 
than the treating investigator), and the results are entered into an electronic device, and 
transferred to a central database.  All EDSS results will then be checked in accordance 
with the Standard Operating Procedure (SOP) entitled “EDSS Assessment Check for the 
Roche Trials WA25046, WA21092, and WA21093” (see Appendix 1). 
3.4 
DATA MONITORING 
An independent Data Monitoring Committee (iDMC) is reviewing cumulative data from 
the studies at approximately 4-month intervals until the primary analysis is completed.  
After all patients have completed the 96-week comparative treatment period, the iDMC 
will review cumulative data less frequently, but it is anticipated at least once per year.  
The iDMC is reviewing both efficacy and safety data; however, the studies will not be 
stopped for efficacy reasons.  No iDMC review is conducted post unblinding of the study. 
4. 
STATISTICAL METHODS 
4.1 
ANALYSIS POPULATIONS 
One patient population will be defined for the purpose of the safety analysis, and two 
patient populations will be defined for the efficacy analysis.  All efficacy analyses will be 
performed using the intent-to-treat (ITT) population.  The per-protocol population will be 
used for the primary analysis of the primary endpoint (ARR at 96 weeks) and the primary 


 
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analysis of the first secondary endpoint (time to onset of confirmed disability progression 
at a minimum of 12 weeks with the initial event of neurological worsening occurring 
during the 96-week, double-blind, double-dummy treatment period) in order to evaluate 
the influence of major protocol violators and as a sensitivity check to the ITT analysis. 
4.1.1 
Intent-to-Treat Population 
All randomized patients will be included in the ITT population.  Patients who prematurely 
withdrew from the study for any reason and for whom an assessment was not performed 
for whatever reason will still be included in the ITT analysis.  Patients who received an 
incorrect therapy from that which was intended will be summarized according to their 
randomized treatment. 
4.1.2 
Per-Protocol Population 
The per-protocol population will include all patients in the ITT population who adhere to 
the protocol.  Patients may be excluded if they significantly violated the inclusion or 
exclusion criteria or deviated from the study plan.  Specific reasons for warranting 
exclusion will be agreed to and documented in the Data Analysis Plan on the basis of 
the final version of the protocol prior to unblinding of the treatment groups.  Only those 
patients with violations that are deemed to potentially affect the efficacy of study 
treatment will be excluded from the per-protocol population.  Patients who received an 
incorrect therapy from that which was intended will be excluded from the per-protocol 
population. 
The following patients will also be excluded from the per-protocol population: 
• 
Diagnosis of primary progressive MS 
• 
Disease duration from the onset of MS symptoms of more than 10 years in patients 
with an EDSS ≤ 2.0 at screening 
• 
Known presence of other neurological disorders that may mimic MS 
• 
Pregnancy or lactation 
• 
Any concomitant disease that may require chronic treatment with systemic 
corticosteroids or immunosuppressants during the course of the study 
• 
History or currently active primary or secondary immunodeficiency 
• 
Treatment with any investigational agent within 24 weeks of screening or five half-
lives of the investigational drug (whichever is longer); or treatment with any 
experimental procedures for MS  
• 
Contraindication to interferon beta-1a 44 μg SC or incompatibility with interferon 
beta-1a 44 μg SC use 
• 
Previous treatment with B-cell targeted therapies 
• 
Any previous treatment with alemtuzumab (Campath), anti-CD4, cladribine, 
mitoxantrone, daclizumab, teriflunomide, laquinimod, total body irradiation, or bone 
marrow transplantation 


 
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• 
Treatment with cyclophosphamide, azathioprine, mycophenolate mofetil (MMF), 
cyclosporine, methotrexate (MTX), or natalizumab within 24 months prior to 
screening 
• 
Treatment with fingolimod (FTY720, Gilenya) or other S1P receptor modulator (i.e., 
BAF312) or with BG12, within 24 weeks prior to screening 
• 
Treatment with IV immunoglobulin within 12 weeks prior to baseline  
• 
No diagnosis of relapsing MS, in accordance with the revised McDonald criteria 
(2010) 
• 
Less than two documented clinical attacks within the last 2 years prior to screening 
and no clinical attack in the year prior to screening; or at least one clinical attack 
within 30 days prior to screening 
• 
Neurological status instability within 30 days prior to both screening and baseline. 
• 
Received no dose of ocrelizumab / ocrelizumab placebo and interferon beta-1a 
44 μg SC / interferon beta-1a 44 μg SC placebo 
• 
Received ocrelizumab + interferon beta-1a 44 μg SC placebo / ocrelizumab 
placebo + interferon beta-1a 44 μg SC verum but was not randomized 
• 
Received ocrelizumab + interferon beta-1a 44 μg SC placebo / ocrelizumab 
placebo + interferon beta-1a 44 μg SC verum other than the group to which the 
patient was randomized at any point during the study 
• 
Received study medication that has been mishandled (e.g., incorrect storage 
temperature) and was not approved subsequently for use 
 
4.1.3 
Pharmacokinetic Evaluable Population 
The PK population will include all patients in the ocrelizumab treatment arm who had at 
least one measurable concentration value.  
4.1.4 
Safety Population 
The Safety Population will include all patients who received any study drug.  
Randomized patients who receive an incorrect therapy from that which was intended will 
be summarized in the group according to the therapy actually received.  Patients who 
are not randomized but who receive study drug will be included in the safety population 
and summarized according to the therapy actually received.  Patients who received 
more than one study therapy will be summarized in the ocrelizumab group.  Patients 
who received only ocrelizumab placebo but not interferon beta-1a 44 μg SC will be 
included in the interferon beta-1a44 μg SC−arm group as a conservative approach. 
4.1.5 
OLE Intent-to-Treat Population 
All patients receiving any study drug during the OLE Phase will be included in the OLE 
ITT population.  Patients will be summarized according to their randomized treatment 
during the double blind treatment period 


 
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4.1.6 
OLE Safety Population 
Similar to the safety population, all patients receiving any study drug during the OLE 
Phase will be included in the OLE safety population.  Patients will be summarized 
according to the therapy received during the double blind treatment period, consistent 
with the safety population.  
4.2 
ANALYSIS OF STUDY CONDUCT 
All data up to the point of the clinical cutoff date for each study will be included to 
evaluate study conduct.  This will include complete data from the 96-week, double-blind, 
double-dummy treatment period and all available data from the OLE and SFU phases at 
the time of cutoff for the primary analysis.  Data from Study WA21092 that relate to the 
period after the Study WA21092 clinical cutoff date but before the Study WA21093 
clinical cutoff date will not be included in the Study WA21092 database that will be used 
in the primary analysis. 
The following analyses will be performed to evaluate the study conduct:  
• 
Summary of protocol violations 
• 
Summaries of ITT, per-protocol-defined, and safety populations, including numbers 
of patients in each population, and reasons for exclusion from the per-protocol 
population 
• 
Summary of patient disposition, including the number of Doses received, the 
number of patients entering into the SFU phase, and the number of patients 
entering into the OLE phase 
• 
Summary and Kaplan-Meier plots of the following:  
– 
Time to discontinuation of study treatment during the 96-week, double-blind, double-
dummy treatment period  
– 
Time to discontinuation from the study (available data from all study phases to be 
included) 
 
After 96 weeks of double-blind phase, all eligible patients from both treatment groups, 
including patients from IFN group start receiving ocrelizumab treatment in the open-label 
extension phase.  OLE allows additional data being collected for long-term safety and 
efficacy assessments.  Patients who withdraw from treatment during OLE may start 
safety follow-up.  
Analysis to evaluate study conduct as mentioned above will be repeated for the OLE 
phase as appropriate. 
4.3 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
For continuous variables, the mean, median, SD, minimum, and maximum will be 
calculated.  For categorical variables, number and percentage in each category will be 
displayed.  The units/categories to be used are indicated within the brackets and 
separated by commas.  


 
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Except where stated, all assessments of treatment group comparability will utilize the 
date of the baseline visit (not the date of the screening visit) as the reference point in 
time. 
Summaries will be presented for ITT and safety populations. 
4.3.1 
Demography 
• 
Age (years):  summary statistics calculated will include mean, median, SD, 
minimum, and maximum, percentage, and number in each category (18−39, ≥ 40, 
also age categories < 18, 18−65, > 65, used in the Development Safety Update 
Report [DSUR]) will be displayed (age at randomization will be used) 
• 
Sex:  the number and percentage of male and female patients 
• 
Race:  the number and percentage of White; Black or African American; Asian 
(Indian Subcontinent, Other than Indian subcontinent), American Indian or Alaskan 
native; Native Hawaiian or other Pacific Islander; and Other 
• 
Stratification Factor: (Geographical region) the number and percentage of United 
States and Rest of World patients 
– 
Sub-region:  the number and percentage of patients from European 
Union/Switzerland/Norway, Latin America, Non-EU/Israel/Africa, and 
USA/Canada/Australia 
• 
Ethnicity:  the number and percentage of Hispanic or Latino and not Hispanic or 
Latino 
• 
Weight (kg):  summary statistics as described for age 
• 
Body Mass Index (BMI):  summary statistics as described for age 
 
4.3.2 
Baseline Disease Characteristics 
• 
Stratification Factor (Baseline EDSS):  the number and percentage of patients in 
each EDSS category (< 4.0, and ≥ 4.0); EDSS mean, median, SD, minimum, and 
maximum will be summarized.  The baseline EDSS is defined as the average EDSS 
score from the screening and baseline visit EDSS scores (only values recorded up 
to and including the date of randomization will be used).  For the analysis of mean 
change of EDSS, disability progression, and disability improvement, the exact value 
of the average EDSS score will be used.  However, for the stratification factor, and 
for the randomization algorithm, the average will be rounded up to the next EDSS 
score, in order to assign a valid score (e.g., round 3.75 to 4.0, round 5.25 to 5.5). If 
one of the EDSS scores from the screening or baseline visit is missing, the other will 
be used for baseline EDSS.  If EDSS score is missing at both the screening and 
baseline visit, the patient should not be randomized.  Unless otherwise specified, 
this definition of baseline EDSS is used throughout. 
• 
Number of relapses in the past year:  the number and percentage of patients in 
each category (0, 1, 2, 3, and ≥ 4); a relapse is considered to happen in the past 
year if:  date of randomization − date of relapse is ≤ 365 days 


 
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• 
Number of relapses in the past 2 years:  the number and percentage of patients in 
each category (0, 1, 2, 3, and ≥ 4); a relapse is considered to happen in the past 
2 years if:  date of randomization − the date of relapse is ≤ (365 ⋅ 2) days 
• 
Time since last onset of MS relapse prior to randomization (year):  the number and 
percentage of patients in each category (> 6 months prior to randomization, within 
the last 6 months from randomization); summary statistics calculated will include 
mean, median, SD, minimum, and maximum (calculated in years, i.e., divided by 
365.25).  Time is calculated as:  date of randomization − the date of last relapse 
• 
Baseline Functional Systems Scores (FSSs) for each category (pyramidal, 
cerebellar, brainstem, sensory, bowel and bladder, visual, cerebral [or mental]; rated 
0−5 or 0−6 depending on the domain of FSS) and for ambulation (categorical; 
rated 0−12) 
• 
Baseline MSFCS score, raw results for each component:  summary statistics 
calculated will include mean, median, SD, minimum, and maximum 
 
4.3.3 
Multiple Sclerosis Disease History 
• 
Duration since MS symptom onset (years):  summary statistics calculated will 
include mean, median, SD, minimum, and maximum (calculated in years; i.e., divide 
by 365.25) 
• 
Duration since MS diagnosis (years):  summary statistics calculated will include 
mean, median, SD, minimum, and maximum (calculated in years; i.e., divide by 
365.25) 
• 
Duration since MS symptom/diagnosis onset will be calculated up to the 
randomization date.  If the month of symptom/diagnosis onset date is missing, the 
month of January will be used.  If the day of symptom/diagnosis onset date is 
missing, the first (1st) of the month will be used 
 
4.3.4 
Non-MS Disease History 
• 
Did patient have a history of any non-MS diseases?:  number and percentage of 
patients, (yes or no) 
• 
Each non-MS disease:  number and percentage of patients with a history of each 
disease 
 
4.3.5 
Prior Treatments for Multiple Sclerosis 
• 
Did patient receive any prior treatment for MS?:  number and percentage of 
patients, (yes or no) 
• 
Did patient receive any prior treatment for MS with any interferon or glatiramer 
acetate?:  number and percentage of patients, (yes or no) 
• 
Each prior treatment for MS:  number and percentage of patients receiving each 
treatment 
 


 
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4.3.6 
Baseline Magnetic Resonance Imaging Data 
• 
Number of Gd-enhancing T1 lesions at baseline:  the number and percentage of 
patients in each category (0, 1, 2, 3, and ≥ 4); summary statistics calculated will 
include mean, median, SD, minimum, and maximum  
• 
Volume of T2 lesions at baseline:  summary statistics calculated will include mean, 
median, SD, minimum, and maximum 
• 
Number of T2 lesions at baseline:  summary statistics calculated will include mean, 
median, SD, minimum, and maximum. Also the number and percentage of patients 
in each category (0−5, 6−9, and > 9) will be presented. 
• 
Normalized brain volume at baseline: summary statistics calculated will include 
mean, median, SD, minimum, and maximum 
• 
Number of T1 hypo intense lesion (black holes) count at baseline: summary 
statistics calculated will include mean, median, SD, minimum, and maximum 
 
Past MRI Data (recorded at Screening): 
• 
Number of previous Gd-enhancing T1 lesions:  the number and percentage of 
patients in each category (i.e., 0, 1, > 1, and not evaluable) 
• 
Number of previous T2 lesions:  the number and percentage of patients in each 
category (0−5, 6−9, and > 9) 
 
4.3.7 
OLE Baseline 
Demography and baseline characteristics analysis will be repeated and updated for the 
OLE period. 
EDSS at OLE baseline is defined as the latest EDSS score prior to or on the start of the 
OLE period. 
For all other analysis, OLE Baseline score is the latest score prior to or on the OLE first 
dose, collected at Week 96 and/or OLE Week 0, unless specified specifically. Patients 
who have none of these scores available will be excluded from the analyses requiring 
OLE baseline score. 
4.4 
EFFICACY ANALYSIS 
All statistical hypotheses for the primary and secondary endpoints and treatment 
comparisons will be tested at the 5% significance level (α = 0.05) against two-sided 
alternatives. 
For all assessments, the baseline value will be used as the last non-missing value on or 
before the date of the first infusion of study medication.  See Section 4.3.2 for baseline 
EDSS and Section 4.4.2.4 for time-to-confirmed sustained disability progression. 
All primary and secondary efficacy endpoints will be analyzed stratified by geographical 
region (United States vs. ROW) and baseline EDSS (< 4.0 vs. ≥ 4.0).  


 
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For all analyses during OLE and combined periods of double-blind and OLE, a pooled 
efficacy analysis of WA21092 and WA21093 will be performed. 
4.4.1 
Primary Efficacy Endpoint, Annualized Protocol-Defined 
Relapse Rate by 2 Years (96 weeks) 
Significance Level 
The null hypothesis will be tested at the α = 0.05 level (two-sided test). 
• 
H0 (null hypothesis):  there is no statistically significant difference between the 
ocrelizumab group and interferon beta-1a 44 µg SC group in the annualized 
protocol-defined relapse rate at 2 years.  
• 
H1 (alternative hypothesis):  there is a statistically significant difference between the 
ocrelizumab group and interferon beta-1a 44 µg SC group in the annualized 
protocol-defined relapse rate at 2 years. 
 
