A Phase IIIb Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Ocrelizumab in Adults With Primary Progressive Multiple Sclerosis
Phase: PHASE3
Conditions: Multiple Sclerosis, Primary Progressive
Sponsor: Hoffmann-La Roche

 
Official Title: 
A Phase IIIb Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study to Evaluate the Efficacy and Safety of Ocrelizumab 
in Adults with Primary Progressive Multiple Sclerosis 
NCT Number: 
NCT04035005 
Document Date: 
Protocol Amendment Version 6: 04-Jul-2024 
 
 
 

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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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 
1/Protocol WA40404, Version 6 
PROTOCOL 
TITLE: 
A PHASE IIIb, MULTICENTER, RANDOMIZED, 
DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY 
TO EVALUATE THE EFFICACY AND SAFETY OF 
OCRELIZUMAB IN ADULTS WITH PRIMARY 
PROGRESSIVE MULTIPLE SCLEROSIS 
PROTOCOL NUMBER: WA40404 
VERSION NUMBER: 
6 
EU CT NUMBER: 
2023-505980-36-00 
EUDRACT NUMBER: 
2018-001511-73 
IND NUMBER: 
100,593 
NCT NUMBER: 
NCT04035005 
TEST PRODUCT: 
Ocrelizumab (RO4964913) (OCREVUS®) 
SPONSOR’S NAME 
AND LEGAL 
REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd
Grenzacherstrasse 124
4058 Basel, Switzerland
APPROVAL: 
See electronic signature and date stamp on the final 
page of this document. 

 
 
 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
2/Protocol WA40404, Version 6 
PROTOCOL HISTORY 
 
Protocol 
Associated Country-Specific Protocols  
Version 
Date Final 
Country 
Version 
Date Final 
6 
See electronic date stamp on the 
final page of this document. 
 
 
 
5 
13 October 2022 
 
 
 
4 
1 February 2021 
 
 
 
3 
4 August 2020 
 
 
 
2 
12 March 2020 
 
 
 
1 
14 February 2019 
Italy 
1 
13 August 2019 
Ireland  
1 
30 June 2019 
United Kingdom 
1 
26 June 2019 
 

 
 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
3/Protocol WA40404, Version 6 
PROTOCOL AMENDMENT, VERSION 6: 
RATIONALE 
Protocol WA40404 has been amended primarily to update the trial objectives, update the 
duration of follow-up 2 (FU2) and remove the B-cell monitoring (BCM) phase.  Changes 
to the protocol, along with a rationale for each change, are summarized below: 
 
The synopsis has been simplified to align with E.U. CTR and other guidelines. 
 
The primary efficacy objective and the timing of the primary analysis has been 
updated to reflect current planned analyses.  In order to better capture the spectrum 
of disability progression, and in line with the current trend towards composite 
disability endpoints being used as primary endpoints in several ongoing pivotal MS 
trials, the Sponsor combined the primary and key secondary endpoint into a 
composite endpoint (Sections 1.3, 2.1.1, 2.5, 3.1, 3.5 and 6.4.1.1). 
 
The secondary efficacy objective has been updated to reflect current planned 
analyses (Sections 1.3, 2.1.2, 2.5, 3.5 and 6.4.1.2).  
 
Additional exploratory efficacy objectives have been updated to reflect current 
planned analyses (Sections 2.1.3 and 6.4.3). 
 
The FU2 phase has been shortened to 24 weeks for each patient (Section 3.1.1.6, 
3.2 and Appendix 4) and the BCM phase has been removed (Sections 3.1, 3.2, 3.5, 
5.1.1.1, 5.4.2.2, 5.5.2 and Appendix 4) as the safety profile of ocrelizumab is well 
established and does not warrant 48 weeks follow-up and BCM phase. In addition, 
shortening the FU2 and BCM phase will avoid delaying patient access to post study 
treatment.  As a result, the end of study and length of study section has been 
updated (Section 3.2). 
 
A section describing duration of participation has been added to align with E.U. CTR 
requirements (Section 3.3). 
 
Text has been added to allow patients to be premedicated with an oral dose of 
prednisolone or methylprednisolone, should IV methylprednisolone not be available 
(Sections 3.5.4 and 4.3.2.2, Appendix 1 and 2). 
 
Collection of demographic data, including information on race and ethnicity, is of 
importance to the future interpretation of results from the clinical trial.  A rationale 
has been provided in Section 3.4.6. 
 
The language regarding single-patient, emergency and non-emergency unblinding 
requested by the investigator has been updated to align with internal procedures 
(Section 4.2). 
 
Text has been modified to align with updates to the Roche Global Policy on 
Continued Access to Investigational Medicinal Products (Section 4.3.4). 
 
It has been made explicit that expedited safety reports are notified to EudraVigilance 
(Section 5.7). 
 
The biomarker analyses have been simplified in the protocol as the details are 
described in the statistical analysis plan and biomarker analysis plan. (Section 6.8). 

 
 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
4/Protocol WA40404, Version 6 
 
A comprehensive list of investigational medicinal products and auxiliary medicinal 
products has been added to align with E.U. CTR requirements (Appendix 14). 
 
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. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
5/Protocol WA40404, Version 6 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 13 
PROTOCOL SYNOPSIS ................................................................................... 14 
1.1.1 
Primary and Secondary Objectives and Endpoints .................. 14 
1.1.2 
Overall Trial Design ............................................................... 15 
1. 
BACKGROUND ............................................................................ 18 
1.1 
Background on Multiple Sclerosis ............................................ 18 
1.2 
Background on Ocrelizumab.................................................... 19 
1.3 
Study Rationale and Benefit-Risk Assessment ........................ 19 
1.3.1 
Clinical Relevance of Upper Extremity Disability 
Progression, as Measured by the 9-HPT, in PPMS ................. 22 
1.3.2 
Benefit-Risk Assessment of the Conduct of the Study 
during the COVID-19 Pandemic .............................................. 23 
1.3.3 
Benefit-Risk Assessment for Concomitant Use of COVID-
19 Vaccines ............................................................................. 23 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 24 
2.1 
Efficacy Objectives .................................................................. 24 
2.1.1 
Primary Efficacy Objective ....................................................... 24 
2.1.2 
Secondary Efficacy Objective .................................................. 25 
2.1.3 
Exploratory Efficacy Objective ................................................. 25 
2.2 
Safety Objectives ..................................................................... 26 
2.3 
Immunogenicity Objective ........................................................ 26 
2.4 
Pharmacokinetic and Pharmacodynamic Objectives ............... 26 
2.5 
Biomarker Objective ................................................................ 27 
2.6 
Health Status Utility Objective .................................................. 27 
3. 
STUDY DESIGN ........................................................................... 27 
3.1 
Description of the Study ........................................................... 27 
3.1.1 
Study Phases ........................................................................... 34 
3.1.1.1 
Screening Phase ..................................................................... 34 
3.1.1.2 
Double-Blind Treatment Phase ................................................ 35 
3.1.1.3 
An Optional Post‑Double-Progression Ocrelizumab 
Treatment Phase ..................................................................... 36 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
6/Protocol WA40404, Version 6 
3.1.1.4 
Follow-Up 1 Phase .................................................................. 37 
3.1.1.5 
Optional Ocrelizumab Open-Label Extension Phase ............. 37 
3.1.1.6 
Follow-Up 2 Phase .................................................................. 38 
3.2 
End of Study and Length of Study ........................................... 39 
3.3 
Duration of Participation ........................................................ 39 
3.4 
Rationale for Study Design ...................................................... 39 
3.4.1 
Rationale for Ocrelizumab Dose and Schedule ....................... 39 
3.4.2 
Rationale for Patient Population .............................................. 40 
3.4.3 
Rationale for Control Group ..................................................... 40 
3.4.4 
Rationale for the Use of Premedications 
(Methylprednisolone and Antihistamines) ................................ 41 
3.4.5 
Rationale for Biomarker Assessments ..................................... 42 
3.4.6 
Rationale for Collection of Information on Race and 
Ethnicity .................................................................................. 42 
4. 
MATERIALS AND METHODS ...................................................... 43 
4.1 
Patients .................................................................................... 43 
4.1.1 
Inclusion Criteria ...................................................................... 43 
4.1.2 
Exclusion Criteria ..................................................................... 44 
4.1.3 
Eligibility Criteria for Open-Label Extension Phase .................. 47 
4.2 
Methods of Treatment Assignment and Blinding ..................... 48 
4.3 
Study Treatment and Other Treatments Relevant to the 
Study Design ........................................................................... 50 
4.3.1 
Study Treatment Formulation, Packaging, and Handling ......... 51 
4.3.1.1 
Ocrelizumab and Placebo ........................................................ 51 
4.3.1.2 
Non-Investigational/Auxiliary Medicinal Products .................. 51 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .... 51 
4.3.2.1 
Ocrelizumab and Placebo ........................................................ 51 
4.3.2.2 
Premedications ........................................................................ 54 
4.3.2.3 
Re-Treatment Criteria for Ocrelizumab .................................... 54 
4.3.3 
Investigational Medicinal Product Accountability ..................... 55 
4.3.4 
Continued Access to Ocrelizumab ........................................... 56 
4.4 
Concomitant Therapy .............................................................. 57 
4.4.1 
Treatment for Symptoms of Multiple Sclerosis ......................... 57 
4.4.2 
Treatment of Relapses ............................................................ 57 