Annualized protocol-defined relapse rate at 2 years between the ocrelizumab dose 
groups and interferon beta-1a 44 µg SC group will be compared using the negative 
binomial model, adjusting for geographical region (United States vs. ROW) and baseline 
EDSS score (< 4.0 vs. ≥ 4.0).  If the test result for comparing the 600-mg ocrelizumab 
group and the interferon beta-1a 44 µg SC group is statistically significant at 
α < 0.05 level (two-sided test), it will be concluded that the 600-mg ocrelizumab group 
demonstrated a superior effect of reducing the annualized protocol-defined relapse rate 
when compared with the interferon beta-1a 44 µg SC group. 
Protocol-Defined Relapse  
A protocol-defined relapse is defined as the occurrence of new or worsening 
neurological symptoms attributable to MS and immediately preceded by a relatively 
stable or improving neurological state of least 30 days.  Symptoms must persist 
for > 24 hours and should not be attributable to confounding clinical factors (e.g., fever, 
infection, injury, or adverse reactions to concomitant medications).  The new or 
worsening neurological symptoms must be accompanied by objective neurological 
worsening consistent with an increase of at least half a step on the EDSS score, or 
2 points on one of the appropriate FSS, or 1 point on two or more of the appropriate 
FSS.  The change must affect the selected FSS (i.e., Pyramidal, Gait, Cerebellar, 
Brainstem, Sensory, or Visual).  Episodic spasms, sexual dysfunction, fatigue, mood 
change, or bladder or bowel urgency or incontinence will not suffice to establish the 
diagnosis of a relapse.  
Information related to a protocol-defined relapse will be captured on a clinical relapse 
event case report form (CRF) page.  If the following criteria are satisfied, the clinical 
relapse will qualify as a protocol-defined relapse: 
• 
Check-box of “Did symptoms persist for > 24 hours and were not being 
attributable…” on the Clinical MS relapse event is checked. 
• 
EDSS scores from a visit occurring on or after the onset date of relapse needs to be 
at least half a step from the previous EDSS score; OR for FSS domains involved in 


 
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the relapse event (indicated on the Clinical MS Relapse page), an increase of at 
least 2 points on one appropriate FSS domain or at least 1 point on two or more 
appropriate FSS domains. 
• 
There is no protocol-defined relapse within 30 days before the start date of the 
clinical relapse. 
 
Protocol defined relapse will be derived following the steps below: 
1. 
Clinical relapse is reported on eCRF. 
2. 
“Did symptoms persist for > 24 hours and were not being attributable…” is checked 
‘Yes’ on the Clinical MS relapse event form. 
3. 
Check if the first EDSS assessment at a visit (unscheduled or scheduled) on or after 
the onset date of the relapse is increased by ≥ 0.5 steps from the previous EDSS; 
OR SELECTED FSS domains relevant to the relapse event (pyramidal, ambulation, 
cerebellar, brainstem, sensory, or converted visual) are increased by ≥ 2 points on 
one domain or ≥ 1 point on two or more domains.  When deriving this step do the 
following: 
– 
Take the last EDSS/FSS score before each clinical relapse onset date 
– 
Take the first EDSS/FSS score on or after each clinical relapse onset date 
– 
Calculate the difference between the two scores 
– 
Select clinical relapses where there is an increase of ≥ 0.5 in EDSS OR ≥ 2 on one 
appropriate FSS domain OR ≥ 1 on two or more appropriate FSS domains 
4. 
For each relapse that satisfies the 3 criteria above, check if the following relapses 
are within 30 days (i.e., the onset dates are ≤ 30 days apart).  If they are within 
30 days, then the later relapses are not protocol-defined relapses. 
 
Analysis Methods 
The ITT Population analysis will be presented. 
The total number of protocol-defined relapses for each patient will be counted.  The 
exposure time will be calculated as follows:  
Exposure Time = (Early treatment discontinued date or date of 
Week 96 visit)−date of study Day 1 + 1)/365.25  
 
All available data during the 96-week treatment period will be used for the analysis.  For 
patients who discontinue the treatment early, only data that are collected before the 
early treatment discontinuation will be used in this analysis (with the exception of 
subsequent data used to confirm disability progression post-discontinuation of study 
treatment). 
The annualized protocol-defined relapse rate at Week 96 will be analyzed using a 
negative binomial model, fitted in SAS using the GENMOD procedure.  The model will 
include, for each patient, the total number of protocol-defined relapses with onset 
between randomization date and early treatment discontinued date/date of Week 96 as 
response variable and treatment group, baseline EDSS score (< 4.0 vs. ≥ 4.0), and 


 
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geographical region (United States vs. ROW) as covariates.  In order to account for 
different study treatment exposure durations among patients, log-transformed exposure 
time will be included in the model as an “offset” variable for appropriate computation of 
relapse rate.  The rate ratio and the associated two-sided 95% confidence interval will be 
provided to compare the ocrelizumab and interferon beta-1a 44 μg SC groups.  The 
estimated relapse rate and its two-sided 95% confidence intervals will be provided for 
each treatment group. 
Sample SAS code can be found below (SAS code is regarded as “draft” until fully 
validated at the analysis stage): 
 
proc genmod data=ARR; 
 
 
class ARMCD REGION BEDSSCAT; 
 
 
model N_PDR = ARMCD REGION BEDSSCAT / offset=EXPLOG   
 
 
link=log 
dist=negbin type3; 
 
 
lsmeans ARMCD / exp cl; 
 
 
ods output lsmeans=lsm; 
 
 
ods output ParameterEstimates=est; 
 
run; 
 
The unadjusted annualized protocol-defined relapse rate at Week 96 will also be 
presented for each treatment group.  This is defined for each treatment group as the 
total number of protocol-defined relapses for all patients in the treatment group, divided 
by the total number of patient-years of exposure to that study treatment. 
Sensitivity and Robustness Checks 
The primary analysis described above will be repeated for the per-protocol population as 
a sensitivity analysis. 
The primary analysis described above will be repeated for the ITT population but will 
exclude patients who received no study medication, as a sensitivity analysis. 
As a sensitivity analysis, the primary analysis negative binomial model described above 
will be adjusted by the following additional covariates:  number of relapses occurring 
within the 2 years prior to study entry, baseline presence of Gd lesions (present or 
absent), prior MS treatment, and age (<40, ≥ 40).  
A Poisson model with the same covariates as the primary analysis negative binomial 
model will be fitted. 
Three further sensitivity analyses will be undertaken: 
• 
The annualized protocol-defined relapse rate at Week 96 will be calculated including 
all protocol-defined relapses occurring during the 96-week, double-blind, double-
dummy phase or the SFU Phase, up to 96 weeks after randomization.  In this 
analysis, the exposure time will be calculated as follows:  
Exposure Time = ((Date of Week 96 visit or date of last visit up to 96 weeks after 
randomization)− date of study Day 1 + 1)/365.25  


 
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• 
A sensitivity analysis for the annualized protocol-defined relapse rate at 
Week 96 using multiple imputations will be performed to explore the potential 
influence of informative dropouts on the results of the primary efficacy analyses.  
The multiple imputations will be used to impute the events for patients who 
discontinued treatment early during the 96-week, double-blind, double-dummy 
phase without any protocol-defined relapse during the 30 days prior to 
discontinuation of study treatment.  Multiple imputation inference involves three 
distinct phases: 
1. 
The missing data are filled in “m” times to generate “m” complete data sets.  Instead 
of filling in a single value for each missing value, multiple imputation replaces each 
missing value with a set of “m” plausible values that represent the uncertainty about 
the right value to impute. 
2. 
The “m” complete data sets are analyzed using standard statistical analyses. 
3. 
The results from the “m” complete data sets are combined to produce inferential 
results. 
 
In this analysis, 50% of the patients who discontinued treatment early during the 96-
week, double-blind, double-dummy phase without any protocol-defined relapse during 
the 30 days prior to discontinuation of study treatment will be randomly assigned to have 
an event at the date of treatment discontinuation; the other 50% of these patients will be 
censored at the date of treatment discontinuation.  A total of 1000 (m = 1000) imputed 
datasets will be produced. 
The primary model described in the “Analysis Methods” section above will be applied to 
each of the imputed datasets.  Each imputed dataset will produce an estimate of the 
difference between ocrelizumab and interferon beta-1a 44 μg SC.  The multiple 
imputation estimator of the difference between ocrelizumab and interferon beta-1a 44 μg 
SC is the average of the individual 1000 estimators.  The variance of the estimator is the 
combination of the between- and within-imputation variability (Carpenter and Kenward 
2007). 
• 
The annualized protocol-defined relapse rate at Week 96 will be calculated such 
that patients who discontinued treatment early during the 96-week, double-blind, 
double-dummy phase without any protocol-defined relapse during the 30 days prior 
to discontinuation of study treatment will be counted as having had a relapse on the 
date of treatment discontinuation.  This approach is similar to above, but here the 
described approach is applied to 100% of such patients (hence no imputation), 
rather than randomly to 50% of such patients (with multiple imputation). 
 
OLE Phase 
The annualized protocol-defined relapse rate as defined above will be calculated for 
every year from Study Day 1 and from the start of the OLE period (Year 3).  
Each yearly interval will be defined as the follows, 


 
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• 
Year 1: Treatment start date up to -1 day before Week 48; if WEEK 48 is missing 
then take the minimum of treatment start date + 48*7 or treatment end date as the 
last day 
• 
Year 2 (only exists if treatment end date is strictly after the last day of Year 1): Year 
1 end date + 1 up to either OLE start date if it is available, or the treatment end date 
• 
Year 3 (only exists if OLE start date is not missing and OLE end date is strictly after 
the last day of Year 2): Year 2 end date + 1 up to 1 day before OLE Week 48; if OLE 
Week 48 is missing then take the minimum of (OLE start date + 48*7 or OLE end 
date or last known alive date as the last day). 
• 
Year 4: Similar to Year 3 but from OLE Week 48 + 1 up to 1 day before OLE Week 
96. 
• 
The subsequent years will be similar to Year 4 definition with addition of 48 weeks 
for yearly interval. 
 
So, ARR will be calculated and presented at every 48 weeks interval.  
A GEE Poisson model will be performed, with repeated measurements for each patient, 
the yearly total number of protocol-defined relapses as response variable and treatment 
group, baseline EDSS score (< 4.0 vs. ≥ 4.0), geographical region (United States vs. 
ROW), year number, and the interaction between treatment group and year number as 
covariates.  
Summary table should contain; 
• 
ARR for each treatment arm and rate ratio within each year 
• 
Rate ratio between consecutive years for each treatment arm 
• 
Rate ratio between Year 1 ocrelizumab arm and OLE Year 1 (i.e., Year 3) interferon 
beta-1a44 µg SC arm and corresponding p-value 
• 
Rate ratio between Year 2 ocrelizumab arm and OLE Year 2 (i.e., Year 4) interferon 
beta-1a44 µg SC arm and corresponding p-value 
 
p-values will be reported for rate ratio within each year and between consecutive years 
for comparison between treatments.  
4.4.2 
Secondary Efficacy Endpoints 
4.4.2.1 
Rationale for Hierarchy of Secondary Efficacy Endpoints 
The hierarchical order of secondary efficacy endpoints is shown below, with endpoints 
listed in descending order of importance.  The rationale for this hierarchical order of 
secondary endpoints is based primarily on clinical meaningfulness (i.e., those endpoints 
that are clinically more meaningful are listed higher in the hierarchy).  In situations where 
endpoints have similar clinical relevance, those endpoints with a greater chance of 
achieving a statistically significant treatment difference are listed higher in the hierarchy.  
Established, rather than novel, endpoints are generally given higher priority within the 
hierarchy. 


 
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For patients, reduction in disability progression is a highly meaningful clinical outcome, 
reflecting the degree to which they are able to maintain independence and quality of life.   
The following is list of all secondary endpoints, also called key endpoints:  
• 
The time to onset of confirmed disability progression for at least 12 weeks, with the 
initial event of neurological worsening occurring during the 96-week, double-blind, 
double-dummy treatment period is listed as the first secondary efficacy endpoint on 
the basis of its clinical meaningfulness. 
• 
The second and third secondary efficacy endpoints listed in the hierarchy are MRI 
parameters (T1 Gd-enhancing lesions and new and/or enlarging T2 hyperintense 
lesions) that historically have shown to correlate well with the clinical course. 
• 
The fourth secondary efficacy endpoint, disability improvement, is a clinical endpoint 
that, if achieved, would have even greater impact on the quality of life of patients 
than reduction in disability progression.  However, it represents a novel endpoint.  
Therefore, this endpoint is placed lower within the hierarchy than the above 
endpoints. 
• 
The fifth secondary efficacy endpoint is the time to onset of confirmed disability 
progression for at least 24 weeks, with the initial event of neurological worsening 
occurring during the 96-week, double-blind, double-dummy treatment period, but the 
modality being tested here (EDSS) is identical to that of the first secondary 
endpoint.  Given that the number of 24-week CDP events will be lower than the 
number of 12 week CDP events, there is likely a lower chance of achieving a 
statistically significant treatment difference, and hence, the 24 week CDP is listed 
lower than the 12 week CDP.  It is, however, listed relatively higher in the hierarchy 
as the fifth endpoint, given the greater clinical meaningfulness of disability 
progression than the remaining endpoints. 
• 
The sixth and eighth secondary endpoints, chronic black holes and brain volume, 
are indicators of brain tissue loss.  The possible correlation of such brain-atrophy 
measures and long-term clinical outcomes has been suggested in other studies 
(Barkhof et al. 2009).  Therefore, because they are imaging modalities and the 
correlation to clinical outcomes is weaker than the imaging endpoints that are listed 
higher in the hierarchy, these endpoints are listed lower in the hierarchy than the 
clinical endpoints. 
• 
The EDSS does not adequately assess upper limb function and cognitive 
impairment; therefore, the MSFC scale is used to address this gap in clinical 
disability assessment.  However, since the MSFC scale is not as widely used in 
other studies and not as well-accepted as a validated endpoint, it is listed seventh in 
the hierarchy. 
• 
The SF-36 is one of the most widely used and validated instruments for measuring 
quality of life in patients with MS.  It is, however, listed as ninth in the hierarchy 
below all the other clinical measures because quality-of-life instruments in general 
are not as widely used in confirmatory clinical studies compared with the other 
clinical measures. 


 
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32/Statistical Analysis Plan WA21092 and WA21093 
• 
The tenth and final secondary endpoint is a composite measure encompassing the 
absence of disease activity based on clinical and MRI parameters (i.e., consisting of 
the primary endpoint and secondary endpoints 1, 2, and 3 above).  It is a highly 
meaningful endpoint for patients but is listed as last in the hierarchy because it is a 
combination of previous secondary endpoints. 
 
4.4.2.2 
Statistical Testing Strategy for Secondary Efficacy Endpoints 
Secondary efficacy endpoints will be tested in the sequence presented in the 
hierarchical order listed in Figure 1, all at the α = 0.05 level. 
All p-values will be reported and will be interpreted as either confirmatory or non-
confirmatory (i.e., descriptive only).  The circumstances for confirmatory and for non-
confirmatory interpretation of p-values are described below, and the sequence of the 
confirmatory tests is illustrated in Figure 1. 
The first secondary endpoint in the hierarchy is the time to onset of confirmed disability 
progression for at least 12 weeks with the initial event of neurological worsening 
occurring during the 96-week, double-blind, double-dummy treatment period, and the 
fifth secondary endpoint is the same, except progression is defined as sustained for at 
least 24 weeks during the 96-week comparative treatment period.  The fourth secondary 
endpoint is the proportion of patients who have confirmed disability improvement for at 
least 12 weeks with the initial event of neurological improvement occurring during the 
96-week, double-blind, double-dummy treatment.  For these three endpoints, only when 
data from both Studies WA21092 and WA21093 are combined will there be sufficient 
statistical power to detect relevant treatment differences.  For the other secondary 
efficacy endpoints and the primary efficacy endpoint (annualized protocol-defined 
relapse rate by 2 years), there is sufficient statistical power within each study to detect 
relevant treatment differences, without needing to combine data from the two studies. 
As a consequence of this, for analyses of secondary efficacy endpoints at the individual 
study level: 
• 
For the first secondary efficacy endpoint (the time to onset of confirmed disability 
progression for at least 12 weeks), the study-level p-value will be interpreted as non-
confirmatory, due to inadequate statistical power at the study level to detect relevant 
treatment differences. 
• 
The second secondary efficacy endpoint (total number of T1 Gd-enhancing lesions 
at Weeks 24, 48, and 96) will be tested in a confirmatory manner if and only if, in the 
analysis of both studies combined, the first secondary efficacy endpoint reaches a 
significance level of 0.05 (i.e., pooled analysis p ≤ 0.05).  If, in the analysis of the 
combined studies, the first secondary efficacy endpoint pooled analysis p > 0.05, 
then the second and subsequent secondary efficacy endpoint p-values within the 
hierarchy will be interpreted as non-confirmatory. 
• 
The third secondary efficacy endpoint (total number of new and/or enlarging 
T2 hyperintense lesions at Weeks 24, 48, and 96) will be tested in a confirmatory 
manner if and only if the second secondary efficacy endpoint (total number of 


 
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T1 Gd-enhancing lesions at Weeks 24, 48, and 96) reaches a significance level of 
0.05 (i.e., p ≤ 0.05).  If the second secondary efficacy endpoint p > 0.05, then the 
third and subsequent secondary efficacy endpoint p-values within the hierarchy will 
be interpreted as non-confirmatory. 
• 
For the fourth (proportion of patients who have confirmed disability improvement for 
at least 12 weeks) and fifth (time to onset of confirmed disability progression for at 
least 24 weeks) secondary efficacy endpoints, the study-level p-value will be 
interpreted as non-confirmatory, due to inadequate statistical power at the study 
level to detect relevant treatment differences. 
• 
The sixth secondary efficacy endpoint (total number of new T1-hypo-intense lesions 
(chronic black holes) at Weeks 24, 48, and 96) will be tested in a confirmatory 
manner if and only if, in the analysis of the combined studies, the fifth secondary 
efficacy endpoint (time to onset of confirmed disability progression for at least 
12 weeks) reaches a significance level of 0.05 (i.e., pooled analysis p ≥ 05).  If, in the 
analysis of both studies combined, the fifth secondary efficacy endpoint pooled 
analysis p > 0.05, then the sixth and subsequent secondary efficacy endpoint p-
values within the hierarchy will be interpreted as non-confirmatory. 
• 
The seventh (and subsequent) secondary efficacy endpoint will be tested in a 
confirmatory manner if and only if the sixth (or immediately previous) secondary 
efficacy endpoint reaches a significance level of 0.05 (i.e., p ≤ 0.05).  If the sixth (or 
immediately previous) secondary efficacy endpoint p > 0.05, then the seventh (or 
current) and all subsequent secondary efficacy endpoint p-values within the 
hierarchy will be interpreted as non-confirmatory. 
 