Ocrelizumab—F. Hoffmann-La Roche Ltd 
7/Protocol WA40404, Version 6 
4.4.3
Prohibited Therapy and Alternative Treatment Post 
Ocrelizumab ............................................................................. 57
4.4.4
Immunizations .......................................................................... 58
4.5
Study Assessments ................................................................. 58
4.5.1
Informed Consent Forms and Screen Failures ........................ 59
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data ................................................................... 59
4.5.3
Physical Examinations ............................................................. 59
4.5.4
Vital Signs ................................................................................ 60
4.5.5
Neurological Examination ........................................................ 60
4.5.6
9-Hole Peg Test ....................................................................... 61
4.5.7
Assessment of Disability:  Expanded Disability Status 
Scale ........................................................................................ 61
4.5.8
Assessment of Relapse ........................................................... 62
4.5.9
Symbol Digit Modalities Test .................................................... 62
4.5.10
Mandatory and Optional MRI Sequences ................................ 63
4.5.11
Laboratory, Biomarker, and Other Biological Samples ............ 65
4.5.12
Patient-Reported Outcomes .................................................... 67
4.5.12.1
EQ-5D-5L................................................................................. 68
4.5.12.2
Multiple Sclerosis Impact Scale, Version 2 .............................. 68
4.5.12.3
Modified Fatigue Impact Scale ................................................. 68
4.5.12.4
ABILHAND ............................................................................... 68
4.5.12.5
Quality of Life in Neurological Disorders Upper Extremity 
Function ................................................................................... 68
4.5.12.6
Patient Global Impression of Change for Fatigue .................... 69
4.5.12.7
Patient Global Impression of Change for Upper Limb 
Function ................................................................................... 69
4.5.13
Samples for Whole Genome Sequencing ................................ 69
4.5.14
Optional Samples for Research Biosample Repository ........... 70
4.5.14.1
Overview of the Research Biosample Repository .................... 70
4.5.14.2
Approval by the Institutional Review Board or 
Ethics Committee ..................................................................... 71
4.5.14.3
Sample Collection .................................................................... 71
4.5.14.4
Confidentiality .......................................................................... 72

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
8/Protocol WA40404, Version 6 
4.5.14.5 
Consent to Participate in the Research Biosample 
Repository................................................................................ 72 
4.5.14.6 
Withdrawal from the Research Biosample Repository ............. 73 
4.5.14.7 
Monitoring and Oversight ......................................................... 73 
4.5.15 
Optional Smartphone-Based Digital Outcome Assessment ..... 73 
4.5.16 
Optional CSF Collection .......................................................... 74 
4.6 
Overview of Clinical Visits ........................................................ 74 
4.6.1 
Delayed Dosing Visit ................................................................ 74 
4.6.2 
Unscheduled Visits .................................................................. 75 
4.7 
Treatment, Patient, Study, and Site Discontinuation ................ 75 
4.7.1 
Study Treatment Discontinuation ............................................. 75 
4.7.2 
Patient Discontinuation from Study .......................................... 76 
4.7.3 
Study Discontinuation .............................................................. 77 
4.7.4 
Site Discontinuation ................................................................. 77 
5. 
ASSESSMENT OF SAFETY ......................................................... 77 
5.1 
Safety Plan .............................................................................. 77 
5.1.1 
Risks Associated with Ocrelizumab ......................................... 78 
5.1.1.1 
Identified Risks and Adverse Drug Reactions .......................... 78 
5.1.1.2 
Potential Risks ......................................................................... 80 
5.1.2 
Risks Associated with Corticosteroids ..................................... 82 
5.1.3 
Risks Associated with Antihistamines ...................................... 82 
5.1.4 
Management of Patients Who Experience Adverse Events ..... 82 
5.1.4.1 
Dose Modifications .................................................................. 82 
5.1.4.2 
Treatment Interruption ............................................................. 82 
5.1.4.3 
Management Guidelines .......................................................... 82 
5.2 
Safety Parameters and Definitions .......................................... 83 
5.2.1 
Adverse Events ........................................................................ 83 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) .................................................................................. 84 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ...................................................... 85 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................... 85 
5.3.1 
Adverse Event Reporting Period .............................................. 86 

Ocrelizumab—F. Hoffmann-La Roche Ltd 
9/Protocol WA40404, Version 6 
5.3.2
Eliciting Adverse Event Information ......................................... 86
5.3.3
Assessment of Severity of Adverse Events ............................. 86
5.3.4
Assessment of Causality of Adverse Events............................ 87
5.3.5
Procedures for Recording Adverse Events .............................. 88
5.3.5.1
Infusion-Related Reactions ...................................................... 88
5.3.5.2
Diagnosis versus Signs and Symptoms ................................... 88
5.3.5.3
Adverse Events That Are Secondary to Other Events ............. 89
5.3.5.4
Persistent or Recurrent Adverse Events .................................. 89
5.3.5.5
Abnormal Laboratory Values ................................................... 90
5.3.5.6
Abnormal Vital Sign Values ..................................................... 90
5.3.5.7
Abnormal Liver Function Tests ................................................ 91
5.3.5.8
Deaths ..................................................................................... 91
5.3.5.9
Preexisting Medical Conditions ................................................ 92
5.3.5.10
Lack of Efficacy or Worsening of MS ....................................... 92
5.3.5.11
Hospitalization or Prolonged Hospitalization ............................ 92
5.3.5.12
Patient-Reported Outcome Data .............................................. 93
5.4
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................... 93
5.4.1
Emergency Medical Contacts .................................................. 93
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest .......................................... 94
5.4.2.1
Events That Occur prior to Study Drug Initiation ...................... 94
5.4.2.2
Events That Occur after Study Drug Initiation .......................... 94
5.4.3
Reporting Requirements for Pregnancies ................................ 94
5.4.3.1
Pregnancies in Female Patients .............................................. 94
5.4.3.2
Abortions.................................................................................. 95
5.4.3.3
Congenital Anomalies/Birth Defects ........................................ 95
5.4.4
Reporting Requirements for Cases of Accidental Overdose 
or Medication Error .................................................................. 95
5.5
Follow-Up of Patients after Adverse Events ............................. 96
5.5.1
Investigator Follow-Up ............................................................. 96
5.5.2
Sponsor Follow-Up .................................................................. 97
5.6
Adverse Events That Occur after the Adverse Event 
Reporting Period ...................................................................... 97

Ocrelizumab—F. Hoffmann-La Roche Ltd 
10/Protocol WA40404, Version 6 
5.7
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............... 97
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ......... 98
6.1
Determination of Sample Size ................................................. 98
6.2
Summaries of Conduct of Study .............................................. 99
6.3
Summaries of Demographic and Baseline Characteristics ...... 99
6.4
Efficacy Analyses ..................................................................... 99
6.4.1
Primary Analysis ...................................................................... 99
6.4.1.1
Estimands for the Primary Analysis ...................................... 101
6.4.1.2
Estimands for the Key Secondary Endpoint of Time to 
Confirmed Disability Progression ........................................... 104
6.4.1.3
Control of the Type I Error ..................................................... 105
6.4.2
Secondary Efficacy Endpoints ............................................... 106
6.4.3
Exploratory Efficacy Endpoints .............................................. 107
6.5
Safety Analyses ..................................................................... 108
6.6
Pharmacokinetic Analyses ..................................................... 109
6.7
Immunogenicity Analyses ...................................................... 110
6.8
Biomarker Analyses ............................................................... 110
6.9
Interim Analysis ..................................................................... 111
6.9.1
Planned Interim Analysis ....................................................... 111
7.
DATA COLLECTION AND MANAGEMENT ............................... 111
7.1
Data Quality Assurance ......................................................... 111
7.2
Electronic Case Report Forms ............................................... 111
7.3
Electronic Patient Reported Outcome Data ........................... 111
7.4
Source Data Documentation .................................................. 112
7.5
Use of Computerized Systems .............................................. 112
7.6
Retention of Records ............................................................. 113
8.
ETHICAL CONSIDERATIONS .................................................... 113
8.1
Compliance with Laws and Regulations ................................ 113
8.2
Informed Consent .................................................................. 113
8.3
Institutional Review Board or Ethics Committee .................... 115
8.4
Confidentiality ........................................................................ 115
8.5
Financial Disclosure ............................................................... 116

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
11/Protocol WA40404, Version 6 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................... 116 
9.1 
Study Documentation ............................................................ 116 
9.2 
Protocol Deviations ................................................................ 116 
9.3 
Management of Study Quality ................................................ 116 
9.4 
Site Inspections ..................................................................... 117 
9.5 
Administrative Structure ......................................................... 117 
9.6 
Publication of Data and Protection of Trade Secrets ............. 117 
9.7 
Protocol Amendments ........................................................... 118 
10. 
REFERENCES............................................................................ 119 
 
 
LIST OF TABLES 
Table 1 
Analysis of Time to 12-Week Confirmed 20% Increase in 
9-HPT Score and Time to Composite 12-Week Confirmed 
Disability Progression of EDSS and 9-HPT (All Randomized 
Patients:  Study WA25046) ........................................................ 20 
Table 2 
Analysis of Time to 12-Week Confirmed 20% Increase in 
9-HPT Score and Time to Composite 12-Week Confirmed 
Disability Progression of EDSS and 9-HPT by Population 
(All Randomized Patients:  Study WA25046) ........................... 21 
Table 3 
Overview of the Dosing Regimen across Study Phases ............. 32 
Table 4 
Overview of Ocrelizumab or Placebo Dosing and Schedule ....... 53 
Table 5 
Alternative Shorter Infusions of Ocrelizumab 600 mg ................. 53 
Table 6 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 87 
Table 7 
Causal Attribution Guidance ....................................................... 88 
Table 8 
Operating Characteristics for Possible True Underlying 
Hazard Ratio Values ................................................................... 99 
 
 
LIST OF FIGURES 
Figure 1 
Study Design .............................................................................. 29 
Figure 2 
Patient Flow Schema .................................................................. 31 
Figure 3 
Graphical Representation of the Control of the Type I Error ..... 105 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
12/Protocol WA40404, Version 6 
 
LIST OF APPENDICES 
Appendix 1 
 Schedule of Activities:  Double-Blind Treatment ...................... 124 
Appendix 2 
 Schedule of Activities:  Follow-Up 1 (and PDP OCR) .............. 130 
Appendix 3 
 Schedule of Activities:  Open-Label Extension......................... 135 
Appendix 4 
 Schedule of Activities:  Follow-Up 2 ......................................... 139 
Appendix 5 
 Progressive Multifocal Leukoencephalopathy:  Guidance for 
Diagnosis of Progressive Multifocal Leukoencephalopathy ...... 141 
Appendix 6 
 EQ-5D-5L ................................................................................. 146 
Appendix 7 
 Multiple Sclerosis Impact Scale, Version 2 .............................. 149 
Appendix 8 
 Modified Fatigue Impact Scale ................................................. 151 
Appendix 9 
 ABILHAND ............................................................................... 154 
Appendix 10 
 Quality of Life in Neurological Disorders-Upper Extremity 
Function (Fine Motor, ADL) ....................................................... 156 
Appendix 11 
 Patient Global Impression of Change for Fatigue .................... 158 
Appendix 12 
 Patient Global Impression of Change for Upper Limb 
Function .................................................................................... 159 
Appendix 13 
 Pregnancy Outcome and Infant Health Information on First 
Year of Life ................................................................................ 160 
Appendix 14  Investigational and Auxiliary Medicinal Product 
Designations for use in European Economic Area and 
United Kingdom ....................................................................... 167 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
13/Protocol WA40404, Version 6 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE IIIb, MULTICENTER, RANDOMIZED, 
DOUBLE-BLIND, PLACEBO-CONTROLLED 
STUDY TO EVALUATE THE EFFICACY AND 
SAFETY OF OCRELIZUMAB IN ADULTS WITH 
PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS 
PROTOCOL NUMBER: WA40404 
VERSION NUMBER: 
6 
EUDRACT NUMBER: 
2018-001511-73 
IND NUMBER: 
100,593 
NCT NUMBER: 
NCT04035005 
TEST PRODUCT: 
Ocrelizumab (RO4964913) (OCREVUS®) 
SPONSOR: 
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 to the Sponsor or their designee.  
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
14/Protocol WA40404, Version 6 
PROTOCOL SYNOPSIS 
This study will evaluate the efficacy and safety of ocrelizumab (Ocrevus ®) compared with 
placebo in patients with PPMS, including patients later in their disease course.  
1.1.1 
Primary and Secondary Objectives and Endpoints 
Primary Objective 
Corresponding Endpoint  
 Evaluate the efficacy of ocrelizumab 
compared with placebo in all 
randomized patients and in 
patients with MRI activity (MRI 
activity is defined as presence of T1 
Gd+ lesion[s] and/or new and/or 
enlarging T2 lesion[s] as detected 
by MRI scans during the screening 
phase)  
Time to onset of composite 12-week CDP defined 
as the time from randomization to the first 
occurrence of at least one of the following 
progression events: 
 12-week CDP in 9-HPT, defined as a 20% 
worsening from baseline in 9-HPT confirmed 
for at least 12 weeks  
 12-week CDP in EDSS score, defined as an 
increase of  1.0 point from baseline EDSS 
score in patients with a baseline EDSS 
score   5.5 or an increase of  0.5 point in 
patients with a baseline EDSS score of   5.5 
that is confirmed for at least 12 weeks  
9-HPT  9-Hole Peg Test; CDP  confirmed disability progression; EDSS  Expanded 
Disability Status Scale; Gd  gadolinium; MRI  magnetic resonance imaging.  
 
Secondary Objectives 
Corresponding Endpoints  
 Evaluate the efficacy of ocrelizumab 
compared with placebo for all 
randomized patients 
 Time to 12-week CDP in 9-HPT 
 Time to 12-week CDP in EDSS 
 Time to 24-week CDP in 9-HPT 
 Time to 24-week CDP in EDSS 
 Annual rate of percent change from baseline in 
total volume of T2 lesions 
 Annual rate of percent change from Week 24 in 
total brain volume 
Safety Objective 
Corresponding Endpoints 
 Evaluate the safety of ocrelizumab 
compared with placebo, as well as 
over time, for all patients who 
received ocrelizumab and until they 
receive any other DMT for MS 
 See Section 6.5 of the protocol.   
Immunogenicity Objective 
Corresponding Endpoints 
 Immunogenicity, as the presence of 
ADA during the study relative to 
baseline 
 See Section 6.7 of the protocol. 
Pharmacokinetic Objectives 
Corresponding Endpoints 
 Characterization of the ocrelizumab 
PK profile 
 Evaluation of ocrelizumab 
pharmacodynamics, as measured by 
B-cell levels in blood 
 See Section 6.6 of the protocol.  

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
15/Protocol WA40404, Version 6 
9-HPT  9-Hole Peg Test; ADA  anti-drug antibody; CDP  confirmed disability 
progression; DMT  disease-modifying therapy; EDSS  Expanded Disability Status Scale; 
Gd  gadolinium; MS  multiple sclerosis; MRI  magnetic resonance imaging; 
PK  pharmacokinetic. 
 
Primary and selected secondary objectives for the study are expressed using the estimand 
framework in accordance with the International Council for Harmonisation (ICH) E9 (R1) 
statistical principles for clinical trials (ICH 2020) in Section 6. 
  
1.1.2 
Overall Trial Design 
 
Several key aspects of the study design and study population are summarized below. 
Phase: 
Phase IIIB 
Population Type: 
Adult patients 
Control Method: 
Placebo-
controlled 
Population Diagnosis 
or Condition: 
PPMS  
Interventional Model: Randomization 
Population Age: 
1865 years 
Test Product: 
Ocrelizumab 
Site Distribution: 
Multi-region 
Active Comparator: 
Not applicable 
Trial Intervention 
Assignment Method: 
Randomization 
Number of Arms: 
2 arms 
 
Number of 
Participants to Be 
Enrolled: 
Approximately 
1000, with at least 
350 in the MRI 
active subgroup 
  
Study Treatment  
The ocrelizumab (or placebo) dose administered will be 600 mg every 24 weeks.  The first dose 
of ocrelizumab will be administered as two 300 mg IV infusions given 14 days apart.  For the 
subsequent doses, ocrelizumab will be administered as a single 600 mg infusion every 
24 weeks.  A minimum interval of 20 or 22 weeks, depending on if the previous dose was 
administered in one or two infusions, should be maintained between each infusion. 
 
Duration of Total Trial Participation 
The total duration of study participation for an individual is expected to be approximately 
up to 10.5 years. 
 
Total Planned Duration of Trial Intervention 
The total duration of study treatment for an individual is expected to be approximately up to 
10.5 years. 
 
Blinded Roles 
Investigators, site personnel, participants and the Sponsor will not be made aware of 
treatment group assignment during the study.  
 
Committees 
Independent Committees: Independent Data Monitoring Committee 
Other Committees: 
External Steering Committee 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
16/Protocol WA40404, Version 6 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
9-HPT 
9-Hole Peg Test 
ADA  
anti-drug antibody 
ADL 
activities of daily living 
ANCOVA 
analysis of covariance 
BCM 
B-cell monitoring 
CDP 
confirmed disability progression 
COVID-19 
coronavirus disease 2019 
CSF 
cerebrospinal fluid 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTFG 
Clinical Trial Facilitation Group 
DMT 
disease-modifying therapy 
DPE 
double-progression event  
DSS 
Disability Status Scale 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EDSS 
Expanded Disability Status Scale 
EMA 
European Medicines Agency  
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
FSS 
Functional System Scores 
FU1 
follow-up 1 
FU2 
follow-up 2 
Gd 
gadolinium 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Council for Harmonisation 
iDMC 
independent Data Monitoring Committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
IxRS 
interactive voice or web-based response system  