Furthermore, for analyses of secondary efficacy endpoints where data from both studies 
are combined (so there is sufficient statistical power for all primary and secondary 
efficacy endpoint comparisons): 
• 
The first secondary efficacy endpoint (the time to onset of confirmed disability 
progression for at least 12 weeks) will be tested in a confirmatory manner if and only 
if the primary efficacy endpoint (annualized protocol-defined relapse rate by 
2 years), reaches a significance level of 0.05 (i.e., pooled analysis p ≤ 0.05).  If the 
primary efficacy endpoint pooled analysis p > 0.05, then all secondary efficacy 
endpoint pooled analysis p-values within the hierarchy will be interpreted as non-
confirmatory. 
• 
The second (and subsequent) secondary efficacy endpoint will be tested in a 
confirmatory manner if and only if the first (or immediately previous) secondary 
efficacy endpoint reaches a significance level of 0.05 (i.e., pooled analysis p ≤ 0.05).  
If the first (or immediately previous) secondary efficacy endpoint pooled analysis 
p > 0.05, then the second (or current) and all subsequent secondary efficacy 
endpoint pooled analysis p-values within the hierarchy will be interpreted as non-
confirmatory. 
 
The sequence of the confirmatory testing is illustrated in Figure 1 below. 


 
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34/Statistical Analysis Plan WA21092 and WA21093 
The arrows on the left illustrate the hierarchy of the statistical tests of Study WA21092.  
The arrows on the right illustrate the hierarchy of the statistical tests of Study WA21093.  
The boxes in the middle highlight the analyses performed in the pooled data set of 
WA21092 and WA21093. 
For example, for Study WA21092, the primary endpoint ARR should be positive in both 
studies (p ≤ 0.05).  After the poolability of both Studies WA21092 and WA21093 has 
been observed (see more details in the Pooled SAP), the first secondary endpoint is 
tested in the pooled dataset WA21092 and WA21093.  Then, the analysis of T1 Gd-
enhancing lesions is performed for Study WA21092.  If this is statistically significant (p 
≤ 0.05), the T2 hyperintense lesions are analyzed for Study WA21092.  If this is 
statistically significant (p ≤ 0.05), the analysis of confirmed disability improvement is done 
in the pooled data of Studies WA21092 and WA21093.  If this is statistically significant 
(p ≤ 0.05), then the analysis of Confirmed Disability Progression for at least 24 weeks is 
performed in the pooled data.  If this is statistically significant (p ≤ 0.05), the Chronic 
Black Holes endpoint is analyzed in Study WA21092.  Then, the sequence of tests 
continues in the order of MSFC, brain volume, SF-36 PCS, and NEDA for 
Study WA21092. 


 
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35/Statistical Analysis Plan WA21092 and WA21093 
Figure 1 Hierarchical Order of Key Efficacy Endpoints 
 
 
ARR = annualized relapse rate; CDI = Confirmed Disability Improvement; CDP = confirmed 
disability progression; Gd = gadolinium; MSFC = Multiple Sclerosis Functional Composite Scale; 
NEDA = no evidence of disease activity; SF-36 PCS = short form 36 Physical Component 
Summary.  
  
4.4.2.3 
Time to Onset of Confirmed Disability Progression for at Least 
12 Weeks with the Initial Event of Neurological Worsening 
Occurring during the 96-Week, Double-Blind, Double-Dummy 
Treatment Period 
Disability progression as measured by EDSS will be assessed in all patients by the 
independent examining investigator at screening and baseline visit, and every 12 weeks 
throughout the study until the end of the double-blind, double-dummy treatment period at 
Week 96, after which disability progression is assessed at Weeks 12 and 24 in the OLE 


 
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36/Statistical Analysis Plan WA21092 and WA21093 
and then every 24 weeks thereafter.  Additional EDSS assessments for individual 
patients may be requested between visits (i.e., during an MS relapse). 
Section 2.4 provides additional information on the timing of this analysis. 
The EDSS is based on a standard neurological examination; the seven categories of the 
EDSS representing functional systems (Pyramidal, Cerebellar, Brainstem, Sensory, 
Bowel and Bladder, Visual, plus “Other”) are rated and scored (collectively, FSS).  Each 
score of the FSS is an ordinal clinical rating scale ranging from 0 to 5 or 6.  These 
ratings are then used in conjunction with observations and information concerning 
ambulation and use of assistive devices (which will also be scored) to determine the 
EDSS score.  The EDSS is a disability scale that ranges in 0.5-point steps from 
0 (normal) to 10.0 (death). 
Because of the variability of EDSS, a single measurement at the baseline visit might not 
provide a sufficiently reliable baseline EDSS.  Therefore, using an average score from 
two separate measurements may improve the reliability of baseline EDSS and the 
reliability of confirmed disability progression seen in the study.  Inclusion criteria require 
neurological stability for 30 days prior to both screening and baseline visits.  Generally, it 
takes 2 weeks for screening.  There should be little change in EDSS except for the 
measurement variability during the screening period, assuming patients are clinically 
neurologically stable during this period. 
In the derivation of time-to-onset confirmed-disability progression, baseline EDSS is 
defined as the average of the EDSS scores at the screening and baseline visits, without 
rounding. 
Progression is defined a ≥ 1−point increase in EDSS score from a baseline EDSS score 
of 0.0−5.5 inclusive, and a 0.5-increase from a baseline EDSS score higher than 5.5. 
For example, for a patient with a baseline EDSS score of 5.25 or 5.5, the progression is 
defined as an EDSS score of at least 6.5.  For a patient with a baseline EDSS score of 
5.75 or 6.0, the progression is defined as an EDSS score of at least 6.5.  
The inclusion criterion of EDSS (0−5.5) only applies to screening EDSS.  Hence, it is still 
possible for a patient’s baseline EDSS score (derived from both screening and 
Day 1 EDSS results) to be > 5.5.  Confirmation requires the sustained change in EDSS 
for at least 12 weeks from the initial progression.  Initial progression can happen at any 
visit during the 96-week, double-blind, double-dummy treatment period.  
Confirmation of disability progression must occur at the regularly scheduled visit that is 
at least 12 weeks (84 days) after initial progression.  If a patient has a missing EDSS at 
the scheduled visit occurring at least 84 days after an initial progression or the 
scheduled visit occurs several days before the 84-day window after an initial progression 


 
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37/Statistical Analysis Plan WA21092 and WA21093 
(e.g., the visit window is ± 4 days), confirmation of the disability progression must be on 
the basis of the assessment at the next scheduled visit.  There may be EDSS 
assessments at unscheduled or scheduled visits that are < 84 days after the initial 
progression that are between the initial progression visit and the confirmation visit.  
Disability progression cannot be confirmed unless the EDSS values meet the minimum 
change required for progression.  The non-confirmatory EDSS assessments (if any) 
between the initial disability progression and the confirmation of disability progression 
should be at least as high as the minimum change required for progression.  All initial 
disability progression events up to Week 96 with corresponding confirmation visits at a 
subsequent scheduled visit will be taken into account for the statistical analysis, 
irrespective of whether the confirmation visit occurred during the treatment phase or in 
the SFU phase or OLE phase after study-drug discontinuation.  Thus, patients who 
prematurely discontinue study drug treatment should remain in the SFU phase of the 
study, and every effort should be made to obtain a follow-up EDSS status at the next 
scheduled visit.  Patients who, according to the above definition, did not have onset of 
confirmed disability progression by the Week−96 visit, by the time of the early 
discontinuation of treatment, or are lost to follow up will be censored at the date of the 
last EDSS assessment during the 96-week, double-blind, double-dummy treatment 
period. 
Data from the two studies (with respect to the ocrelizumab group vs. the interferon beta-
1a 44 μg SC group) will be pooled for analysis of this endpoint at the α = 0.05 level.  Only 
data collected during the 96-week treatment period will be used for this analysis, 
although confirmation of disability progression during the 96-week, double-blind, double-
dummy treatment period may occur during a subsequent study phase (i.e., during the 
SFU phase or the OLE phase). 
Time to confirmed disability progression in the ocrelizumab group and in the interferon 
beta-1a 44 μg SC group will be compared using a two-sided log-rank test stratifying by 
geographical region (United States vs. ROW), and baseline EDSS (< 4.0 vs. ≥ 4.0).  The 
proportion of patients with confirmed disability progression will be estimated using 
Kaplan-Meier methodology.  A by-treatment Kaplan-Meier plot will be presented for this 
endpoint.  The overall hazard ratio will be estimated using a stratified Cox regression 
model with treatment group as covariate and the same stratification factors used in the 
stratified log-rank test above. 
Sample SAS code can be found below (SAS code is regarded as “draft” until fully 
validated at the analysis stage): 
* Log-rank test; 
 
proc lifetest data=CDP12; 
 
 
time CDP12TIME*CNSR(1); 
 
 
strata REGION BEDSSCAT / group=ARMCD; 
 
 
ods output HomTests =_logrank; 
 
run; 
 
* Cox regression model; 
proc phreg data=CDP12; 


 
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class ARMCD / descending; 
 
 
model CDP12TIME*CNSR(1) = ARMCD / rl; 
 
 
strata REGION BEDSSCAT; 
 
 
ods output ParameterEstimates=est; 
 
run; 
 
The analysis described above will be repeated for the per-protocol population as a 
sensitivity analysis. 
Additionally, the following sensitivity analyses will be performed: 
• 
Use of two different methods for handling of missing data: 
Method 1:  with use of the same kind of multiple imputation approach described at 
the end of Section 4.4.1, patients with an initial disability progression during the 96-
week, double-blind, double-dummy treatment period who discontinue the treatment 
early and do not have a subsequent visit with EDSS measurement will be randomly 
imputed as an event of confirmed disability progression at the date of initial disability 
progression with a probability of 50%; the other 50% of these patients will be 
censored at the date of initial disability progression.  A total of 1000 (m = 1000) 
imputed datasets will be produced. 
Method 2:  Patients with an initial disability progression during the 96-week, double-
blind, double-dummy treatment period who discontinue the treatment early and do 
not have a subsequent visit with EDSS measurement will be imputed as an event of 
confirmed disability progression at the date of initial disability progression. 
• 
Adjustment for some additional baseline factors:  Sensitivity analysis will use the 
same tests above but will, in addition, adjust for the number of relapses occurring 
within a 2-year period prior to study entry, baseline presence of Gd lesions (present 
or absent), prior MS treatment, and age (< 40 vs. ≥ 40 years). 
 
4.4.2.3.1 
OLE Phase 
CDP12 analysis cannot be repeated for the OLE phase since EDSS assessments are 
performed only at every 24 weeks post OLE Week 24. 
 
4.4.2.4 
Total Number of T1 Gadolinium−Enhanced Lesions as 
Detected by Brain Magnetic Resonance Imaging at 
Weeks 24, 48, and 96 
The total number of T1 Gd−enhanced lesions will be calculated as the sum of the 
individual number of T1 Gd−enhanced lesions at Weeks 24, 48, and 96.  Data from other 
unscheduled assessments will not be included in this summary or analysis. 
The same approach to analysis will be applied here as described in Section 4.4.1, 
“Analysis Methods” section, with the following exceptions: 
• 
In order to account for patients receiving varying numbers of brain MRI scans during 
the study, the log-transformed number of brain MRI scans received will be included 
in the model as an “offset” variable for appropriate computation.  This approach is 
preferable to imputation of missing values using the average of non-missing 


 
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39/Statistical Analysis Plan WA21092 and WA21093 
observations, because only three timepoints would give a high variability in the 
imputed average values.  Additionally, the “offset” variable approach aligns more 
closely with approaches to analysis used a) in regulatory submissions for other MS 
therapies, b) for the primary endpoint, and c) in this program’s Phase II study.  
• 
Baseline covariates here will be as follows:  baseline Gd lesion (present or not), 
treatment group, baseline EDSS score (< 4.0 vs. ≥ 4.0), and geographical region 
(United States vs. ROW). 
 
Sample SAS code can be found below (SAS code is regarded as “draft” until fully 
validated at the analysis stage): 
 
proc genmod data=MRIT1; 
 
 
class ARMCD REGION BEDSSCAT BGDLESFL; 
 
 
model N_MRIT1 = ARMCD REGION BEDSSCAT BGDLESFL /  
 
 
 
offset=MRILOG link=log dist=negbin type3; 
 
 
lsmeans ARMCD / exp cl; 
 
 
ods output lsmeans=lsm; 
 
 
ods output ParameterEstimates=est; 
 
run; 
  
If the model fails to converge due to high number of zero T1 lesion counts, a logistic 
regression model will be performed on Gd lesion (present or not) adjusted for the same 
baseline variables.  Patients withdrawn from treatment and having no T1 lesions:  those 
withdrawn because of lack of efficacy or death are considered as having T1 lesions; 
otherwise, it will be considered a missing observation: 
 
proc logistic data=MRIT1; 
 
 
class ARMCD REGION BEDSSCAT BGDLESFL; 
 
 
model N_MRIT1_CAT = ARMCD REGION BEDSSCAT BGDLESFL; 
 
 
oddsratio ARMCD /cl=wald; 
 
 
ods output OddsRatiosWald = oddsr; 
 
run; 
 
4.4.2.4.1 
OLE Phase 
This analysis will be modified to include data collected during the OLE period.  This 
analysis will be an exploratory analysis and will be performed for each visit from baseline 
up to the last mature visit.  The last mature visit is defined as the visit where the majority 
of patients have completed prior to the data cutoff date.  Of note, MRI is only collected 
once a year during OLE. 
Adjusted rate and adjusted rate ratio based on the negative binomial models may not be 
estimable due to low number of lesions.  Hence, unadjusted rate (total number of lesions 
divided by number of scans), unadjusted rate ratio and corresponding confidence 
intervals based on the exact poisson test will be presented. 
4.4.2.5 
Total Number of New and/or Enlarging T2 Hyperintense 
Lesions as Detected by Brain Magnetic Resonance Imaging at 
Weeks 24, 48, and 96 
The total number of new and/or enlarging T2 lesions will be calculated as the sum of the 
individual number of new and/or enlarging lesions at Weeks 24, 48, and 96.  Data from 
other unscheduled assessments will not be included in this summary or analysis. 


 
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40/Statistical Analysis Plan WA21092 and WA21093 
• 
The same approach to analysis will be applied here as described in Section 4.4.2.4, 
with the following exception. 
• 
Baseline covariates here will be as follows:  baseline T2 lesion count, treatment 
group, baseline EDSS score (< 4.0 vs. ≥ 4.0) and geographical region (United States 
vs. ROW). 
Sample SAS code can be found below (SAS code is regarded as “draft” until fully 
validated at the analysis stage): 
 
proc genmod data=MRIT2; 
 
 
class ARMCD REGION BEDSSCAT; 
 
 
model N_MRIT2 = ARMCD REGION BEDSSCAT BT2LES /  
 
 
 
offset=MRILOG link=log dist=negbin type3; 
 
 
lsmeans ARMCD / exp cl; 
 
 
ods output lsmeans=lsm; 
 
 
ods output ParameterEstimates=est; 
 
run; 
  
If the model fails to converge due to a high number of zero T2 lesion counts, a logistic 
regression model will be performed on new/enlarging T2 lesion (present or not) adjusted 
for the same baseline variables.  Patients withdrawn from treatment and having no 
T2 lesions:  those withdrawn due to lack of efficacy or death are considered as having 
T2 lesions; otherwise, it will be considered a missing observation. 
4.4.2.5.1 
OLE Phase 
This analysis will be modified to include data collected during the OLE period. This 
analysis will be an exploratory analysis and will be performed for each visit from baseline 
up to the last mature visit. The last mature visit is defined as the visit where the majority 
of patients have completed prior to the data cutoff date. Of note, MRI is only collected 
once a year during OLE. 
Adjusted rate and adjusted rate ratio based on the negative binomial models may not be 
estimable due to low number of lesions. Hence, unadjusted rate (total number of lesions 
divided by number of scans), unadjusted rate ratio and corresponding confidence 
intervals based on the exact poisson test will be presented. 
4.4.2.6 
Proportion of Patients Who Have Confirmed Disability 
Improvement Sustained for at Least 12 Weeks with the Initial 
Event of Neurological Improvement Occurring during the 96-
Week, Double-Blind, Double-Dummy Treatment Period 
This endpoint will be analyzed only for the subgroup of patients with a baseline EDSS 
score ≥ 2.0.  Exactly the same approach to data derivation will be used for disability 
improvement as for disability progression (refer to Section 4.4.2.3, although note that 
here the endpoint is a binary improved/not improved variable, rather than a time-to-event 
endpoint).  In particular, the same approach to the timing of the confirmation of disability 
improvement will be applied as for disability progression.  The baseline EDSS is the 
average of the screening EDSS score and the score of the baseline visit, without 
rounding.  For patients with a baseline EDSS score ≥ 2 and ≤ 5.5, disability improvement 
is defined as a reduction in EDSS score ≥ 1.0 compared to baseline EDSS score. For 
patients with a baseline EDSS score > 5.5, disability improvement is defined as a 


 
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41/Statistical Analysis Plan WA21092 and WA21093 
reduction in EDSS score of ≥ 0.5.  All patients without disability improvement will be 
counted as not improved, independent of follow-up time 
This analysis requires both Studies WA21092 and WA21093 to be combined to have 
sufficient statistical power to detect relevant treatment differences.  In the study-level 
analysis, the p-value for this treatment comparison will be interpreted as non-
confirmatory.  
The proportions in treatment groups will be compared using the Cochran-Mantel-
Haenszel (CMH) χ2 test stratified by geographical region (United States vs. ROW), and 
baseline EDSS score ( < 4.0 vs.  ≥ 4.0). 
Sample SAS code can be found below (SAS code is regarded as “draft” until fully 
validated at the analysis stage): 
 
proc freq data=CDI12; 
 
 
tables REGION*BEDSSCAT*ARMCD*CDI12 / cmh; 
 
 
ods output CMH=pval; 
 
 
ods output CommonRelRisks=risks; 
 
run; 
  
4.4.2.6.1 
OLE Phase 
CDI12 analysis won’t be repeated for the OLE phase since EDSS is only collected every 
24 weeks post OLE Week 24. 
4.4.2.7 
Time to Onset of Confirmed Disability Progression for at Least 
24 Weeks with the Initial Event of Neurological Worsening 
Occurring during the 96-Week, Double-Blind, Double-Dummy 
Treatment Period 
This is the same as the 12-week confirmed disability progression, except that the 
confirmation of disability progression must occur at the regularly scheduled visit that 
is ≥ 24 weeks ( ≥ 161 days) after initial disability progression.   
All initial disability progression events up to Week 96 with corresponding confirmation 
visits at the next schedule visit will be taken into account for the statistical analysis.  The 
same analysis principles as described in Section 4.4.2.3 will be applied to the 24-week 
disability endpoint.  The sensitivity analyses will be performed for the 24-week disability 
endpoint in the same way as for the 12-week endpoint. 
Sample SAS code can be found below (SAS code is regarded as “draft” until fully 
validated at the analysis stage): 
* Log-rank test; 
 
proc lifetest data=CDP24; 
 
 
time CDP24TIME*CNSR(1); 
 
 
strata REGION BEDSSCAT / group=ARMCD; 
 
 
ods output HomTests =_logrank; 
 
run; 
 
* Cox regression model; 
 
proc phreg data=CDP24; 
 
 
class ARMCD / descending; 


 
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model CDP24TIME*CNSR(1) = ARMCD / rl; 
 
 
strata REGION BEDSSCAT; 
 
 
ods output ParameterEstimates=est; 
 
run; 
  
4.4.2.7.1 
OLE Phase 
This analysis will be repeated to include EDSS assessments performed during the OLE 
period for the combined DB+OLE period, with the same baseline as for the analysis 
during DB. 
Analysis containing only data from OLE will be performed considering the OLE baseline. 
Moreover, the difference of survival curves will be analyzed every 24 weeks. Greenwood 
formula will be used to compute the corresponding 95% CI and p-value. 
4.4.2.8 
Total Number of New T1-Hypo-Intense Lesions (Chronic Black 
Holes) at Weeks 24, 48, and 96 
The total number of new T1-hypo-intense lesions (chronic black holes) will be calculated 
as the sum of the individual number of new lesions at Weeks 24, 48, and 96.  Data from 
other unscheduled assessments will not be included in this summary or analysis. 
The same approach to analysis will be applied here as described in Section 4.4.2.4, with 
the following exception: 
• 
Baseline covariates here will be as follows:  treatment group, baseline T1-hypo-
intense lesions count, baseline EDSS score ( < 4.0 vs. ≥  4.0) and geographical 
region (United States vs. ROW). 
Sample SAS code can be found below (SAS code is regarded as “draft” until fully 
validated at the analysis stage): 
 
proc genmod data=MRICBH; 
 
 
class ARMCD REGION BEDSSCAT; 
 
 
model N_MRICBH = ARMCD REGION BEDSSCAT BT1LES /  
 
 
 
offset=MRILOG link=log dist=negbin type3; 
 
 
lsmeans ARMCD / exp cl; 
 
 
ods output lsmeans=lsm; 
 
 
ods output ParameterEstimates=est; 
 
run; 
  
If the model fails to converge due to high number of zero chronic black hole counts, a 
logistic regression model will be performed on chronic black hole (present or not), 
adjusted for the same baseline variables.  Patients withdrawn from treatment and having 
no chronic black holes:  those withdrawn due to lack of efficacy or death are considered 
as having chronic black holes; otherwise, it will be considered a missing observation. 
Note that the protocol and previous versions of this SAP did not make it clear that only 
new T1 hypo-intense lesions would be considered. 
4.4.2.8.1 
OLE Phase 
This analysis will be modified to include data collected during the OLE period.  This 
analysis will be an exploratory analysis and will be performed for each visit from baseline 


 
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up to the last mature visit.  The last mature visit is defined as the visit where the majority 
of patients have completed prior to the data cutoff date.  Of note, MRI is only collected 
once a year during OLE. 
Adjusted rate and adjusted rate ratio based on the negative binomial models may not be 
estimable due to low number of lesions.  Hence, unadjusted rate (total number of lesions 
divided by number of scans), unadjusted rate ratio and corresponding confidence 
intervals based on the exact poisson test will be presented. 
4.4.2.9 
Change in Multiple Sclerosis Functional Composite Scale 
Score from Baseline to Week 96 
There are three primary measures in a MSFC score:  1) Timed 25-Foot walk; 2) 9-Hole 
Peg Test (9-HPT); and 3) Paced Auditory Serial Addition Test (PASAT-3 version).  The 
MSFCS is based on the concept that scores for these three dimensions (arm, leg, and 
cognitive function) are combined to create a single score (the MSFC) that can be used to 
detect change over time in a group of patients with MS.  Since the three primary 
measures differ in what they actually measure (time for the 9-HPT and 25-Foot Timed 
Walk, but number of correct answers for the PASAT-3), a common metric for these 
variables has been used to create a composite score for the three different measures.  
Z-score was selected for this purpose.  The results from each of these three tests are 
transformed into Z-scores and averaged to yield a composite score for each patient at 
each timepoint. 
MSFC Score = {Zarm, average + Zleg, average + Zcognitive} / 3.0 
Where Zxxx = Z-score 
The following are MSFC components: 
• 
Trial 1, Timed 25-Foot Walk 
• 
Trial 2, Timed 25-Foot Walk 
• 
Trial 1, Dominant Hand, 9-HPT 
• 
Trial 2, Dominant Hand, 9-HPT 
• 
Trial 1, Non-Dominant Hand, 9-HPT 
• 
Trial 2, Non-Dominant Hand, 9-HPT 
• 
PASAT-3 
 
There are three derived results for three tests:  1) the average (reciprocal) scores from 
the four trials on the 9-HPT (the two trials for each hand are averaged, converted to the 
reciprocals of the mean times for each hand and then the two reciprocals are averaged); 
2) the average scores of two 25-Foot Timed Walk trials; and 3) the number correct from 
the PASAT-3.  The Z-score will be created for these three derived results to yield the 
composite score by the following formula. 


 
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Formula for Creating the MSFC Score to Compare Groups within a Study (The Preferred 
Method) 
MSFC Score = { {(Average (1/9-HPT) − Baseline Mean (1/9-HPT))/ Baseline Std Dev (1/9 HPT)} 
+ {(Average 25-Foot Walk − Baseline Mean 25-Foot Walk)/Baseline Std-Dev 25-Foot Walk} 
+ {(PASAT-3 − Baseline Mean PASAT-3) /Baseline Std Dev PASAT-3} } / 3.0 
 
Note:  “Average (1/9-HPT)” is the average of the inverse (reciprocal) for the mean 
time of the two trials on the right hand and reciprocal of the mean time of the two left-
hand trials from the test patient; Baseline Mean (1/9-HPT) and Std Dev (1/9-HPT) are 
the baseline values from each patient in all study groups combined at the baseline 
assessment; “Average 25-Foot Walk” is the mean time from the two trials of the 25-
foot timed walk; and we take the negative value of the Z-score to make the direction 
of change the same as the other components.  Similarly, the Baseline Mean and Std 
Dev 25-Foot Walk are of all Baseline Groups combined; and “PASAT-3” is the score 
from the test patient, and the Baseline Mean PASAT-3 and Std Dev PASAT-3 of the 
combined baseline assessments.  These are discussed below. 
Note that changing the signs of the Z-scores for the 25-Foot Walk and using inverse 
value of 9-HPT to ensure that a negative value implies worsening, and a positive value 
implies improvement.  More details can be found in the MSFC Manual. 
• 
Missing data will be imputed as follows: 
• 
For results within a given test: 
25-Foot Timed Walk trials:  If the test results are not available due to a "physical 
limitation," impute the maximum possible value for the scale.  If the test results 
are not available but it is NOT due to a "physical limitation," use the result from 
the other trial to impute the missing value. 
9-HPT:  If the test results are not available due to a "physical limitation," impute 
the maximum possible value for the scale.  If the test results are not available 
but it is NOT due to a "physical limitation," impute the missing test score using 
the result from the other trial of the same hand.  If the result from the other trial 
of the same hand is also missing, use the average score from the other hand 
(or available score from one trial if the result from one trial only is available). 
• 
For the composite score: 
All available data will be used for analysis regardless of the timing of any 
protocol-defined relapse. 
 
Outliers will be applied with the following rules: 
• 
For 9-HPT, the lower bound is set to be 10 seconds (Oxford Grice et al. 2003), and 
the upper bound is set to be 300 seconds, according to the MSFC Manual. 
• 
For 25-FWT, the lower bound is set to be 2.2 seconds (Bohannon 1997), and upper 
bound is set to be 180 seconds, according to the MSFC Manual. 


 
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• 
For PASAT, the lower and upper bounds are set to be 0 and 60 according to the 
MSFC Manual.  
• 
For values outside the lower and upper bounds, they will be treated as missing, and 
the imputation rule applied as defined above. 
 
The MSFC score will be summarized at baseline and at Weeks 12, 24, 36, 48, 60, 72, 
84, and 96 using descriptive statistics for each treatment group.  Data from other 
unscheduled assessments will not be included in this summary or analysis.  The change 
from baseline to Weeks 12, 24, 36, 48, 60, 72, 84, and 96 in MSFC score will be 
computed and summarized using descriptive statistics for each treatment group. 
For the assessment of differences in the mean change from baseline in MSFC score up 
to Week 96, a Mixed-Effect Model Repeated Measures analysis (MMRM) incorporating 
post-randomization data collected up to 96 weeks of treatment will be used to assess all 
data collected over time with consideration of the variance−covariance matrix of the 
repeated measures.  This method allows for a general unstructured variance−covariance 
matrix and will include data from patients with incomplete data from some scheduled 
timepoints. 
The model will be implemented in SAS using the MIXED procedure and will include the 
change from baseline in MSFC score as the dependent variable.  The fixed effects in the 
model will include independent variables of randomized treatment, visit (nominal 
post ≤ baseline visits as per the Schedule of Assessments) and treatment-by-visit 
interaction, along with the following baseline covariates:  baseline MSFC score, baseline 
MSFC score by visit interaction, geographical region (United States vs. ROW), and 
baseline EDSS score ( < 4.0 vs ≥  4.0).  Visit will be treated as a repeated variable within a 
patient.  Patient, treatment, and visit will be treated as factor variables. An unstructured 
variance−covariance structure will be applied to model the within-patient errors.  The 
model will be fitted using the Restricted Maximum Likelihood method (REML).  
Denominator degrees of freedom will be estimated using Satterthwaite’s approximation. 
To estimate the difference between the ocrelizumab and interferon beta-1a 44 µg SC 
groups in mean change from baseline to Week 96, a treatment-by-visit interaction 
contrast will be constructed (i.e., the treatment group contrast at Week 96).  On the basis 
of this analysis, least square means, standard errors, and the 95% confidence interval 
for the treatment difference will be reported. 
Graphical presentations for least square means and 95% confidence intervals will be 
used to illustrate trends over time. 
Sample SAS code can be found below (SAS code is regarded as “draft” until fully 
validated at the analysis stage): 
 
proc mixed data=MSFCS method=REML; 
 
 
class REGION BEDSSCAT ARMCD VISIT USUBJID; 
 
 
model change  =  BFCS  REGION  BEDSSCAT  ARMCD  VISIT 


 
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       BFCS*VISIT  ARMCD*VISIT / ddfm= satterthwaite; 
 
 
repeated VISIT / type=un subject = USUBJID; 
 
 
lsmeans ARMCD*VISIT / pdiff cl; 
 
 
ods output lsmeans = lsm;  * contains the adjusted means; 
 
 
ods output diffs = dif;  * contains treatment differences; 
 
run; 
  
4.4.2.9.1 
OLE Phase 
This analysis won’t be repeated for the OLE phase as this data is not being collected 
during the OLE phase. 
4.4.2.10 
Percentage Change in Brain Volume as Detected by Brain 
Magnetic Resonance Imaging Scan from Week 24 to Week 96 
Brain volume is recorded as an absolute “normalized” value at the baseline visit then 
recorded at subsequent visits as a percentage change relative to the absolute value at 
the baseline visit.  Therefore, brain volume at Week 24 will be calculated as the brain 
volume at the baseline visit multiplied by 1 + ([percentage change in brain volume from 
baseline visit to Week 24]/100).  This value will be used to determine the percentage 
change in brain volume at Weeks 48 and 96 relative to Week 24. 
Percentage change in brain volume relative to Week 24, as detected by brain MRI scan, 
will be computed and summarized at Weeks 48 and 96 using descriptive statistics for 
each treatment group.  Data from other unscheduled assessments will not be included in 
this summary or analysis. 
For the assessment of differences in the mean percentage change in brain volume on 
MRI scans from Week 24 to Week 96, an MMRM analysis will be undertaken using the 
same approach as described in Section 4.4.2.9, except for the following: 
• 
The response variable will be the percentage change from Week 24 to subsequent 
visits (Weeks 48 and 96).  Baseline brain volume data will not feature in this 
analysis. 
• 
Baseline covariates here will be as follows:  brain volume at Week 24, geographical 
region (United States vs. ROW), and baseline EDSS score ( < 4.0 vs ≥ 4.0) 
• 
To estimate the difference between the ocrelizumab and interferon beta-1a 44 µg 
SC groups in mean change from Week 24 to Week 96, a treatment-by-visit 
interaction contrast will be constructed (i.e., the treatment group contrast at Week 
96) 
 