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
17/Protocol WA40404, Version 6 
Abbreviation 
Definition 
JC 
John Cunningham 
MFIS  
Modified Fatigue Impact Scale 
MMRM 
mixed effect model repeat measurement 
MRI 
magnetic resonance imaging 
MS 
multiple sclerosis 
MSIS 
Multiple Sclerosis Impact Scale 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria 
for Adverse Events 
Neuro-QoL-UE 
Quality of Life in Neurological Disorders-Upper 
Extremity Function 
NfL 
neurofilament light chain 
OLE 
open-label extension 
PDP OCR 
post-double-progression ocrelizumab  
PGIC 
Patient Global Impression of Change 
PGIC-F 
Patient Global Impression of Change for fatigue 
PGIC-UL 
Patient Global Impression of Change for upper limb 
function 
PK 
pharmacokinetic 
PML 
progressive multifocal leukoencephalopathy 
PPMS 
primary progressive multiple sclerosis 
PRO 
patient-reported outcome 
PY 
patient years 
QoL 
quality of life 
RBR 
Research Biosample Repository 
RCRM 
random coefficient regression model 
RMS 
relapsing multiple sclerosis 
RPM 
remote patient monitoring 
RRMS 
relapsing-remitting MS 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SDMT 
Symbol Digit Modalities Test 
SmPC 
summary of product characteristics  
ULN 
upper limit of normal 
USPI 
U.S. prescribing information  
WES 
whole exome sequencing 
WGS 
whole genome sequencing 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
18/Protocol WA40404, Version 6 
1. 
BACKGROUND 
1.1 
BACKGROUND ON MULTIPLE SCLEROSIS 
Multiple sclerosis (MS) is a chronic, inflammatory, and demyelinating disease of the CNS 
that affects approximately 2.3 million people worldwide (MSIF 2013).  While MS is 
a global disease, its prevalence is highest in North America and Europe (140 and 108 
per 100,000 people, respectively) (MSIF 2013).  MS is commonly diagnosed during 
reproductive age, between 20 and 40 years (Tullman 2013).  Overall, MS is 
approximately twice as prevalent in women as in men, except in individuals with the 
primary progressive- form of the disease, where there is no gender prevalence 
difference (MSIF 2013; Tullman 2013).  Reasons for these observed differences are 
unclear.  However, progression, once it begins, continues at similar rates in women and 
men (Leray et al. 2010). 
In approximately 85% of patients, MS begins as a relapsing, episodic disorder with 
gradual complete or incomplete recovery (referred to as relapsing-remitting MS 
[RRMS]).  If left untreated, the majority of these patients will transition to a progressive 
form characterized by worsening neurologic disability, either with or without occasional 
super-imposed relapses (relapsing or non-relapsing secondary progressive MS).  
Patients accumulate disability as a result of incomplete recovery from acute relapses 
and/or gradual disease progression (Tullman 2013).  Primary progressive MS (PPMS) is 
a less common form of MS, accounting for approximately 10% of all cases 
(approximately 40,000 individuals in the United States).  PPMS is characterized by 
a progressive course from disease onset, with infrequent superimposed discrete clinical 
attacks or relapses (Lublin et al. 2014).  Unlike RRMS, the typical age of onset for PPMS 
is older at approximately 40 years, and men are affected nearly as often as women 
(Cottrell et al. 1999).  The absence of relapses imposes special challenges for diagnosis, 
requiring clinical evidence that the disease has advanced for at least 1 year from 
symptom onset independent of clinical relapse (Thompson et al. 2018). 
Natural history studies of patients with PPMS suggest a disabling course from symptom 
onset.  In a well-characterized cohort of patients with PPMS from Ontario, Canada, the 
median time to the use of a unilateral cane or brace (Disability Status Scale [DSS] or 
DSS 6) was 8 years and the median time to wheelchair use (DSS 7) was under 20 years 
(Cottrell et al. 1999).  A higher proportion of patients with PPMS present initially with 
motor impairment, cerebellar ataxia, and brainstem symptoms than relapsing-onset 
patients, and spastic paraparesis is a common early clinical presentation (Andersson 
et al. 1999).  Evidence suggests that inflammation is present in the CNS throughout all 
MS clinical courses, from RRMS to secondary progressive MS, and in PPMS (Frischer 
et al. 2009).  Differences between disease phenotypes are due to the differential 
contribution of each of the inflammatory and neurodegenerative processes to the 
pathophysiology of CNS damage over time (Frischer et al. 2009, 2015). 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
19/Protocol WA40404, Version 6 
1.2 
BACKGROUND ON OCRELIZUMAB 
Ocrelizumab is a recombinant humanized, glycosylated, monoclonal IgG1 antibody that 
selectively targets and depletes CD20-expressing B cells, while preserving the capacity 
of B-cell reconstitution and preexisting humoral immunity.  CD20 is a B-cell surface 
molecule that is restricted in expression to pre-B cells and mature B cells but is not 
expressed earlier in the development of B cells (Banchereau and Rousset 1992).  Based 
on the results of ocrelizumab Phase III studies in patient populations with relapsing MS 
(RMS) and PPMS, ocrelizumab was approved by the US Food and Drug Administration 
(FDA) on 28 March 2017 for the treatment of adult patients with RMS and PPMS and by 
the European Medicines Agency (EMA) on 12 January 2018 for patients with active 
relapsing forms of MS defined by clinical or imaging features and for patients with early 
PPMS in terms of disease duration and level of disability, and with imaging features 
characteristic of inflammatory activity. 
Two identical randomized, active-controlled studies (OPERA I [Study WA21092] and 
OPERA II [Study WA21093]) have demonstrated superior efficacy outcomes versus 
interferon -1a in patients with RMS (Hauser et al. 2017); one randomized 
placebo-controlled study (ORATORIO [Study WA25046]) has demonstrated superior 
efficacy in PPMS versus placebo (Montalban et al. 2017).  Results of these studies show 
that depletion of CD20 B cells leads to a significant impact on a broad range of clinical 
measures of disease, including disability progression, in addition to an impact on 
magnetic resonance imaging (MRI) outcomes related to disease progression and 
reflective of neural tissue loss, thus further supporting the hypothesis that B cells are 
central to the pathogenesis of both RMS and PPMS.  Ocrelizumab has demonstrated 
a favorable safety profile in patients with RMS and PPMS (Hauser et al. 2017; 
Montalban et al. 2017).  The proportion of patients with adverse events was similar in 
patients treated with ocrelizumab compared with interferon -1a (both 83.3%) or placebo 
(95.1% vs. 90.0%).  The proportion of patients experiencing a serious adverse event 
was similar between ocrelizumab and the comparator groups (in RMS: 6.9% 
[ocrelizumab] and 8.7% [interferon -1a]; in PPMS: 20.4% [ocrelizumab] and 22.2% 
[placebo]). 
Refer to the Ocrelizumab Investigator's Brochure and/or local prescribing information for 
details on nonclinical and clinical studies of ocrelizumab. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
The pivotal Phase III Study WA25046 (ORATORIO) was a global, multicenter, 
randomized, parallel-group, double-blind, placebo-controlled trial evaluating the efficacy 
and safety of ocrelizumab in adults with PPMS.  The primary endpoint was the time to 
onset of confirmed disability progression (CDP) during the treatment period, defined as 
an increase in the Expanded Disability Status Scale (EDSS) score that was sustained 
for at least 12 weeks.  Disability was assessed using the EDSS (Kurtzke 1983).  
In Study WA25046, an event of disability progression was defined as an increase from 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
20/Protocol WA40404, Version 6 
baseline EDSS of 1 point or more for patients with a baseline EDSS score of  5.5, or an 
increase of 0.5 point or more for patients with a baseline EDSS score of  5.5.  This 
sustained increase in EDSS is considered a clinically meaningful change as described in 
the EMA MS Guideline of 2015 (EMA 2015).  Study WA25046 met its primary endpoint 
(24% reduction in the risk of 12-week CDP compared with placebo [hazard ratio  0.76; 
95% CI: 0.59, 0.98; p  0.0321]) and demonstrated significant reduction in both clinical 
and subclinical measures of disease progression compared with placebo.  In 
Study WA25046, the results of the 9-Hole Peg Test (9-HPT), a pre-specified exploratory 
endpoint, showed a significant 44% reduction in progression for patients treated with 
ocrelizumab versus placebo (p  0.0004) (see Table 1 below and Section 5.1 in the 
Primary Clinical Study Report for Study WA25046).  In a post-hoc exploratory analysis, 
the results of the composite 12-week CDP of EDSS and 9-HPT showed a significant 
25% reduction in disability progression for patients treated with ocrelizumab versus 
placebo (p=0.0136) (Table 1). 
Table 1 
Analysis of Time to 12-Week Confirmed 20% Increase in 9-HPT 
Score and Time to Composite 12-Week Confirmed Disability 
Progression of EDSS and 9-HPT (All Randomized Patients:  
Study WA25046) 
Endpoint 
Patients with Event 
Hazard Ratio 
(95% CI) 
p-value 
(log-rank) 
Placebo 
(N  244) 
Ocrelizumab  
(N  488) 
20% increase in 9-HPT 
confirmed at 12 weeks 
66/244 
83/488 
0.56 (0.41, 0.78) 
0.0004 
Composite 12-week CDP 
of EDSS and 9-HPT 
119/244 
199/488 
0.75 (0.60, 0.95) 
0.0136 
9-HPT  9-Hole Peg Test; CDP  Confirmed Disability Progression; EDSS  Expanded 
Disability Status Scale. 
Source:  Unpublished data. 
 