Sample SAS code can be found below (SAS code is regarded as “draft” until fully 
validated at the analysis stage): 
 
proc mixed data=MRINBV method=REML; 
 
 
class REGION BEDSSCAT ARMCD VISIT USUBJID; 
 
 
model change  =  W24NBV  REGION  BEDSSCAT  ARMCD  VISIT 
       W24NBV*VISIT  ARMCD*VISIT / ddfm= satterthwaite; 
 
 
repeated VISIT / type=un subject = USUBJID; 
 
 
lsmeans ARMCD*VISIT / pdiff cl; 
 
 
ods output lsmeans = lsm;  * contains the adjusted means; 
 
 
ods output diffs = dif;  * contains treatment differences; 
 
run; 
  


 
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The choice of Week 24 as “baseline” in this analysis, rather than the baseline visit, is a 
widely accepted approach to establish a stable baseline and avoid the effect of 
pseudoatrophy commonly reported for immunomodulatory therapies. 
4.4.2.10.1 
OLE Phase 
This analysis will be extended to include data collected during the OLE period. 
Percentage change from Week 24, baseline and OLE baseline until the last mature visit 
will be analyzed. 
4.4.2.11 
Change in Quality of Life, as Measured by the Short Form 36 
Version 2 Physical Component Summary Score from Baseline 
to Week 96 
The Short Form 36 Version 2 (SF-36v2) is a 36-item, self-reported, generic measure of 
quality of life that has been widely used in multiple disease areas.  It is composed of 
eight health domains:  Physical Functioning (PF), Role-Physical (RP), Bodily Pain (BP), 
General Health (GH), Vitality (VT), Social Functioning (SF), Role-Emotional (RE), and 
Mental Health (ME).  On the basis of these domain scores, the PCS Score and the 
Mental Component Summary (MCS) Score will be computed.  The standard form of the 
instrument, with a 4-week recall, is being administered in the studies. 
Scoring and rules for missing items will follow the SF-36v2 User’s Manual.  In brief, 
scoring for each health domain scale involves (a) recoding item response values, 
(b) summing recoded response values for all items in a given scale to obtain the scale 
raw score, and (c) transforming the scale raw score to a 0−100 score.  The PCS score is 
computed by (a) multiplying each health domain Z-score by a scale-specific physical 
factor score coefficient, (b) summing the resulting products, and (c) converting the 
product total to a T score.  The MCS score is computed in the same manner, using 
scale-specific mental factor score coefficients. 
The PCS scores will be summarized at baseline and Weeks 48 and 96 using descriptive 
statistics for each treatment group.  Data from other unscheduled assessments will not 
be included in this summary or analysis.  The change from baseline to Weeks 48 and 96 
in PCS scores will be computed and summarized using descriptive statistics for each 
treatment group. 
For the assessment of differences in the mean change in PCS score during the 96-week 
comparative treatment period from baseline up to Week 96, MMRM analyses will be 
undertaken using the same approach as described above in Section 4.4.2.9, except 
baseline covariates here will be as follows:  Baseline PCS score, geographical region 
(United States vs. ROW), and baseline EDSS score ( < 4.0 vs. ≥ 4.0). 
Sample SAS code can be found below (SAS code is regarded as “draft” until fully 
validated at the analysis stage): 
 
proc mixed data=PCSS method=REML; 
 
 
class REGION BEDSSCAT ARMCD VISIT USUBJID; 


 
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model change  =  BPCS  REGION  BEDSSCAT  ARMCD  VISIT 
       BPCS*VISIT  ARMCD*VISIT / ddfm= satterthwaite; 
 
 
repeated VISIT / type=un subject = USUBJID; 
 
 
lsmeans ARMCD*VISIT / pdiff cl; 
 
 
ods output lsmeans = lsm;  * contains the adjusted means; 
 
 
ods output diffs = dif;  * contains treatment differences; 
 
run; 
  
4.4.2.11.1 
OLE Phase 
Additional data from the OLE period will be descriptively analyzed. 
4.4.2.12 
Proportion of Patients Who Have No Evidence of Disease 
Activity by Week 96 
This endpoint will be defined only for those patients with a baseline EDSS score ≥ 2.0.  
All available data during the 96-week treatment period will be used for the analysis.  
Patients who complete the 96-week treatment period will be considered as having 
evidence of disease activity if at least one protocol-defined relapse, a CDP event or at 
least one MRI scan showing MRI activity (defined as Gd-enhancing T1 lesions, or new 
or enlarging T2 lesions) was reported during the 96-week treatment period, otherwise 
the patient will be considered as having NEDA.  Patients who discontinue treatment 
early with at least one event before early discontinuation will be considered as having 
evidence of disease activity.  
Even if an event was not reported before early discontinuation, the patient will be 
considered as having evidence of disease activity if the reason for early discontinuation 
is lack of efficacy or death; otherwise, it will be considered a missing observation. 
Only data collected during the 96-week treatment period will be used for this analysis, 
although confirmation of disability progression during the 96-week, double-blind, double-
dummy treatment period may occur during a subsequent study phase (i.e., during the 
SFU phase or the OLE phase). 
The proportion of patients with NEDA within treatment groups will be compared using 
the CMH χ2 test stratified by geographical region (United States vs. ROW), and baseline 
EDSS score ( < 4.0 vs. ≥  4.0). 
Sample SAS code can be found below (SAS code is regarded as “draft” until fully 
validated at the analysis stage): 
 
proc freq data=NEDA; 
 
 
tables REGION*BEDSSCAT*ARMCD*NEDA / cmh; 
 
 
ods output CMH=pval; 
 
 
ods output CommonRelRisks=risks; 
 
run; 
  
4.4.2.12.1 
OLE Phase 
Proportion of patients with NEDA between OLE start and OLE Week 96 will be 
presented by randomized arms in the OLE ITT population. 


 
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4.4.3 
Exploratory Efficacy Endpoints 
4.4.3.1 
Proportion of Relapse-Free Patients by 96 Weeks 
All available data during the 96-week treatment period will be used for the analysis.  
Patients who complete the 96-week treatment period will be considered as not relapse-
free if at least one protocol-defined relapse was reported during the 96-week treatment 
period; otherwise, the patient will be considered as relapse-free.  Patients who 
discontinued treatment early with at least one relapse before early discontinuation will be 
considered as not relapse-free.  Even if the patient did not have a relapse before early 
discontinuation, if the reason for early discontinuation is lack of efficacy or death, the 
patient will be considered as not relapse-free; otherwise, it will be considered as a 
missing observation. 
The proportions within treatment groups will be compared using CMH χ2 test stratified by 
geographical region (United States vs. ROW), and baseline EDSS score ( < 4.0 
vs.  ≥ 4.0). 
4.4.3.1.1 
OLE phase 
Time to the first protocol defined relapse will also be analyzed during the DB and OLE 
period. Hazard ratio between randomized arms based on the Cox model, p-value based 
on the log-rank test and Kaplan-Meier estimates will be presented.  
4.4.3.2 
Percentage Change in Total T2 Lesion Volume as Detected by 
Brain Magnetic Resonance Imaging from Baseline to Week 96 
The total volume of T2 lesions on MRI scans of the brain will be summarized at baseline 
and Weeks 24, 48, and 96 using descriptive statistics for each treatment group.  Data 
from other unscheduled assessments will not be included in this summary or analysis.  
The percentage change from baseline to Weeks 24, 48, and 96 in total volume of 
T2 lesions on MRI scans of the brain will be computed and summarized using 
descriptive statistics (e.g., mean, SD, median, minimum, maximum, and n) for each 
treatment group. 
For the assessment of differences in the mean percentage change in total T2 lesion 
volume during the 96-week comparative treatment period from baseline up to Week 96, 
an MMRM analysis will be undertaken using the same approach as described 
in  Section 4.4.2.9, except baseline covariates here will be as follows:  Baseline T2 
lesion volume, geographical region (United States vs. ROW), and baseline 
EDSS ( < 4.0 vs. ≥ 4.0). 
This analysis has been modified as described in Section 4.4.3.23, due to the normality 
assumption for the percentage change in total T2 lesion volume being violated. 


 
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4.4.3.3 
Annualized Relapse Rate, Based on All Clinical Relapses at the 
End of the 96-Week Comparative Treatment Period 
All clinical relapses reported on the MS relapse page will be used for this analysis 
(protocol-defined relapse is a subset of clinical relapse). 
The annualized clinical relapse rate by Week 96 will be analyzed using the same general 
approach as described in Section 4.4.1, “Analysis Methods” for protocol-defined relapse 
(primary efficacy endpoint).  However, the sensitivity and robustness checks described 
in Section 4.4.1 will not be performed here.  
4.4.3.4 
Annualized Protocol-Defined Relapse Rate by 2 Years 
(96 weeks) for Relapses Requiring Intravenous Steroid Therapy 
All protocol-defined relapses requiring treatment with IV steroids will be used for this 
analysis.  
The annualized relapse rate by Week 96 will be analyzed using the same general 
approach as described in Section 4.4.1, “Analysis Methods” for protocol-defined relapse 
(primary efficacy endpoint).  However, the sensitivity and robustness checks described 
in Section 4.4.1 will not be performed here. 
4.4.3.5 
Percentage Change in Brain Volume as Detected by Brain 
Magnetic Resonance Imaging from Baseline to Week 96 
Percentage change in brain volume relative to the baseline visit, as detected by brain 
MRI scan, will be computed and summarized at Weeks 24, 48 and 96 using descriptive 
statistics for each treatment group.  Data from other unscheduled assessments will not 
be included in this summary or analysis. 
For the assessment of differences in the mean percentage change in brain volume on 
MRI scans during the 96-week comparative treatment period from baseline up to 
Week 96, an MMRM analysis will be undertaken using the same approach as described 
in Section 4.4.2.9, except baseline covariates here will be as follows:  baseline brain 
volume, geographical region (United States vs. ROW), and baseline EDSS score 
( < 4.0 vs.  ≥ 4.0). 
4.4.3.5.1 
OLE Phase 
This analysis will be performed as described in Section 4.4.2.10.1.  
4.4.3.6 
Time to Onset of Confirmed Disability Progression for at Least 
48 Weeks with the Initial Event of Neurological Worsening 
Occurring during the 96-Week, Double-Blind, Double-Dummy 
Treatment Period 
This is the same as the 12-week confirmed disability progression, except that the 
confirmation of disability progression must occur at the regularly scheduled visit that 
is ≥ 48 weeks ( ≥ 329 days) after initial disability progression. 


 
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All initial disability progression events up to Week 96 with corresponding confirmation 
visits at the next schedule visit will be taken into account for the statistical analysis.  The 
same analysis principles as described in Section 4.4.2.3 will be applied to the 48-week 
disability endpoint. 
4.4.3.6.1 
OLE Phase 
This analysis will be repeated to include the EDSS assessments performed during the 
OLE period for the combined DB + OLE period, with the same baseline as for the 
analysis during DB.  Analysis containing only data from OLE will be performed 
considering the OLE baseline. 
Moreover, the difference of survival curves will be analyzed every 24 weeks.  
Greenwood formula will be used to compute the corresponding 95% CI and p-value. 
4.4.3.7 
Time to Confirmed EDSS ≥ 6 for at least 24 weeks during 96-
Week, Double-Blind, Double-Dummy Treatment Period 
In the derivation of time-to-onset confirmed EDSS ≥ 6, only patients with baseline ≤ 5.5 
will be considered. Baseline EDSS is defined as the average of the EDSS scores at the 
screening and baseline visits, without rounding. An increase in EDSS score to ≥ 6.0 from 
a baseline EDSS ≤ 5.5 during the 96-week, double-blind, double-dummy treatment period 
which sustains for at least 24 weeks will be considered as an event.  
Data from the two studies will be pooled for analysis of this endpoint.  Only events with 
onset during the 96-week treatment period will be used for this analysis, although 
confirmation of EDSS ≥ 6 may occur during a subsequent study phase (i.e., during the 
SFU phase or the OLE phase). 
Time to confirmed EDSS ≥ 6 will be analyzed using a two-sided log-rank test stratifying 
by geographical region (United States vs. ROW), and baseline EDSS ( < 4.0 vs.  ≥ 4.0).  
The proportion of patients with confirmed EDSS ≥ 6 will be estimated using Kaplan-Meier 
methodology.  A Kaplan-Meier plot will be presented for this endpoint by treatment 
groups.  The overall hazard ratio will be estimated using a stratified Cox regression 
model with treatment group as covariate and stratified by the same stratification factors 
used in the stratified log-rank test above. 
4.4.3.7.1 
OLE Phase 
This analysis will be repeated to include the EDSS assessments performed during the 
OLE period for the combined DB + OLE period, with the same baseline as for the 
analysis during DB. Analysis containing only data from OLE will be performed 
considering the OLE baseline. 
Moreover, the difference of survival curves will be analyzed every 24 weeks.  
Greenwood formula will be used to compute the corresponding 95% CI and p-value. 


 
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4.4.3.8 
Time to Confirmed EDSS ≥ 6 for at least 48 weeks during 96-
Week, Double-Blind, Double-Dummy Treatment Period 
This is the same as the time to 24-week confirmed EDSS ≥ 6, except that the 
confirmation must occur at the regularly scheduled visit that is ≥ 48 weeks ( ≥ 329 days) 
after initial disability progression.  The same analysis as described in Section 4.4.3.7 will 
be applied to the 48-week confirmed EDSS ≥ 6 endpoint.  
4.4.3.8.1 
OLE Phase 
This analysis will be repeated to include the EDSS assessments performed during the 
OLE period for the combined DB + OLE period, with the same baseline as for the 
analysis during DB.  Analysis containing only data from OLE will be performed 
considering the OLE baseline. 
Moreover, the difference of survival curves will be analyzed every 24 weeks.  
Greenwood formula will be used to compute the corresponding 95% CI and p-value. 
4.4.3.9 
Ratio in Timed 25-Foot Walk relative to Baseline at Week 96 
The average time (for the 25-foot walk) from two trials will be used in this analysis.  The 
imputation method for missing values in either of the two trials will be the same as 
described in Section 4.4.2.9.  
All available data at Weeks 12, 24, 36, 48, 60, 72, 84 and 96 will be used for analysis, 
regardless of the timing of any protocol-defined relapses.  
The timed 25-foot walk will be summarized at baseline and at Weeks 12, 24, 36, 48, 60, 
72, 84, and 96 using descriptive statistics for each treatment group.  Data from other 
unscheduled assessments will not be included in this summary or analysis.  The change 
from baseline to Weeks 12, 24, 36, 48, 60, 72, 84, and 96 in the timed 25-foot walk will 
be computed and summarized using descriptive statistics for each treatment group.  
For the assessment of ratio in the timed 25-foot walk relative to baseline up to Week 96, 
MMRM analyses will be undertaken.  
The model will be implemented in SAS using PROC MIXED and will include the log-
transformed ratio of post-baseline to the baseline in timed 25-foot-walk at each visit as 
the dependent variable.  The fixed effects in the model will include independent variables 
of randomized treatment, visit (nominal post-baseline visits as per the Schedule of 
Assessments), baseline-by-visit interaction and treatment-by-visit interaction, along with 
the following baseline covariates, log-transformed 25-foot-timed-walk at baseline visit, 
geographical region (U.S. vs. rest of world), and baseline EDSS score ( < 4.0 vs. ≥ 4.0).  
Visit will be treated as a repeated variable within a patient.  Patient, treatment and visit 
will be treated as factor variables.  An unstructured variance−covariance structure will be 
applied to model the within-patient errors.  The Restricted Maximum Likelihood method 
(REML) will be used for estimates of variance components.  Denominator degrees of 
freedom will be estimated using Satterthwaite’s approximation. 