Study WA25046 included patients aged 1855 years with a baseline EDSS score 
ranging from 3.0 to 6.5.  Within this population, patients with more advanced disability 
consisting of EDSS score  5.5 and patients with an abnormal 9-HPT time of 
 25 seconds at baseline showed more rapid rates of upper limb disability progression on 
the 9-HPT.  In the post-hoc analyses of these more advanced subgroups of patients, 
ocrelizumab showed a significant 44% reduction in 20% 9-HPT progression versus 
placebo (p  0.0085 and p  0.0023, respectively) (see Table 2).  EDSS score  5.5 
corresponds to patients with lower extremity impairment requiring unilateral assistance 
(e.g., cane or crutch) with or without upper extremity impairment.  Thus, the Study 
WA25046 results imply that ocrelizumab may reduce the rate of progression of upper 
limb disability in patients even if significant lower extremity disability has ensued.  9-HPT 
times above a threshold of 25 seconds can be regarded as abnormal based on 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
21/Protocol WA40404, Version 6 
a reference population of patients aged 1859 years (consistent with the age of the 
ORATORIO population) from a large-scale normative database (N  4319) 
(Wang et al. 2015).  Patients with an abnormal 9-HPT time of  25 seconds at baseline 
progressed more rapidly than patients with normal 9-HPT time of  25 seconds; 
however, both patient groups showed a comparable benefit from treatment with 
ocrelizumab (44% [hazard ratio0.56; 95% CI: 0.38, 0.82; p  0.0023] and 49% [hazard 
ratio  0.51; 95% CI:  0.27, 0.97; p0.0358] risk reduction, respectively) (see Table 2).  
Presence of inflammatory activity as detected by mandatory MRI at baseline correlates 
with a greater treatment benefit.  Pre-specified, non-powered, subgroup analysis of the 
primary endpoint (time to 12-week CDP progression) in Study WA25046 suggests that 
patients with T1 gadolinium (Gd)-enhancing lesions at baseline received a greater 
treatment benefit than patients without T1 Gd-enhancing lesions (with T1 Gd-enhancing 
lesions at baseline: HR  0.65 [95% CI: 0.401.06], without T1 Gd-enhancing lesions at 
baseline: HR  0.84 [95% CI: 0.621.13]; EMA 2018).  With regard to inflammatory 
activity and hand function, ocrelizumab-treated patients with MRI-detected 
T1 Gd-enhancing lesions at baseline experienced a significant 58% reduction in 20% 
9-HPT progression versus placebo (p  0.0034); a reduction of 36% (p  0.0242) in 20% 
9-HPT progression versus placebo was observed in ocrelizumab-treated patients without 
MRI-detected T1 Gd-enhancing lesions at baseline (see Table 2). 
Table 2 
Analysis of Time to 12-Week Confirmed 20% Increase in 9-HPT 
Score and Time to Composite 12-Week Confirmed Disability 
Progression of EDSS and 9-HPT by Population (All 
Randomized Patients:  Study WA25046) 
Population 
Percent of Patients with 
Event at Week 120 
(Placebo Arm) a 
Percent of Patients with 
Event at Week 120 
(Ocrelizumab Arm) a 
Hazard Ratio 
(95% CI) 
p-value 
(log-rank) 
12-week confirmed 20% increase in 9-HPT 
EDSS  5.5 
39% 
21% 
0.56 (0.36, 0.87) 
0.0085 
T1 Gd  
39% 
16% 
0.42 (0.23, 0.76) 
0.0034 
T1 Gd  
18% 
14% 
0.64 (0.43, 0.95) 
0.0242 
9-HPT  25 seconds 
33% 
18% 
0.56 (0.38, 0.82) 
0.0023 
9-HPT  25 seconds 
12% 
9% 
0.51 (0.27, 0.97) 
0.0358 
Composite 12-week CDP of EDSS and 9-HPT 
EDSS  5.5 
58% 
46% 
0.75 (0.53, 1.05) 
0.0927 
T1 Gd   
54% 
39% 
0.66 (0.43, 1.04) 
0.0693 
T1 Gd   
40% 
36% 
0.81 (0.62, 1.06) 
0.1184 
9-HPT  25 seconds 
55% 
41% 
0.69 (0.52, 0.91) 
0.0083 
9-HPT  25 seconds 
31% 
31% 
0.83 (0.56, 1.22) 
0.3359 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
22/Protocol WA40404, Version 6 
9-HPT  9-Hole Peg Test; EDSS  Expanded Disability Status Scale; Gd  gadolinium; 
CDP  Confirmed Disability Progression. 
a Kaplan-Meier estimates. 
Source:  Unpublished data. 
 
Therefore, given the encouraging results from Study WA25046, the primary objective of 
this study is to evaluate the efficacy of ocrelizumab compared with placebo on the 
composite 12-week CDP of EDSS and 9-HPT in a population that also includes patients 
with more advanced PPMS who acquired significant lower extremity impairment.  The 
study will include patients with a baseline EDSS score from 3.0 to 8.0, inclusive.  CDP in 
upper limb function using the same 9-HPT measure that was used in Study WA25046 
will also be evaluated as a key secondary objective.  Moreover, the upper limit of age of 
the enrolled population will be 65 years, and the treatment effect of ocrelizumab will be 
explored according to the presence of inflammatory activity as detected by mandatory 
MRI at baseline.  Additional secondary and exploratory objectives will evaluate the 
efficacy of ocrelizumab on its ability to reduce disease progression on other clinical and 
subclinical measures.  These will include clinical measures of other neurological 
functional systems, subclinical imaging and biomarker measures, and measures of 
fatigue and quality of life. 
1.3.1 
Clinical Relevance of Upper Extremity Disability Progression, 
as Measured by the 9-HPT, in PPMS 
Patients with PPMS with high EDSS scores, including those who are 
wheelchair-restricted, have a devastating reduction in quality of life if they lose any 
residual function in their arms and/or hands.  For this reason, preserving upper limb 
function is highly relevant to the quality of life of the patient and an important therapeutic 
clinical goal in PPMS.  Dysfunction of the upper limbs is clinically relevant as it 
significantly limits the ability to perform activities of daily living, affects the level of 
independence, and negatively impacts quality of life (Kraft et al. 2014).  Patients with 
more advanced PPMS have been recognized as a much-underserved population with 
very limited therapeutic options (Kraft et al. 2014).  Therefore, exploring the therapeutic 
effects of ocrelizumab in this PPMS population will be both consistent with and expand 
on the results of Study WA25046 as well as fulfill a significant medical need for these 
patients. 
The 9-HPT has become one of the most frequently used measures of upper extremity 
function in MS (Earhart et al. 2011).  The 9-HPT provides a brief, standardized approach 
to assess upper limb function and can be administered by a wide variety of trained 
examiners (Earhart et al. 2011).  The test has high inter-rater reliability and good 
test-retest reliability (Erasmus et al. 2001).  There is also evidence for concurrent and 
convergent validity as well as sensitivity to detect minor impairments of hand function 
(Parker et al. 1986; Wang et al. 2015).  A 20% worsening in test time is commonly used 
to define clinically meaningful worsening (Feys et al. 2017) as it corresponds to 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
23/Protocol WA40404, Version 6 
predefined clinically meaningful changes of established clinician and patient-reported 
measures. 
1.3.2 
Benefit-Risk Assessment of the Conduct of the Study during 
the COVID-19 Pandemic 
A benefit-risk assessment was conducted to determine whether there is any impact of 
the coronavirus disease 2019 (COVID-19) pandemic on the conduct of this study.  
Based on that assessment, no impact is anticipated, and the existing information on 
identified and potential risks, safety monitoring, and management guidelines and risk 
mitigation measures provided in the study protocol are considered adequate. 
The available safety data from patients with MS treated with ocrelizumab to date 
suggests that severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) 
infections follows a similar course in these patients as in the general population, with risk 
factors for severe SARS-COV-2 infections that are similar in the general population, the 
overall MS population, and in those treated with ocrelizumab (Hughes et al. 2021). 
The protocol’s eligibility criteria mitigate the known risk factors for severe SARS‑COV‑2 
infection outcomes, such as older age, more advanced MS disease status, and 
presence of relevant comorbidities, and exclude patients with MS with any known or 
suspected active infection (including SARS-CoV-2, based on the investigator's 
assessment) from participating in the study.  As per Section 4.3.2.3, absence of active 
infection is also required for patients to receive further re-treatment with ocrelizumab.  
The risk of MS progression may potentially increase over time, if highly effective 
treatments are delayed. 
In summary, protocol-mandated safety monitoring and management guidelines, study 
eligibility criteria, and ocrelizumab re-treatment criteria are considered adequate in the 
context of conducting the study during the COVID-19 pandemic.  Investigators should 
manage SARS-CoV-2 infection in the same way as infections caused by any other 
pathogen, as per local guidelines. 
1.3.3 
Benefit-Risk Assessment for Concomitant Use of COVID-19 
Vaccines 
A benefit-risk assessment was conducted to determine whether there is any impact on 
the concomitant use of COVID-19 vaccines on the conduct of this study.  Based on this 
assessment, no interaction between the concomitant use of COVID-19 vaccines and 
ocrelizumab has been identified.  There is no anticipated impact affecting the efficacy 
and safety of ocrelizumab in patients enrolled in ocrelizumab clinical trials.  Existing key 
safety information as described in the protocol (namely immunizations 
[see Section 4.4.4], and impaired response to vaccination [see Section 5.1.1.1]), safety 
monitoring, and risk mitigation measures related to administration of vaccines (including 
COVID-19 vaccines) are considered adequate. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
24/Protocol WA40404, Version 6 
As described in Section 5.1.1.1 (impaired response to vaccination), data from the pivotal 
Phase III studies (WA21092/93, WA25046) of ocrelizumab in RMS and PPMS show that 
preexisting humoral immunity to common viral and bacterial antigens is not affected by 
ocrelizumab treatment.  Additionally, for patients receiving vaccines while treated with 
ocrelizumab, the vaccination study BN29739 (VELOCE) showed that patients 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 
in patients who received ocrelizumab, albeit with reduced levels of antibodies compared 
to patients in the control arm.  Vaccines were given as early as 12 weeks following the 
first ocrelizumab infusion (as early as 10 weeks following the second ocrelizumab 
infusion of the first dose).  Booster doses were given at least 4‑weeks before the next 
dose of ocrelizumab.  Other immune responses, such as cellular responses, were not 
investigated in the VELOCE study. 
The Sponsor is continually collecting evidence from clinical and biological sources to 
better understand immune response mechanisms of the COVID-19 vaccines in patients 
treated with ocrelizumab.  
As with any other medication or vaccine, COVID-19 vaccines should be reported as 
concomitant medications by using the standard fields in the clinical database 
(see immunizations [see Section 4.4.4], and medical history, baseline conditions, 
concomitant medications, and demographic data [see Section 4.5.2]). 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy and safety of ocrelizumab (Ocrevus®) compared with 
placebo in patients with PPMS, including patients later in their disease course.  Specific 
objectives and corresponding endpoints for the study are outlined below. 
2.1 
EFFICACY OBJECTIVES 
2.1.1 
Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of ocrelizumab 
compared with placebo in all randomized patients and in patients with MRI activity (MRI 
activity is defined as presence of T1 Gd+ lesion[s] and/or new and/or enlarging T2 
lesion[s] as detected by MRI scans during the screening phase) on the basis of the 
following endpoint:  
Time to onset of composite 12-week CDP defined as the time from randomization to the 
first occurrence of at least one of the following progression events: 
 