 
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To estimate the difference between the ocrelizumab and interferon beta-1a 44 μg SC 
groups in ratio relative to baseline at Week 96, a treatment-by-visit interaction contrast 
will be constructed (i.e., the treatment group contrast at Week 96).  On the basis of this 
analysis, back-transformed estimates of least square means, and the 95% confidence 
interval (CI) for the ratio of timed 25-foot walk at each visit relative to the baseline will be 
reported.  Graphical presentations for least square means and 95% CIs will be used to 
illustrate trends over time. 
Sample SAS code can be found below (SAS code is regarded as “draft” until fully 
validated at the analysis stage): 
proc mixed data=T25FW method=REML; 
 
 
class REGION BEDSSCAT ARMCD VISIT USUBJID; 
 
 
model log(AVAL/BASE) = log(BASE) REGION BEDSSCAT 
ARMCD VISIT log(BASE)*VISIT ARMCD*VISIT / 
 
 
ddfm= satterthwaite; 
 
 
repeated VISIT / type=un subject=USUBJID; 
 
 
lsmeans ARMCD*VISIT / pdiff cl; 
 
 
ods output lsmeans = lsm;  * contains the adjusted means; 
 
 
ods output diffs = dif;  * contains treatment differences; 
 
run; 
  
4.4.3.9.1 
OLE Phase 
This analysis will be extended to include data collected during the OLE period. Ratio 
relative to baseline at all scheduled visits until the last mature visit during the combined 
DB+OLE period and ratio relative to OLE baseline at all scheduled visits until the last 
mature visit during the OLE period will be analyzed. 
4.4.3.10 
Ratio in 9-Hole Peg Test relative to Baseline at Week 96  
The average score of the 9-hole peg test from four trials will be used in this analysis. The 
method for calculating the average score and the imputation method for missing values 
from any of the four trials will be the same as in Section 4.4.2.9.  
All available data at Weeks 12, 24, 36, 48, 60, 72, 84, and 96 will be used for analysis 
regardless of the timing of any protocol-defined relapses.  
The 9-hole peg test will be summarized at baseline and at Weeks 12, 24, 36, 48, 60, 72, 
84, and 96 using descriptive statistics for each treatment group. Data from other 
unscheduled assessments will not be included in this summary or analysis. The change 
from baseline to Weeks 12, 24, 36, 48, 60, 72, 84, and 96 in the 9-hole peg test will be 
computed and summarized using descriptive statistics for each treatment group.  
For the assessment of ratio in the 9-hole peg test relative to baseline up to Week 96, 
MMRM analyses will be undertaken using the same approach as described in 
Section 4.4.3.9.  
Baseline covariates here will be as follows: log-transformed baseline 9-hole peg test, 
geographical region (United States vs. ROW), and baseline EDSS score ( < 4.0 vs. ≥ 4.0). 


 
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4.4.3.10.1 
OLE Phase 
This analysis will be extended to include data collected during the OLE period. Ratio 
relative to baseline at all scheduled visits until the last mature visit during the combined 
DB + OLE period and ratio relative to OLE baseline at all scheduled visits until the last 
mature visit during the OLE period will be analyzed. 
4.4.3.11 
Change in PASAT from Baseline to Week 96  
All available data at Weeks 12, 24, 36, 48, 60, 72, 84 and 96 will be used for analysis, 
regardless of the timing of any protocol-defined relapses.  
The PASAT will be summarized at baseline and at Weeks 12, 24, 36, 48, 60, 72, 84, and 
96 using descriptive statistics for each treatment group. Data from other unscheduled 
assessments will not be included in this summary or analysis.  The change from 
baseline to Weeks 12, 24, 36, 48, 60, 72, 84, and 96 in the PASAT will be computed and 
summarized using descriptive statistics for each treatment group.  
For the assessment of differences in the mean change in the PASAT during the 96-week 
comparative treatment period from baseline up to Week 96, MMRM analyses will be 
undertaken using the same approach as described in Section 4.4.2.9.  
Baseline covariates here will be as follows: Baseline PASAT, geographical region 
(United States vs. ROW), and baseline EDSS score ( < 4.0 vs. ≥ 4.0). 
4.4.3.11.1 
OLE Phase 
This analysis won’t be repeated for the OLE phase as this data is not being collected 
during the OLE period.   
4.4.3.12 
Change in Fatigue, as Measured by the Modified Fatigue 
Impact Scale Total Score from Baseline to Week 96  
The Modified Fatigue Impact Scale (MFIS) measures fatigue effects in terms of physical, 
cognitive, and psychological impact.  A higher score indicates greater impact of fatigue 
on a patient’s activities. 
• 
The Physical Subscale is the sum of items 4, 6, 7, 10, 13, 14, 17, 20, and 21 on the 
MFIS.  Range is 0−36. 
• 
The Cognitive Subscale is the sum of items 1, 2, 3, 5, 11, 12, 15, 16, 18, and 19.  
Range is 0−40. 
• 
The Psychosocial Subscale is the sum of items 8 and 9.  Range is 0−8. 
• 
The Total MFIS score is the sum of all items.  Range is 0−84. 
 
Subscale scores will not be computed for patients with missing items on the subscale.  
Per the developer of the questionnaire, the Total MFIS score may be computed if up to 
two items are missing by first dividing the total score by the number of items answered 
and then multiplying by the number of total items in the scale.  If more than two items are 
missing, the form will be set to missing. 


 
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The MFIS total score will be summarized at baseline and Weeks 48 and 96 using 
descriptive statistics for each treatment group.  Data from other unscheduled 
assessments will not be included in this summary or analysis.  The change from 
baseline to Weeks 48 and 96 in the MFIS total score will be computed and summarized 
using descriptive statistics for each treatment group.  The MFIS subscale scores will only 
be listed. 
For the assessment of differences in the mean change in MFIS total during the 96-week 
comparative treatment period from baseline up to Week 96, MMRM analyses will be 
undertaken using the same approach as described above in Section 4.4.2.9, except 
baseline covariates here will be as follows:  baseline total MFIS score, geographical 
region, and baseline EDSS score ( < 4.0 vs. ≥ 4.0). 
4.4.3.13 
Change in Patient-Reported Depressive Symptoms, as 
Measured by the Center for Epidemiologic Studies Depression 
Scale, from Baseline to Week 96 
The CES-D is a 20-item self-report questionnaire measuring depressive symptomology.  
It includes mood, well-being, somatic, and interpersonal domains. 
Items are scored using the following table: 
Table 3 
Center for Epidemiologic Studies Depression Scale 
CES-D Items 
Rarely or none 
of the time 
Some or a little of 
the time 
Occasionally or a 
moderate amount 
of time 
Most or all of the 
time 
4, 8, 12, and 16 
3 
2 
1 
0 
All other items 
0 
1 
2 
3 
CES-D = Center for Epidemiologic Studies Depression Scale. 
  
A total CES-D score is computed by summing the scored items.  The total score 
ranges 0−60.  If four or fewer items on a patient’s questionnaire are missing, the 
computational mean is used for imputation.  If more than four items are missing, the form 
is set to missing. 
The total CES-D score will be summarized at baseline and Weeks 48 and 96 using 
descriptive statistics for each treatment group.  Data from other unscheduled 
assessments will not be included in this summary or analysis.  The change from 
baseline to Weeks 48 and 96 in total CES-D score will be computed and summarized 
using descriptive statistics for each treatment group. 
For the assessment of differences in the mean change in total CES-D score during the 
96-week comparative treatment period from baseline up to Week 96, an MMRM analysis 
will be undertaken using the same approach as described in Section 4.4.2.9, except 
baseline covariates here will be as follows:  baseline total CES-D score, geographical 
region (United States vs. ROW), and baseline EDSS score ( < 4.0 vs. ≥  4.0). 


 
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4.4.3.14 
Change in Karnofsky Performance Status Score from Baseline 
to Week 96 
The Karnofsky Performance Scale allows for the classification of patients according to 
their functional impairment.  This scale is usually used to compare effectiveness of 
different therapies and to assess the prognosis in individual patients.  The Karnofsky 
score ranges 100−0, where 100 is “perfect” health (normal, no complaints, or no 
evidence of disease) and 0 is death.  Scores at 10-point intervals between 100 and 0 are 
assigned to represent health status. 
The Karnofsky Performance Status Score will be summarized at baseline and Weeks 
24, 48, 72, and 96 using descriptive statistics for each treatment group.  Data from other 
unscheduled assessments will not be included in this summary or analysis.  The change 
from baseline to Weeks 24, 48, and 96 in Karnofsky Performance Status Score will be 
computed and summarized using descriptive statistics for each treatment group (i.e., 
frequency counts or summary statistics, as appropriate). 
For the assessment of differences in the mean change in Karnofsky Performance Status 
Score during the 96-week comparative treatment period from baseline up to Week 96, 
an MMRM analysis will be undertaken using the same approach as described in 
Section 4.4.2.9, except baseline covariates here will be as follows:  baseline Karnofsky 
Performance Status Score, geographical region (United States vs. ROW), and baseline 
EDSS score ( < 4.0 vs.  ≥ 4.0). 
4.4.3.15 
Percentage Change in Cortical Grey Matter Volume as Detected 
by Brain MRI from Baseline to Week 96 
Cortical grey matter volume as assessed on MRI scans of the brain will be summarized 
at baseline and Weeks 24, 48, and 96 using descriptive statistics for each treatment 
group.  Data from other unscheduled assessments will not be included in this summary 
or analysis.  The percentage change from baseline to Weeks 24, 48, and 96 in cortical 
grey matter volume on MRI scans of the brain will be computed and summarized using 
descriptive statistics for each treatment group. 
For the assessment of differences in the mean percentage change in cortical grey matter 
volume on MRI scans during the 96-week comparative treatment period from baseline 
up to Week 96, an MMRM analysis will be undertaken using the same approach as 
described in Section 4.4.2.9, except baseline covariates here will be as follows:  baseline 
cortical grey matter volume, geographical region (United States vs. ROW), and baseline 
EDSS score ( < 4.0 vs.  ≥ 4.0). 
4.4.3.15.1 
OLE Phase 
This analysis will be extended to include data collected during the OLE period. 
Percentage change from Week 24, baseline and OLE baseline until the last mature visit 
will be analyzed. 


 
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4.4.3.16 
Percentage Change in White Matter Volume as Detected by 
Brain MRI from Baseline to Week 96 
White matter volume as assessed on MRI scans of the brain will be summarized at 
baseline and Weeks 24, 48, and 96 using descriptive statistics for each treatment group.  
Data from other unscheduled assessments will not be included in this summary or 
analysis.  The percentage change from baseline to Weeks 24, 48, and 96 in white matter 
volume on MRI scans of the brain will be computed and summarized using descriptive 
statistics for each treatment group. 
For the assessment of differences in the mean percentage change in white matter 
volume on MRI scans during the 96-week comparative treatment period from baseline 
up to Week 96, an MMRM analysis will be undertaken using the same approach as 
described above in Section 4.4.2.9, except baseline covariates here will be as follows:  
baseline white matter volume, geographical region (United States vs. ROW), and 
baseline EDSS score ( < 4.0 vs. ≥ 4.0). 
4.4.3.16.1 
OLE Phase 
This analysis will be extended to include data collected during the OLE period. 
Percentage change from Week 24, baseline and OLE baseline until the last mature visit 
will be analyzed.  
4.4.3.17 
Proportion of Patients who Have Disability Improvement 
Sustained for At Least 24 Weeks with the Initial Event of 
Neurological Improvement Occurring during the 96-Week, 
Double-Blind, Double-Dummy Treatment Period 
This endpoint is the same as the 12-week confirmed disability improvement endpoint 
(refer to Section 4.4.2.6), but based on a 24-week period of disability improvement. 
The same approach to analysis as described in Section 4.4.2.6 will be applied to the 
24−week confirmed disability improvement endpoint. 
4.4.3.17.1 
OLE Phase 
This analysis will be repeated to include the EDSS assessments performed during the 
OLE period for the combined DB + OLE period, with the same baseline as for the 
analysis during DB.  Analysis containing only data from OLE will be performed 
considering the OLE baseline. 
4.4.3.18 
Proportion of Patients Who have Disability Improvement 
Sustained for at Least 12 Weeks and Sustained until the End of 
the 96-Week, Double-Blind, Double-Dummy Treatment Period, 
with the Initial Event of Neurological Improvement Occurring 
during the 96-Week, Double-Blind, Double-Dummy Treatment 
Period 
This endpoint is similar to the 12-week confirmed disability improvement endpoint (see 
Section 4.4.2.6), but it is required that improvement is sustained until the end of the 96-


 
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week double-blind double-dummy treatment period.  Otherwise, patients will be 
classified as not improved. 
The same approach to analysis as described in Section 4.4.2.6 will be applied here. 
4.4.3.19 
Duration of Confirmed Disability Improvement 
This analysis will be performed for the patients with a Confirmed Disability Improvement 
for 12 weeks identified as in Section 4.4.2.6. 
The duration of the Confirmed Disability Improvement is the time from the date of onset 
of the event, until the first visit where the EDSS score no longer fulfills the criteria for 
disability improvement.  For the patients who have a sustained improvement until after 
the end of the double-blind treatment period, the duration of the confirmed disability 
improvement will be censored at the last EDSS score measured during the 96 week, 
double-blind, double-dummy treatment period.  For patients with the onset of the CDI at 
the last visit during this period and confirmed in the open-label or safety follow-up phase, 
the duration of the CDI will be censored at Day 1.  The Kaplan-Meier estimates of the 
duration of CDI will be calculated.  No comparison between the randomized arms will be 
made, since this analysis is performed only for the patients with a CDI.  
4.4.3.20 
Proportion of Patients Who at Week 96 Have Improved, Stable 
or Worsened Disability, Compared with Baseline 
Stable disability is defined as a difference in EDSS score of no greater 
than  ± 0.5 comparing the Week 96 and baseline scores.  Worsened disability is defined 
as an increase in EDSS score of > 0.5 at Week 96 compared to baseline.  Improved 
disability is defined as a reduction in EDSS score of > 0.5 at Week 96 compared with 
baseline.  The proportion of patients with improved, stable, or worsened disability 
compared with baseline in each treatment group will be reported.  In addition, the 
proportion of patients with improved or stable disability (combining the proportion or 
patients improved and the proportion stable) in each treatment group will be reported. 
Patients with missing EDSS data at baseline or Week 96 are excluded from this 
analysis.  Interval EDSS scores are not taken into account in this analysis. 
The proportions with improved, stable, and worsened disability within treatment groups 
will be analyzed using multinomial logistic regression with baseline covariates, 
geographical region (United States vs. ROW), and baseline EDSS score ( < 4.0 
vs.  ≥ 4.0). 
4.4.3.21 
Change in EDSS Score from Baseline to Week 96 
The EDSS scores will be summarized at baseline (without rounding) and Weeks 48 and 
96 using descriptive statistics for each treatment group.  Data from other unscheduled 
assessments will not be included in this summary or analysis.  The change from 
baseline to Weeks 48 and 96 in EDSS scores will be computed and summarized using 
descriptive statistics for each treatment group. 


 
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For the assessment of differences in the mean change in EDSS score during the 96-
week comparative treatment period from baseline up to Week 96, MMRM analyses will 
be undertaken using the same approach as described above in Section 4.4.2.9, except 
baseline covariates here will be as follows:  geographical region (United States vs. 
ROW) and baseline EDSS (continuous without rounding). 
Graphical presentations for least square means and 95% confidence intervals will be 
used to illustrate trends over time. 
4.4.3.21.1 
OLE Phase 
This analysis will be extended to include data collected during the OLE period. Change 
from baseline at all scheduled visits until the last mature visit during the combined 
DB + OLE period and change from OLE baseline at all scheduled visits until the last 
mature visit during the OLE period will be analyzed. 
4.4.3.22 
Change in Quality of Life, as Measured by the Short Form 36 
Version 2 Mental Component Summary Score from Baseline to 
Week 96 
The derivation of the SF-36 MCS Score was described previously in Section 4.4.2.11. 
The MCS Score will be summarized and analyzed in exactly the same way as the SF-
36 PCS Score, as described in Section 4.4.2.11. 
4.4.3.22.1 
OLE Phase 
Additional data from the OLE period will be descriptively analyzed. 
4.4.3.23 
Ratio in Total T2 Lesion Volume as Detected by Brain MRI 
Scans relative to Baseline at Week 96 
The total volume of T2 lesions on MRI scans of the brain will be summarized at baseline 
and Weeks 24, 48, and 96 using descriptive statistics for each treatment group. Data 
from other unscheduled assessments will not be included in this summary or analysis. 
The percentage change from baseline to Weeks 24, 48, and 96 in total volume of T2 
lesions on MRI scans of the brain will be computed and summarized using descriptive 
statistics (e.g., mean, SD, median, minimum, maximum, and n) for each treatment 
group. 
For the assessment of ratio in total T2 lesion volume relative to baseline up to Week 96, 
MMRM analyses will be undertaken using the same approach as described above in 
Section 4.4.3.9, except the baseline covariates here will be as follows: log-transformed 
baseline T2 lesion volume, geographical region (U.S. vs. ROW), and baseline EDSS 
score ( < 4.0 vs. ≥ 4.0). 
All T2 lesion volumes below the lower limit of quantification of 0.009 cm3 (3 ,voxels) will 
be set to this limit. 