12-week CDP in 9-HPT, defined as a 20% worsening from baseline in 9-HPT 
confirmed for at least 12 weeks  
 
12-week CDP in EDSS score, defined as an increase of  1.0 point from baseline 
EDSS score in patients with a baseline EDSS score   5.5 or an increase 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
25/Protocol WA40404, Version 6 
of  0.5 point in patients with a baseline EDSS score of   5.5 that is confirmed for 
at least 12 weeks  
 
The estimand of this endpoint will be discussed in Section 6.4.1.1.  
2.1.2 
Secondary Efficacy Objective 
The secondary efficacy objective for this study is to evaluate the efficacy of ocrelizumab 
compared with placebo for all randomized patients on the basis of the endpoints below, 
in hierarchical order.  The secondary efficacy endpoints will also be evaluated as 
exploratory analyses for the MRI-active subgroup. 
 
Time to 12-week CDP in 9-HPT  
 
Time to 12-week CDP in EDSS 
 
Time to 24-week CDP in 9-HPT  
 
Time to 24-week CDP in EDSS 
 
Annual rate of percent change from baseline in total volume of T2 lesions  
 
Annual rate of percent change from Week 24 in total brain volume   
 
The estimand for the secondary endpoint of time to 12-week CDP in 9-HPT and time to 
12-week CDP in EDSS is described in Sections 6.4.1.2.1 and 6.4.1.2.2, respectively. 
2.1.3 
Exploratory Efficacy Objective 
An exploratory efficacy objective for this study is to evaluate the efficacy of ocrelizumab 
compared with placebo in patients, as measured by the primary and secondary 
endpoints in the following patient subgroups: 
 
Age  55 versus  55 
 
EDSS score  6.5 versus  6.5 
 
MRI-inactive versus MRI-active 
 
Males and females (all randomized patients, MRI-active subgroup and MRI-inactive 
subgroup) 
 
Additional exploratory objectives include the efficacy of ocrelizumab compared with 
placebo in patients from all randomized patients and the MRI-active subgroup as 
measured by the following endpoints: 
 
Change from baseline to Week 120 in fatigue as measured by Modified Fatigue 
Impact Scale (MFIS) 
 
Annual rate of percent change from baseline and from Week 24 in cervical spinal 
cord volume on MRI scans  
 
Change from baseline to Week 120 in a measure of manual ability for adults with 
upper limb impairments (ABILHAND) 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
26/Protocol WA40404, Version 6 
 
Change from baseline to Week 120 in the upper limb domain of a life quality 
measure for patients with neurological disorders (Quality of Life in Neurological 
Disorders-Upper Extremity Function [Neuro-QoL-UE]) 
 
Change from baseline to Week 120 in the Patient Global Impression of Change for 
upper limb function (PGIC-UL) 
 
Change from baseline to Week 120 in the Patient Global Impression of Change for 
fatigue (PGIC-F) 
 
Change from baseline to Week 120 in the Multiple Sclerosis Impact Scale (MSIS)29 
physical score 
 
Proportion of patients at Week 120 with a clinically meaningful decline on the 
MSIS-29 
 
Change from baseline to Week 120 in the Symbol Digit Modalities Test (SDMT) 
 
Rate of decline in fine motor skills of upper extremities and manual/finger dexterity 
as measured by smartphone-based digital outcome assessment (Floodlight remote 
patient monitoring [RPM]) 
 
The number of Gd-enhancing T1 lesions and number of new or enlarging T2 
hyperintense lesions as detected by mandatory MRI 
 
Annual rate of percent change from baseline in total non-enhancing T1 lesion 
volume on MRI scan of the brain  
 
2.2 
SAFETY OBJECTIVES 
The safety objectives for this study are to evaluate the safety of ocrelizumab compared 
with placebo, as well as over time, for all patients who received ocrelizumab and until 
they receive any other DMT for MS. 
Safety endpoints considered include adverse events, serious adverse events, adverse 
events leading to study treatment withdrawal, vital signs, change from baseline in 
laboratory test results, association of decrease in certain laboratory parameters, and 
serious infections.  For details on the analyses and the population, see Section 6.5. 
2.3 
IMMUNOGENICITY OBJECTIVE 
The immunogenicity objective is as follows: 
 
Immunogenicity, as the presence of anti-drug antibody (ADA) during the study 
relative to baseline.  The relationship between ADA status and pharmacokinetics, 
pharmacodynamics, efficacy, and safety may be explored. 
 
2.4 
PHARMACOKINETIC AND PHARMACODYNAMIC OBJECTIVES 
The pharmacokinetic (PK) and pharmacodynamic objectives are as follows: 
 
Characterization of the ocrelizumab PK profile 
 
Evaluation of ocrelizumab pharmacodynamics, as measured by B-cell levels in 
blood 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
27/Protocol WA40404, Version 6 
2.5 
BIOMARKER OBJECTIVE 
The exploratory biomarker objective for this study is to identify biomarkers that are 
predictive of response to ocrelizumab (i.e., predictive biomarkers), are early surrogates 
of efficacy, are associated with progression to a more severe disease state 
(i.e., prognostic biomarkers), are associated with acquired resistance to ocrelizumab, are 
associated with susceptibility to developing adverse events or can lead to improved 
adverse event monitoring or investigation (i.e., safety biomarkers), can provide evidence 
of ocrelizumab activity (i.e., pharmacodynamic biomarkers), or can increase the 
knowledge and understanding of disease biology and drug safety, on the basis of the 
following endpoints: 
 
Neurofilament light chain (NfL) levels (actual value and percentage change from 
baseline) at each visit up to time of clinical cutoff of primary analysis 
 
The prognostic or predictive relationship between baseline NfL and efficacy 
(including the study primary endpoint, imaging, or key secondary endpoints)  
 
The prognostic relationship between on-treatment NfL (measured at Weeks 24 or 
48) and subsequent disability progression on the study primary endpoint and other 
clinical outcomes  
 
Relationship between biomarkers in blood (plasma and/or serum) and/or 
cerebrospinal fluid (CSF) (listed in Section 4.5.11) and efficacy, safety, PK, 
immunogenicity, or other biomarker endpoints 
 
2.6 
HEALTH STATUS UTILITY OBJECTIVE 
The exploratory health status utility objective for this study is to evaluate health status 
utility scores of patients treated with ocrelizumab on the basis of the following endpoint: 
 
Relationship between EQ-5D-5L index score and clinical measurements that may 
support pharmacoeconomic modeling 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
Study WA40404 is a Phase IIIb, randomized, double-blind, placebo-controlled, 
parallel-group, multicenter study to evaluate efficacy and safety of ocrelizumab 
administered at a 600 mg IV infusion every 24 weeks in patients with PPMS, including 
patients later in their disease course.  This study will consist of the following phases:  
screening, double-blind treatment, an optional post-double-progression ocrelizumab 
(PDP OCR) treatment, follow-up 1 (FU1), an optional open-label extension (OLE), and 
follow-up 2 (FU2). 
Patients providing informed consent will undergo screening prior to the study drug 
administration.  Eligible patients will be randomized (1:1) in a blinded fashion to either 
placebo or ocrelizumab.  Randomization will be performed through an interactive voice 
or web-based response system (IxRS). 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
28/Protocol WA40404, Version 6 
The expected sample size will be approximately 1000 patients, with at least 350 patients 
in the MRI-active subgroup.  The MRI-active subgroup will consist of patients with 
T1 Gd lesion(s) and/or new and/or enlarging T2 lesion(s) as detected by MRI scan 
during screening.  If during the study conduct more than 650 patients have enrolled 
without MRI activity (referred to as MRI-inactive subgroup thereafter), then subsequently 
only patients with MRI activity may be enrolled to ensure that at least 350 patients with 
MRI activity will be randomized. 
Patients will be treated for 144 weeks (6 study drug doses, with each dose 24 weeks 
apart) in the double-blind treatment phase or until the primary analysis, whichever 
occurs earlier.  The primary analysis will be performed after the last randomized patient 
reaches 144 weeks of double-blind treatment (+ 12 weeks to allow for the confirmation of 
the latest event) or when at least 340 events are reached, whichever occurs earlier.  
Patients who experience a double‑progression event (DPE; defined as a confirmed 20% 
increase in 9-HPT time sustained for 24 weeks, and a CDP sustained for 12 weeks) 
during the double-blind treatment phase will be given the option to switch to PDP OCR 
after they have completed at least 120 weeks of double-blind treatment and 120-week 
visit assessments.  See Section 3.1.1.3 for definitions of DPE and PDP OCR.  
Patients will be recruited globally.  Patients who prematurely discontinue from study 
treatment will continue to be followed in the FU1 phase until 144 weeks from 
randomization for each patient or until the primary analysis, whichever occurs earlier 
(see Section 3.1.1.4). 
An independent Data Monitoring Committee (iDMC) will be employed to monitor and 
evaluate patient safety throughout the study, until the primary analysis is performed.  
Monitoring details will be described in the iDMC Charter.  
Figure 1 presents an overview of the study design.  Figure 2 shows the patient 
progression through the study.  The schedules of activities are provided in Appendix 1, 
Appendix 2, Appendix 3, and Appendix 4.  Overview of the dosing regimen across study 
phases is provided in Table 3. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
29/Protocol WA40404, Version 6 
Figure 1 Study Design 
  
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
30/Protocol WA40404, Version 6 
Figure 1 Study Design (cont.) 
DPE  double-progression event; FU1  follow-up 1; FU2 = follow-up 2; MRI  magnetic resonance imaging; OLE = open-label extension; 
PDP OCR  post-double-progression ocrelizumab. 
a Patients will be treated in the double-blind treatment phase for 144 weeks (6 study drug doses, with each dose 24 weeks apart) or until the 
primary analysis, whichever occurs earlier.  Eligible patients who either have completed 144 weeks of double-blind treatment or are ongoing in 
the double-blind treatment phase at the time of the primary analysis will switch to open-label treatment at the next scheduled visit.   
b Patients who experience a DPE during the double-blind treatment phase will be given the option to switch to the PDP OCR phase after they 
completed at least 120 weeks of double-blind treatment and 120-week visit assessments (see Section 3.1.1.3 for definitions of DPE and 
PDP OCR).  To maintain the blinding in the treatment arm, the first dose of PDP OCR treatment will be two infusions of 300 mg given 14 days 
apart for all patients.  Subsequent doses will then be 600 mg IV infusions every 24 weeks.  Patients who discontinue from the PDP OCR phase 
may continue to be followed in the FU2 phase.  
c At the Week 144 visit, patients will complete the efficacy assessments in a blinded manner as part of the double-blind treatment phase and will 
receive open label ocrelizumab.  Each patient will remain in the OLE phase for at least 2 years (at least 4 doses of ocrelizumab).  To maintain the 
blinding in the treatment arm, the first dose of open-label treatment will be two infusions of 300 mg given 14 days apart for all patients.  
For subsequent doses, patients will continue open-label treatment with a single IV infusion of 600 mg ocrelizumab every 24 weeks.  Patients who 
discontinue from the OLE phase may continue to be followed in the FU2 phase.   
d The primary analysis will be performed after the last randomized patient reaches 144 weeks of double-blind treatment ( + 12 weeks to allow 
for the confirmation of the latest event) or when at least 340 events are reached, whichever occurs earlier.  

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
31/Protocol WA40404, Version 6 
Figure 2 Patient Flow Schema 
 
DPE  double-progression event; FU  follow up; OCR  ocrelizumab; OLE  open-label extension; 
PDP OCR  post-double-progression ocrelizumab. 
Notes:  A patient may discontinue treatment and/or discontinue from the study at any time.  
Qualifications for advancing and the duration of each study phase are detailed in Section 3.1.1.  
The size of the boxes in this diagram does not represent the duration of each phase; for visit 
schedule and assessments required, see the schedule of activities for each phase. 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
32/Protocol WA40404, Version 6 
Table 3 
Overview of the Dosing Regimen across Study Phases 
 
Double-Blind Treatment Phase 
PDP OCR 
OLE Phase 
6 Treatment Doses (144 Weeks) a, b, c, d 
Variable b, d, e 
At Least 4 Treatment Doses b, d, f, 
g 
Dose 1 
Dose 2 Dose 3 Dose 4 Dose 5 
Dose 6 a, c 
(Every 
24 Wks) 
PDP OCR  
Dose 1 h 
PDP OCR 
Dose 2, 3, 
N 
OLE Dose 1 e, g 
OLE Dose 2, 
N 
(Subsequent 
Treatment 
Doses)  g  
(Every 
24 Wks) 
Double Infusion g 
Day 1 Day 15 Wk 24 
Wk 48 
Wk 72 
Wk 96 
Wk 120+ 
Day 1 
Day 15 
Day N 
Day 1 
Day 15 
Day N  
A 
OCR 
300 mg 300 mg 600 mg 600 mg 600 mg 600 mg 
600 mg 
OCR  
300 mg 
OCR  
300 mg 
OCR  
600 mg 
OCR  
300 mg 
OCR  
300 mg 
OCR  
600 mg  
B 
Placebo 
Placeb
o 
Placeb
o 
Placebo Placebo Placebo Placebo 
Placebo 
OCR  
300 mg 
OCR  
300 mg 
OCR  
600 mg 
OCR  
300 mg 
OCR  
300 mg 
OCR  
600 mg  
9-HPT  9-Hole Peg Test; CDP  confirmed disability progression; DPE  double-progression event; OCR  ocrelizumab; OLE  open-label 
extension; PDP OCR  post-double-progression ocrelizumab; wk  week. 
Note:  Each study drug dose has a duration of 24 weeks (  5 days). 
a The double-blind treatment phase consists of a 144-week (6 study drug doses, with each dose 24 weeks apart) period. 
b After the first infusion, an evaluation will be performed before each subsequent infusion to ensure the patient remains eligible for further 
treatment (see also Section 4.3.2.3 for re-treatment criteria for ocrelizumab). 
c Enrolled patients will undergo ocrelizumab (or placebo) treatment of 6 treatment doses at 24-week intervals. 
d A dose of 100 mg of methylprednisolone IV and oral or IV antihistamine (e.g., IV diphenhydramine 50 mg), or equivalent dose of alternative, will 
be administered prior to ocrelizumab or placebo infusions.  In patients where methylprednisolone is contraindicated, equivalent doses of other 
IV steroids (e.g., dexamethasone) should be used as premedication. 
e Patients who experience a DPE during the double-blind treatment phase will be given the option to switch to the PDP OCR phase after they 
have completed at least 120 weeks of double-blind treatment.  A DPE is defined as a confirmed 20% increase in 9-HPT time sustained for 
24 weeks, and a CDP sustained for 12 weeks that occurs during the double-blind treatment phase. 
f The OLE phase for eligible patients begins after the completion of the double-blind treatment phase or at the time of primary analysis.  The 
OLE phase can be terminated at any point (see Section 3.1.1.5). 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
33/Protocol WA40404, Version 6 
Table 3 
Overview of the Dosing Regimen across Study Phases (cont.)  
g During the OLE phase, the first dose of ocrelizumab will be administered as two 300 mg IV infusions given 14 days apart.  For the subsequent 
doses, patients will continue open-label treatment with a single IV infusion of 600 mg ocrelizumab every 24 weeks.  The first infusion of 
ocrelizumab in the OLE phase may occur once the patient meets the re-treatment criteria (see Section 4.3.2.3) at a scheduled visit following 
communication with the Sponsor. 
h To maintain the original blinding, PDP OCR will be offered to all patients who qualify regardless of their original treatment assignment.  Patients 
who experience a DPE during the double-blind treatment phase will be given the option to switch to the PDP OCR phase after they have 
completed at least 120 weeks of double-blind treatment.  The first dose of the PDP OCR will be administered as two 300 mg ocrelizumab 
infusions (given 14 days apart) 24 weeks after the last dose of blinded study drug.  