 
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4.4.3.23.1 
OLE Phase 
This analysis will be extended to include data collected during the OLE period. Ratio 
relative to baseline at all scheduled visits until the last mature visit during the combined 
DB + OLE period and ratio relative to OLE baseline at all scheduled visits until the last 
mature visit during the OLE period will be analyzed. 
4.4.3.24 
Ratio in Total T1 Lesion Volume as Detected by Brain MRI 
Scans relative to Baseline at Week 96 
The total volume of T1 lesions on MRI scans of the brain will be summarized at baseline 
and Weeks 24, 48, and 96 using descriptive statistics for each treatment group.  Data 
from other unscheduled assessments will not be included in this summary or analysis.  
The percentage change from baseline to Weeks 24, 48, and 96 in total volume of T1 
lesions on MRI scans of the brain will be computed and summarized using descriptive 
statistics (e.g., mean, SD, median, minimum, maximum, and n) for each treatment 
group. 
For the assessment of ratio in total T1 lesion volume relative to baseline up to Week 96, 
MMRM analyses will be undertaken using the same approach as described above in 
Section 4.4.3.9, except the baseline covariates here will be as follows: log-transformed 
baseline T1 lesion volume, geographical region (U.S. vs. ROW), and baseline EDSS 
score ( < 4.0 vs. ≥ 4.0).  
All T1 lesion volumes below the lower limit of quantification of 0.009 cm3 (3 ,voxels) will 
be set to this limit. 
4.4.3.24.1 
OLE Phase 
This analysis will be extended to include data collected during the OLE period. Ratio 
relative to baseline at all scheduled visits until the last mature visit during the combined 
DB + OLE period and ratio relative to OLE baseline at all scheduled visits until the last 
mature visit during the OLE period will be analyzed. 
4.4.3.25 
Time to Onset of Composite Confirmed Disability Progression 
(cCDP) for at Least 12 Weeks and at Least 24 Weeks 
Time to onset of cCDP over the double-blind treatment period, defined as an increase in 
EDSS that is sustained for at least 12/24 weeks (0.5 or 1, same criteria as for the 
secondary endpoint time to onset of 12/24-weeks CDP) or a 20 percent increase in T25-
FW that is sustained for at least 12/24 weeks or a 20 percent increase in 9-HPT that is 
sustained for at least 12/24 weeks.  These analyses will be performed for the double-
blind period only. 
4.4.3.26 
Change in EuroQoL 5 Dimension 3 Levels (EQ-5D-3L) VAS and 
Index from Baseline to Week 48 and Week 96 
The EQ-5D questionnaire comprises the following 5 dimensions, each describing a 
different aspect of health: mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression.  Each dimension has three levels: no problems (1), some problems 


 
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(2) and extreme problems (3). This part, called the EQ-5D descriptive system, provides a 
5-dimensional description of health status. 
A unique health state is defined by combining one level from each of the 5 dimensions. 
A total of 243 possible health states is defined in this way.  Each state is referred to in 
terms of a 5-digit code.  For example, state 11111 indicates no problems on any of the 5 
dimensions, while state 11223 indicates no problems with mobility and self-care, some 
problems with performing usual activities, moderate pain or discomfort and extreme 
anxiety or depression. The EQ-5D-3L health state is then converted into a single 
summary number, the EQ-5D-3L index value, using validated translations provided by 
EuroQoL that can be found in the EuroQoL website (https://euroqol.org/eq-5d-
instruments/eq-5d-3l-about/valuation/).  The EQ-5D-3L index is frequently used in 
economic evaluations: it represents societal preference values for the full set of EQ-5D-
3L health states with the best state (perfect health) and death being assigned values of 1 
and 0, respectively. 
The United Kingdom value set of this questionnaire will be used for all participants 
regardless of their country.  
The EQ-5D-3L descriptive system is followed by a VAS (EQ VAS), which records the 
respondent’s self-rated health ranging from 0 (worst imaginable health state) to 100 
(best imaginable health state).  
The EQ-5D-3L index score and VAS score will be summarized at baseline and Weeks 
48 and 96 using descriptive statistics for each treatment group.  The change from 
baseline to Weeks 48 and 96 will be also presented. 
4.4.3.26.1 
OLE Phase 
This analysis will be extended to include data collected during the OLE period.  Change 
from baseline at all scheduled visits until the last mature visit during the combined 
DB + OLE period will be analyzed. 
4.4.3.27 
NfL 
NfL data collected during the double-blind and open label phase will be summarized 
descriptively.  Summary statistics of the absolute NfL values will be presented at all 
scheduled visits along with the percentage change from baseline.  A corresponding plot 
will be produced.  The analyses will be performed for the DB period only as well as for 
the combined DB + OLE period.  
4.4.4 
Subgroup Analyses 
The primary and some secondary efficacy endpoints (12 and 24 week CDP) will be 
summarized and analyzed by the following subgroups: 
• 
Demography:  age ( ≥ 40 vs. < 40 years) 
• 
Demography:  sex (male vs. female) 


 
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• 
Demography:  race (White vs. Other) 
• 
Body weight:  ≥ 75 kg versus < 75 kg 
• 
Stratification factor:  geographical region (United States vs. ROW) 
• 
Stratification factor:  baseline EDSS score ( < 4.0 vs. ≥ 4.0) 
• 
Previous lesions:  baseline Gd-enhancing lesion (0 vs. >  0) 
 
Estimates of treatment effect and associated 95% CIs will be presented in forest plots.  
Unadjusted p-values will also be presented for these analyses. 
4.4.4.1 
Efficacy Data from the Safety Follow-Up Phase 
Exploratory analyses of efficacy data collected in the safety follow-up phase are not 
envisioned. 
4.5 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
4.5.1 
Pharmacokinetic Analyses 
Ocrelizumab serum concentration−time data will be analyzed using a population 
approach.  The primary population PK parameters (clearances and volumes) for 
ocrelizumab will be estimated by means of a non-linear mixed effect model fitted to the 
PK data collected in studies WA21092, WA21093, and WA21493.  Clearances with 
associated inter-patient variability may be characterized by a saturable and non-
saturable clearance as well as an intercompartmental clearance depending on the final 
structural model.  Volumes with associated inter-patient variability may be characterized 
by central and peripheral volumes depending on the final structural model.  Exposure 
(area under the concentration−time curve [AUC]) to ocrelizumab will be estimated.  The 
selection of other parameters will depend on the final PK model used for this analysis.  
Patients who have measurable concentrations of ocrelizumab will be included in the PK 
analysis unless major protocol deviations or unavailability of information (e.g., exact 
blood sampling time) occurred that may interfere with PK evaluation.  The influence of 
covariates, such as age, gender, weight, ADA, and baseline CD19 + cell count on these 
individual PK parameter estimates will be investigated. 
Details will be described in a Modeling and Simulation Analysis Plan, and results will be 
reported separately from the main CSR.  
4.5.2 
Pharmacodynamic Analyses 
The correlation between individual ocrelizumab exposure and selected safety and 
efficacy parameters will be explored in order to characterize the exposure and /or dose-
response relationship.  This may include but is not limited to CD19 + cell count, ARR, 
infusion-related reactions (IRRs), serious infections, and other safety or efficacy 
parameters if of interest.  Any such analyses will be reported separately in the PK report. 


 
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4.6 
SAFETY ANALYSES 
Safety data include but are not restricted to adverse event data, laboratory data, 
previous and concomitant treatment data, infusion information including IRR data, 
withdrawal data, fatalities, ECG, vital signs, ADA data, and dosing information. 
This SAP describes the analyses of all available safety data collected until the end of the 
trial.  The safety data will be summarized descriptively for the DBP, OLE and SFU 
periods: 
4.6.1 
Exposure of Study Medication 
This section deals with exposure in the context of safety analyses.  In the context of 
efficacy analyses, exposure time is as defined above in Section 4.4. 
Exposure of ocrelizumab/ocrelizumab placebo and interferon beta-1a 44 μg SC / 
interferon beta-1a 44 μg SC placebo over the course of the study will be summarized 
using descriptive statistics. 
“Duration of Observation” and “Duration of Exposure” are used interchangeably within 
this SAP. 
Definition of the Dose:  A Dose of ocrelizumab can be given as one infusion or two 
infusions administered 2 weeks apart. 
Patients will be considered to have received a Dose of treatment if at least part of one 
infusion of that Dose (either Day 1 or Day 15 for dual infusions) was given.  If a Dose is 
completely missed instead of delayed, the next Dose number will be based on the 
number of previous doses received. 
The duration of observation for a patient will be calculated as: 
(Date of last contact* − date of first Dose) + 1 
 
* Earliest of 1) date of CCOD for the reporting event, 2) date of last contact from the 
study completion page, or 3) date of death. 
For the controlled treatment period, the CCOD will be variable for each patient at 
96 weeks from treatment.  
For patients who are receiving interferon beta-1a 44 µg SC and who switch to active 
ocrelizumab treatment, exposure of interferon beta-1a 44 µg SC will end on the study 
day prior to their first active Dose of ocrelizumab. 
The duration of observation, within a Dose is defined in a similar manner as: 
 
(Day prior to first infusion in n + 1th Dose* − date of first infusion in nth Dose) + 1 


 
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*With the exception of the last Dose received by the patient where date of last contact is 
used as defined above. 
Exposure to ocrelizumab and exposure to interferon beta-1a 44 µg SC during the 
controlled treatment phase will be summarized.  For ocrelizumab, the treatment duration, 
number of infusions received, and the total cumulative dose (derived to mg) will be 
summarized by study treatment arm.  An additional summary will be presented, 
summarizing at each infusion the percentage of patients who received < 80% and ≥ 80% 
of the planned infusion.  The number and percentage of infused patients who were pre-
treated with steroids will be summarized.  For interferon beta-1a 44 µg SC, the number 
of Doses and dose intensity (based on the number of syringes received rather than the 
actual Dose) will be presented by study treatment arm. 
4.6.2 
Columbia-Suicide Severity Rating Scale  
The number and percentage of patients with suicidal ideation, suicidal behavior, and 
self-injurious behavior without suicidal intent at any time after the start of study 
treatment, based on the Columbia Suicide Severity Rating Scale (C-SSRS), will be 
presented.  In addition, shift tables will be presented to show changes from baseline in 
C-SSRS categories.  A listing of patients with suicidal ideation, suicidal behavior, or self-
injurious behavior, based on the C-SSRS, will be presented. 
4.6.3 
Adverse Events 
Adverse events will be defined as all adverse events including IRRs and serious 
MS relapses, but excluding non-serious MS relapses.  Therefore, those adverse events 
recorded on the “adverse event” and “infusion-related reaction” CRF pages will be 
included. 
For each adverse event recorded, the term entered by the investigator describing the 
event (the “reported term”) will be assigned a standardized term (the “preferred term” 
[PT]) based on the Medical Dictionary for Regulatory Activities (MedDRA) World Health 
Organization (WHO) dictionary of terms.  All analyses of adverse event data will be 
performed using the PTs unless otherwise specified. 
All adverse events will be mapped to PTs and super class terms.  For all summary 
tables, the adverse events will be sorted by body system (in decreasing order of overall 
incidence) and then by PT (in decreasing order of overall incidence).  Additionally, the 
most frequent adverse events ( ≥ 5% in any treatment arm) will be presented by PT. 
Adverse events will be assigned to a Dose if the adverse event onset date is on or after 
the date of the first infusion of that Dose, but before the first infusion of the next 
treatment Dose.  Adverse events that are reported during the safety follow-up period or 
B-cell monitoring period will be assigned to the last Dose received.  Hence the last Dose 
for a patient may be of a variable length from 24 to 72 weeks or longer.  Adverse events 


 
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that start prior to the first Dose and worsen during treatment (i.e. treatment emergent) 
will be assigned to the first treatment Dose. 
All summaries and listings of adverse events will be based on the safety population 
unless otherwise stated.  Summaries of adverse events will be generated by 
summarizing the incidence of treatment-emergent adverse events only.  Treatment-
emergent events are defined as those adverse events with observed or imputed onset 
date on or after the start date of study treatment.  Only where the most extreme intensity 
is greater than the initial intensity will events with an onset date prior to the start of study 
treatment (and with an end date on or after the start of study treatment) be considered 
treatment emergent.  An adverse event with a completely missing non-imputed start date 
will be assumed to be treatment emergent unless the adverse event has a complete 
non-imputed end date that is prior to start of study treatment.  
For each treatment group, the incidence count for each adverse event PT will be defined 
as the number of patients reporting at least one treatment emergent occurrence of the 
event.  The incidence rate will be calculated as the incidence count divided by the total 
number of patients in the population.  Each table will also present the overall number of 
patients experiencing at least one adverse event and the total number of adverse events 
reported (multiple occurrences of the same adverse event in 1 patient will be counted 
only once). 
The number of patients who experienced a related adverse event will be summarized by 
system organ class (SOC) and PT.  Adverse events will be summarized by SOC and PT 
by intensity grade.  Multiple occurrences of the same event within a patient will be 
counted once at the greatest intensity/highest grade for this PT.  For adverse events 
leading to death, the most extreme intensity will be overwritten by Grade 5 (death).  Any 
adverse events and the SOC overall rows of the summary table will count patients 
according to adverse events by intensity/grades. 
All patient deaths, regardless of treatment received, will be listed. 
Serious adverse events will be defined as all serious adverse events including serious 
MS relapses and serious IRRs.  The number of patients who experienced a serious 
adverse event will be summarized by SOC and PT.  Related serious adverse events will 
be summarized by SOC and PT.  Additionally, the most frequent serious adverse events 
( ≥ 1%) will be presented by PT. 
A separate listing with relapses considered as serious adverse events will be presented. 
A patient may experience an adverse event that leads to the discontinuation of their 
study treatment.  Discontinuation of study treatment for an adverse event may not 
necessarily lead to discontinuation from the study because patients can enter the safety 
follow-up periods of the protocol.  Only adverse events that led to the discontinuation of 


 
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study treatment are of interest.  Patients who withdraw early from the study because of 
adverse events will be summarized under disposition.  Because of the double-dummy 
design, the study-drug regimen consists of more than one combination of two treatments 
(ocrelizumab and interferon beta-1a 44 μg SC).  An analysis of adverse events leading 
to study drug discontinuation will not be performed for the individual treatments of the 
regimen within one study arm, because the investigators were instructed to discontinue 
both treatments.  The number of patients who experienced an adverse event that led to 
discontinuation of study treatment will be summarized by SOC and PT. 
The number of patients who experienced an adverse event that led to modification or 
interruption of study drug will be summarized by SOC and PT. 
4.6.3.1 
Selected Adverse Events 
Infection 
Infections will be defined from the adverse event data using the MedDRA SOC of 
“Infections and Infestations.”  During Primary CSR, adverse events that are reported as 
an infection by the investigator will also be included. 
During Primary CSR, an infection has been defined as serious if the event is a serious 
adverse event or if the non-serious infection was treated with an IV anti-infective. For 
subsequent reporting, an infection has been defined as serious if the event is a serious 
adverse event. 
The number of infections and serious infections per 100 patient-years will be calculated 
and summarized separately.  The ninety-five percent CI of the incidence rates will be 
calculated using exact method based on Poisson distribution. 
Summary of infections will be presented by SOC and PT, severity, and Dose. Similar 
summary tables will be also produced by serious infections. 
Summary tables of infections and serious infections by pathogen information codes as 
well as listing of infections/serious infections with pathogen codes will be produced. 
Infusion-Related Reactions 
An IRR and its corresponding symptoms are collected on the dedicated eCRF. 
The symptom(s) of an IRR and the IRR itself may be of different intensities.  As other 
symptoms can be recorded as free-text on the eCRF page, symptoms will be coded in 
the MedDRA and summarized by PTs. 
IRRs are categorized by the time of the event occurring (1) during the infusion, (2) after 
completion of the infusion while patient is in the clinic, and (3) within 24 hours of 
completion of the infusion and patient is not in the clinic.  The number and percentage of 
patients with at least one IRR will be presented by infusion (patients with multiple events 
within an infusion will count only once).  In addition, the total number of IRRs will be 


 
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summarized (multiple events will be counted).  The total and percentage (based on the 
total number of patients with at least one IRR) will be summarized by most extreme 
intensity. 
IRRs will be summarized by intensity and by infusion.  For multiple events within a 
patient, the most extreme intensity will be taken. 
Symptoms of IRR and symptoms of serious IRR will also be presented by infusion.  This 
analysis will be produced for both the controlled treatment period and the OLE period.  
The number of patients with at least one IRR, the total number of IRRs, and the number 
of IRRs will be summarized by the time of events.  
Pregnancies 
Any pregnancies that occur during the study will be listed. 
4.6.4 
Magnetic Resonance Imaging Data 
Non-MS pathology that is reported by the local safety radiologist will be listed by 
treatment group. 
4.6.5 
Laboratory Data 
General laboratory evaluation  
All laboratory assessments will be summarized or listed when applicable. 
Absolute value and change from baseline values at each visit will be summarized.  The 
baseline value will be the last value prior to the first dose of study medication.  When 
laboratory data are presented over time, these laboratory values will be time-windowed 
into a common visit structure.  If multiple values of the same laboratory parameter occur 
within the same time window, the worst value for that parameter will be presented in the 
summary table. 
A summary of the number and percentage of patients with abnormal laboratory 
outcomes will be produced by treatment group for each parameter. 
In addition, for the liver laboratory parameters, the number and percentage of patients 
with an elevated post-baseline AST or ALT level during the 96-week controlled treatment 
period will be summarized by treatment. 
CD19 
The median CD19 cell count will be displayed graphically over time from the first infusion 
of study medication.  The absolute CD19 count and change from baseline in the CD19 
count will be summarized over time.  At each timepoint, the number and percentage of 
patients whose CD19 counts have repleted will be presented.  Repletion is defined as 
the CD19 count having returned to their baseline value or lower limit of normal 
(≥ 80 cells/μL), whichever is lowest. 


 
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Immunoglobulins  
The mean immunoglobulin levels (IgG, IgM, and total Ig) will be displayed graphically 
over time from the first infusion of study medication.  The absolute values and change 
from baseline will be summarized over time.  At each timepoint, the number and 
percentage of patients with immunoglobulin levels lower than the lower limit of normal 
will be presented.  
Anti-Drug Antibodies 
Anti-drug antibodies (ADAs), also called human anti-human antibodies (HAHAs), will be 
summarized over the 96-week controlled treatment period by treatment group.  The 
baseline prevalence and post-baseline incidence of ADAs will be displayed.  The 
number of patients with treatment-induced ADA will also be displayed.  A table will be 
presented that summarizes ocrelizumab serum concentrations (µg/mL) at timepoints 
where ADA samples were collected and analyzed.  A listing by treatment of anti-
ocrelizumab antibody data will be presented for patients with at least one ADA sampled 
datum. 
Antibody Titers 
If data are available, antibody titers for mumps, rubella, varicella, and Streptococcus 
pneumoniae will be summarized for number and percentages of patients with positive 
level. 
For Mumps, an assay method was updated due to bacterial contamination in tubes. And, 
results from both the assay methods, Diamedix Elisa and Diasorin Liaison XL to be 
presented for OLE Phase.  
4.6.6 
Vital Signs 
Vital signs, physical examination, and ECG results will be presented in patient listings.  
Change from study baseline in vital signs at each visit will be summarized by treatment 
group.  Changes in vital signs from baseline to post-infusion timepoints will also be 
summarized for each infusion. 
4.6.7 
Safety by Treatment and Period 
To explore safety by treatment and period, all of the available safety data will be 
presented by treatment regimen and by period (i.e., All periods and OLE period 
separately, as appropriate). 
The adverse event profile will be produced by treatment regimen for each period 
separately.  The number of events per 100 patient-years will be presented to account for 
differing amounts of exposure.  
Adverse events and serious adverse events will be presented by SOC and PTs for each 
period separately.  Also, infection and serious infection will be presented by SOC and 
PTs for overall as well as each period separately. 


 
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4.6.8 
Double-Blind Period 
All safety data prior to the first active dose of ocrelizumab in OLE will be presented by 
the actual treatment received during the DB period, including the SFU data post-Week 
96 until the start of OLE and SFU data post-Week 96 for patients who withdrew during 
the double-blind period.   
4.6.9 
OLE Period 
All data collected after the first dose of OLE ocrelizumab will be presented by the actual 
treatment received during the DB period, including all SFU and B-cell monitoring data for 
patients who withdraw during the OLE.  Some of the analyses performed for the double-
blind treatment period will be repeated and updated for the safety endpoints collected 
during the OLE period.  In general, AE, SAE profile, infections, serious infections, IRRs, 
conmeds and laboratory analysis such as CD19, Immunoglobulins will be presented. 
Analyses pooling all safety data from the first dose of ocrelizumab (double blind and 
OLE periods) across multiple MS trials are described separately in a Global Safety 
Pooling SAP. 
4.6.10 
Type I Interferon-Neutralizing Antibody Data 
Type I interferon-neutralizing antibody data will be summarized in listings and additional 
analysis will be performed as appropriate. 
4.6.11 
COVID-19 analyses:  
In line with the guidance from the Sponsor and health authorities, several patient listings 
and summaries will be prepared in order to assess the impact of the COVID-19 
pandemic on the study conduct and results.  Summaries and listings will be prepared for 
major protocol deviations due to the pandemic, patients infected with COVID-19 and 
AEs & death associated with COVID-19.  Further details will be provided in the COVID-
19 CSR Appendix. 
4.7 
MISSING DATA 
All methods for handling missing data and associated sensitivity analyses are described 
above, section by section, for each endpoint. 
4.8 
INTERIM ANALYSES 
Updated efficacy analysis of additional data from OLE period are performed on a yearly 
basis after the CSR primary database lock.  Regular safety updates are assessed in 
safety pooling analysis from multiple studies. 
 
 


 
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5. 
REFERENCES 
Barkhof F, Calabresi PA, Miller DH, et al. Imaging outcomes for neuroprotection and 
repair in multiple sclerosis trials. Nat Rev Neurol 2009; 5:256−266. 
Bohannon RW. Comfortable and maximum walking speed of adults aged 20−79 years: 
reference values and determinants. Age Ageing 1997;26:15−19. 
Carpenter JR, Kenward MG. Missing data in randomised controlled trials:  A practical 
guide. 2007. Final report available at 
http://missingdata.lshtm.ac.uk/downloads/rm04_jh17_mk.pdf. 
Oxford Grice KA, Vogel KA, Le V, et al. Adult Norms for a Commercially Available Nine 
Hole Peg Test for Finger Dexterity. Am J Occup Ther 2003;57:570−3. 
 
 


 
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Appendix 1 Standard Operating Procedure “EDSS Assessment 
Check for the Roche Trials WA25046, WA21092, and WA21093” 




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TABLE OF CONTENTS 
1. 
AIM .................................................................................................. 3 
2. 
BACKGROUND .............................................................................. 3 
3. 
PROCESSES .................................................................................. 4 
3.1 
Flow Chart on query resolution (detail in 3.3) ............................ 4 
3.2 
Roles & Responsibilities ............................................................ 5 
3.3 
Reporting and Review Process in written form .......................... 6 
3.4 
Handling of EDSS assessments checked prior to the 
implementation of the process outlined in this SOP ................... 8 
4. 
GLOSSARY & DEFINITIONS ......................................................... 8 
5. 
REFERENCES.............................................................................. 10 


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1. 
AIM 
The aim of this SOP is to describe the process and the roles and responsibilities for the 
review of the Expanded Disability Status Scale (EDSS) assessments.  In addition this 
SOP further outlines how to detect and handle inconsistent EDSS assessments and 
John Kurtzke’s Functional Systems scores (FSS) in the Roche pivotal Multiple Sclerosis 
trials WA25046, WA21092 and WA21093 according to ICH guidelines. 
2. 
BACKGROUND 
Currently, John Kurtzke’s Functional Systems and the EDSS are the most widely 
accepted clinical outcome measures for the evaluation of neurological impairment and 
disability in Multiple Sclerosis (MS) clinical trials.  The determination of the EDSS step is 
primarily based on the individual scores of the 7 Functional Systems including visual, 
brainstem, pyramidal, cerebellar, sensory, bowel and bladder, and cerebral, as well as 
on the walking range and the assistance needed to ambulate (Kurtzke JF et al. 1955; 
Kurtzke JF 1983).  During the past years standardized training programs and 
certification of EDSS evaluating physician (EDSS assessor) have been developed and 
introduced to improve inter-rater and intra-rater reliability.  For the Roche trials 
WA25046, WA21092 and WA21093 the EDSS step is assessed by trained neurologists 
who refer to the Neurostatus definitions in the booklet version of 04/10.2 
(www.Neurostatus.net).  Between Jan 1, 2011 and Jan 31, 2012 University Hospital 
Basel (USB) Experts reviewed 1082 EDSS assessments rated by 267 examining 
investigators at 160 study sites participating in the Roche trials WA25046, WA21092 and 
WA21093.  They found in 23% of the cases inconsistencies in the last step of the 
assessment, namely the combination of the Functional Systems and the ambulation 
scores to the final EDSS step.


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3. 
PROCESSES 
3.1 
FLOW CHART ON QUERY RESOLUTION (DETAIL IN 3.3) 


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3.2 
ROLES & RESPONSIBILITIES 
 
Responsible 
Role 
EDSS Evaluating Physician 
Examining investigator / EDSS 
assessor who performs the neurological examination, 
documents the FS scores and assess EDSS steps. The 
examining Investigator will not be involved with any 
aspect of medical 
management of the patient and will not have access to 
patient data. 
CRF Health (CRFHealth eCOA 
Solutions Company) 
Provider of the TrialSlate and 
associated web portal (TrialManager). CRF Health is 
responsible for processing all data clarification forms 
(TrialDCFs) related to the EDSS assessment captured 
in the TrialManager. 
Neurostatus Systems GmbH 
Company responsible for the technical and 
administrative 
implementation of training and certification of physicians 
participating in projects using EDSS in multiple 
sclerosis. 
 
Neurostatus Systems is responsible to check for 
plausibility and inconsistencies of the EDSS 
assessments. 
USB Expert 
USB Experts are medical doctors working at the 
Department of Neurology of the USB specialized in the 
assessments of the EDSS. For contracts see 
attachment. Prof 
 has the oversight of the Expert 
Review process. He will appoint a named person as 
one of the USB Experts who will act as a single point of 
contact for Roche. 
 
USB expert are reviewing EDSS 
assessment of the scoring sheet. 
 
The USB expert is responsible for the content of the 
TrialDCFs. 
 
The USB expert is responsible for being available via 
email / telephone in order to respond to questions by 
the EDSS physician. 
Monitor/CRA 
Clinical Research Associate employed by a Clinical 
Research Organisation (CRO). 
 
Monitor / CRA log into TrialManager to check for 
TrialDCFs and to notify sites that a response is required 
from the examining investigator. 


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Roche Study Management Team 
(SMT) 
The Study Management Team 
(SMT) reviews unresolved TrialDCFs and decides to 
close or continue to follow up the outstanding TrialDCFs 
 
3.3 
REPORTING AND REVIEW PROCESS IN WRITTEN FORM 
Step 1: EDSS assessment by the examining investigator at the study sites 
Functional system score, ambulation score and EDSS step (EDSS assessment) are 
assessed by examining investigators based on a standardized neurological examination 
using the Neurostatus Scoring booklet, version 04/10.2.  These data are captured by 
using TrialSlate (an electronic data capturing device). Range checks are performed 
during data entry onto the device.  The data are then transferred via LAN or Mobile 
network to TrialManager web portal (the database). 
Step 2: Automated Consistency Check 
Neurostatus Systems checks the data on TrialManager for plausibility and 
inconsistencies of the EDSS using automated consistency checks.  The rules for these 
checks are given in the Neurostatus Scoring booklet, version 04/10.2.  A scoring sheet 
consisting of the results of the EDSS assessments is generated by Neurostatus and 
uploaded to TrialManager.  The scoring sheet will flag inconsistencies in the EDSS 
assessment. 
If the scoring sheet doesn’t identify inconsistencies, the assessment remains unchanged 
in TrialManager. 
Step 3: Manual consistency check 
The USB expert will review the scoring sheet with the EDSS assessments within 2 
working days from upload to TrialManager. 
The EDSS assessments with flagged inconsistencies in the scoring sheet are manually 
reviewed by the USB Expert. 
– 
If after review by the USB expert, the flagged EDSS assessment is determined to be 
consistent then it will remain on TrialManager unchanged. 
– 
If after review by the USB expert, the flagged EDSS assessments are confirmed to 
be inconsistent a manual query (TrialDCF) will be generated in TrialManager. The 
query in TrialManager will be reviewed and responded to by the examining 
investigator (See Step 4) 
 
Step 4: TrialDCF 
The TrialDCF are queries described in the study manual query process. 
– 
The USB expert is responsible for the content of the TrialDCF 
– 
CRF Health is responsible for processing all TrialDCFs related to the EDSS 
assessment captured in TrialManager. 


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– 
The Monitor / CRA will log into TrialManager at least once per week for any new 
TrialDCFs.  If new TrialDCFs have been issued, sites will be notified by the monitor/ 
CRA that a response to the TrialDCF is required by the examining investigator 
within two weeks via TrialManager. 
– 
If the examining investigator does not respond to the initial TrialDCF within the two 
weeks as stated above, the monitor/CRA will contact the examining investigator to 
request to resolve the outstanding TrialDCF as per the agreed monitoring plan. 
– 
The Examining investigator and/or monitor/CRA can ask for support by the USB 
expert via email or telephone to ask any question to enable resolution of the 
TrialDCF. 
– 
Call service times are weekly for European countries on every Tuesday 3-4 p.m. 
• 
CET, biweekly on Tuesdays 9-10 a.m. CET for Australia and Asia and 5-6 p.m. 
CET for the Americas. The content of these discussions during the calls will be 
documented and archived by the USB Expert. 
– 
Detailed information on call in numbers and email information will be provided by the 
USB expert. 
– 
All outstanding TrialDCFs will be followed up by the monitor/CRA as per the agreed 
monitoring plan. The Study Management Team (SMT) will review unresolved 
TrialDCFs (as defined in study Integrated Data Review Plan (iDRP)) and will decide 
to close or continue to follow up the outstanding TrialDCFs. 
– 
Any TrialDCFs that are not answered/resolved will have their status changed as 
defined by CRFHealth (following authorisation from the Roche SMT during the 
course of the study (see Step 6). 
 
Step 5: Manual re-check 
All answered TrialDCFs will be re-checked by the same USB Expert who issued the 
initial TrialDCF.  TrialManger will generate a report to notify the USB expert of the 
response from examining investigator at the site and he/she will review the response. 
Step 6: Resolution of TrialDCF in TrialManager 
If the TrialDCFs is resolved, the EDSS assessment will be considered final and 
CRFHealth will implement and verify the change in TrialManger 
The final status of a TrialDCF will be either: 
1. 
“Resolved with change and closed” – TrialDCF is answered and revised data are 
entered by the examining investigator into TrialManager 
2. 
“Resolved without change and closed” – TrialDCF is answered by the Examining 
Investigator who confirms his original assessment in the TrialDCF. 
3. 
“Unresolved and closed” – TrialDCF is not answered and the SMT authorises to 
close due to unresponsiveness 
In all cases the examining investigator remains the final decision maker on the EDSS 
assessment. 


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3.4 
HANDLING OF EDSS ASSESSMENTS CHECKED PRIOR TO 
THE IMPLEMENTATION OF THE PROCESS OUTLINED IN THIS 
SOP 
All previous EDSS assessments, that had gone through the previous automated 
TrialDCF process, whether they had been changed or not as a result of this process will 
go through this new revised Neurostatus Systems edit check process again and the 
process steps outlined in this current SOP 2-6 will be applied.  Automated and new 
TrialDCF data will be stored in TrialManager.
4. 
GLOSSARY & DEFINITIONS 
 
ICH GCP guideline 
International Council for Harmonisation good clinical 
practice guidelines 
CRF Health 
CRFHealth eCOA Solutions Company 
CRA 
Clinical research associate 
CRO 
Contract research organisation 
EDSS 
Expanded Disability Status Scale 
FSS 
Functional system score 
iDRP 
Integrated Data Review Plan 
MS 
Multiple sclerosis 
Neurostatus Systems 
GmbH 
Company responsible for the technical and administrative 
implementation of training and certification of physicians 
participating in projects using EDSS in MS. 
Principal Investigator 
Lead site investigator 
SMT 
Study Management Team 
TrialSlate 
An electronic data capture device provided by CRFHealth 
Trial DCF 
Trial data clarification form (this resides in TrialManager) 
TrialManager 
Webportal Database which collects all questionnaires 
completed on the trialslate including EDSS assessments of the 
study patients 
USB 
University Hospital Basel 


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USB expert 
Medical doctor who works at the University Hospital Basel 
(USB), specialized in the assessment of the EDSS and responsible 
for the quality control of inconsistencies, queries, teaching of the 
EDSS and certification process. 


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5. 
REFERENCES 
Kurtzke JF. A new scale for evaluating disability in multiple sclerosis. Neurology 
1955;5:580-583. 
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability 
status scale (EDSS). Neurology 1983;33(11):1444-1452. 
Neurostatus, Version 04/10.2.  www.Neurostatus.net 


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