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
34/Protocol WA40404, Version 6 
3.1.1 
Study Phases 
This study will consist of the following study phases: 
 
Screening  
 
Double-blind treatment  
 
An optional PDP OCR treatment 
 
Follow-up 1 
 
Open-label extension  
 
Follow-up 2 
 
The details of each study phase are described below and in Figure 1.  The study 
duration will vary for each patient to maximize the safety and efficacy data collected. 
3.1.1.1 
Screening Phase 
The screening phase will last up to 24 weeks.  Patients who are candidates for 
enrollment in the study will be evaluated by the investigator to ensure all eligibility criteria 
are met (see Sections 4.1.1 and 4.1.2).  All patients must sign the Informed Consent 
Form prior to screening and prior to any changes to their existing medication for the 
purposes of enrollment in the study. 
Procedures at screening will include collecting medical history, medical examination, 
complete neurological examination, 9-HPT time and EDSS score, and blood and urine 
sampling (see Appendix 1 for further details on screening assessments and samples 
and Section 4.1 on eligibility criteria for the study).  Because of the potentially long 
screening phase (up to 24 weeks), the investigator is required to verify that the patient 
still meets eligibility criteria prior to randomization.  Patients must be neurologically 
stable for at least 30 days prior to randomization and baseline assessments.  
In particular, laboratory assessments related to eligibility should not be older than 
6 weeks prior to randomization; otherwise, laboratory retests will be required (not 
applicable for CSF testing). 
Two mandatory MRI scans performed at least 6 weeks apart or one mandatory MRI 
that can be compared with a historical MRI performed in the previous 1 year will be 
performed to verify the patient’s MRI activity level.  The MRI performed closer (i.e., from 
6 weeks up to 10 days prior) to randomization will be considered the baseline MRI for 
the study analyses. 
For patients who fail the initial screening, a maximum of two re-screenings will be 
allowed. 
Central randomization will be performed by the IxRS and will be stratified by: 
 
MRI activity, defined as any T1 Gd lesion(s) and/or new and/or enlarging 
T2 lesion(s) during the screening period (yes vs. no) 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
35/Protocol WA40404, Version 6 
 
Age ( 55. vs.  55)  
 
EDSS score ( 6.5 vs.  6.5) 
 
Region (two regions:  European Union, United Kingdom, and Canada vs. other) 
 
To ensure a balanced distribution of patients, demographics across regions by patient 
access to commercial ocrelizumab and enrollment within randomization strata will be 
monitored.  Enrollment caps will be implemented in the IxRS system (e.g., no more than 
650 patients will be randomized to the MRI-inactive subgroup).  Other dynamic 
enrollment caps may be added to ensure that distribution of patients according to 
stratification factors will be balanced across regions by patient’s access to commercial 
ocrelizumab. 
Patient eligibility information will be provided by the investigator or the investigator’s 
research staff to the IxRS at randomization.  The patient will be randomized and 
assigned a unique medication number and randomization number. 
Depending on local availability, patients who choose to and consent to the optional 
smartphone-based digital outcome assessments (Floodlight RPM) at screening will be 
asked to begin performing digital assessments (see Appendix 1).  Screening for 
Floodlight RPM participation will close in November 2022 in order for the last Floodlight 
RPM patient enrollment to occur by the end of December 2022. 
No patient may begin treatment prior to randomization and assignment of a medication 
number.  Under no circumstances are patients who enroll in this study and who have 
completed treatment as specified, 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 patient enrollment. 
3.1.1.2 
Double-Blind Treatment Phase 
All patients will undergo 144 weeks of study treatment (see Table 3 for review of dosing 
regimen) or until the primary analysis, whichever occurs earlier.  Study assessments 
will be performed as described in the schedule of activities (see Appendix 1).  
Randomization (Day 1) will occur only after the patient has met all inclusion and 
exclusion criteria (see Sections 4.1.1 and 4.1.2).  Patients will be randomized to either 
ocrelizumab or placebo control group. 
Study drug (ocrelizumab or placebo) dose will be administered in this study every 
24 weeks.  The first dose of study drug will be administered as two 300 mg IV infusions 
given 14 days apart.  For the subsequent doses, study drug will be administered as 
a single 600 mg IV infusion every 24 weeks.  All patients will receive mandatory 
premedication prior to each infusion.  A minimum interval of 20 weeks should be kept 
between the ocrelizumab second infusion of Dose 1 (i.e., infusion Day 15) and the next 
infusion of Dose 2 (Week 24).  A minimum interval of 22 weeks must be maintained 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
36/Protocol WA40404, Version 6 
between each dose of study drug.  More detailed information on study drug 
administration and premedication is contained in Section 4.3.2.1 and in Table 3. 
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 may be administered within 48 hours of 
randomization provided the investigator ensures 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. 
Patients who prematurely withdraw from study treatment during the double-blind 
treatment phase will remain blinded to treatment and will continue to be followed for 
safety and efficacy, regardless of switching to other medications for 144 weeks after 
randomization for each patient (in the FU1 phase) or until the primary analysis. 
To maintain integrity of the trial results and to prevent potential unblinding of the 
assigned arm during the double-blind treatment phase as a result of adverse events or 
changes to laboratory results, several additional measures, including a “dual assessor 
approach” (i.e., two blinded investigators per site:  Treating Investigator and Examining 
Investigator), will be implemented until the time of the primary analysis; see Section 4.2 
for details and definitions. 
The primary analysis will be performed after the last randomized patient reaches 
144 weeks of double-blind treatment (  12 weeks to allow for the confirmation of the 
latest event) or when at least 340 events are reached, whichever occurs earlier. 
3.1.1.3 
An Optional Post‑Double-Progression Ocrelizumab Treatment 
Phase 
A double-progression event (DPE) is defined as a confirmed 20% increase in 9-HPT 
time sustained for 24 weeks, and a CDP sustained for 12 weeks.  Patients who 
experience a DPE during the double-blind treatment phase will be notified by the 
Sponsor and given the option switch to ocrelizumab (PDP OCR) treatment after they 
have completed at least 120 weeks of double-blind treatment and 120-week visit 
assessments.  Patients will have to provide his or her informed consent prior to switching 
to PDP OCR treatment.  An iDMC will monitor the rate of DPE in the double-blind 
treatment period. 
In order to maintain the original blind, the option for PDP OCR will be offered to all 
patients who qualify, regardless of their original treatment assignment.  The first dose of 
the PDP OCR will be administered as two 300 mg IV infusions (given 14 days apart) 
24 weeks after the last dose of study drug.  Subsequent doses will be 600 mg 
IV infusions every 24 weeks.  Patients may continue on PDP OCR treatment until the 
end of the OLE phase.  Patients who discontinue from the PDP OCR phase earlier may 
continue to be followed in the FU2 phase.  

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
37/Protocol WA40404, Version 6 
3.1.1.4 
Follow-Up 1 Phase 
All patients who discontinue prematurely from the double-blind treatment phase will 
enter the FU1 phase, including patients who receive other DMTs for MS, commercial 
ocrelizumab, or no treatment.  The FU1 phase will run in parallel with the double-blind 
treatment phase until 144 weeks from randomization for each patient or until the 
primary analysis, whichever occurs earlier.  Scheduled visits will be performed every 
12 weeks analogically to the initial (double-blind) schedule of activities and will include 
both efficacy and safety assessments (see Appendix 2).  In the FU1 phase, patients will 
remain blinded to their original (randomized) treatment assignment.  Patients who 
withdraw from treatment should be encouraged to remain in the study for the full 
duration of the FU1 phase.  All patients who are ongoing in the FU1 phase at 144 weeks 
from randomization for each patient or at the time of the primary analysis will continue 
in the FU2 phase (see Section 3.1.1.6). 
3.1.1.5 
Optional Ocrelizumab Open-Label Extension Phase 
An optional OLE phase is planned for eligible patients who have either completed 144 
weeks of the double-blind treatment phase or are ongoing in the double-blind treatment 
phase at the time of the primary analysis and, in the opinion of the investigator, could 
benefit from ocrelizumab treatment.  Patients who are ongoing in the FU1 phase at 144 
weeks from randomization for each patient or at the time of the primary analysis will 
continue in the FU2 phase and will not participate in the OLE phase. 
The OLE phase will be carried out for at least 2 years (at least 4 doses of ocrelizumab) 
for each patient.  The 2-year duration of the OLE phase serves to further evaluate 
long-term safety and efficacy of ocrelizumab treatment in patients with PPMS. 
Patients will continue in the OLE phase or with PDP OCR treatment as per the schedule 
of activities (see Appendix 1 and Appendix 2) and Table 3. 
All patients who do not participate in the OLE phase will enter the FU2 phase 
(see Section 3.1.1.6).   
Eligible patients will need to provide consent for participation in the OLE phase.  Patients 
who consent to participate in the OLE phase will be required to meet the eligibility criteria 
for OLE prior to infusion with ocrelizumab (see Section 4.1.3). 
During the OLE phase, the first dose of ocrelizumab will be given as two 300 mg IV 
infusions given 14 days apart.  For the subsequent OLE doses, patients will continue 
open-label treatment with a single infusion of 600 mg ocrelizumab IV every 24 weeks 
(see Appendix 3 and Section 4.3.2.1).  A minimum 22-week interval between the last 
study ocrelizumab infusion in the double-blind treatment phase and the first OLE 
ocrelizumab infusion must be respected.  The first infusion of ocrelizumab in the OLE 
phase may occur once the patient meets the re-treatment criteria (see Section 4.3.2.3) 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
38/Protocol WA40404, Version 6 
at a scheduled visit.  Refer to Section 4.2 for additional information about study 
unblinding. 
Patients who complete or withdraw from the OLE phase will enter the FU2 phase 
(see Section 3.1.1.6).  The Sponsor may decide to terminate the OLE at any time 
(see Section 4.7.3). 
Study WA40404 will remain blinded until the primary analysis.  The mechanisms 
necessary to ensure that the blinding of the Examining Investigator is maintained are not 
necessary after the primary analysis during the OLE phase.  All required assessments 
during the OLE phase should occur as described in OLE schedule of activities (see 
Appendix 3).  It is recommended that the same Examining Investigator continues to 
perform the assessments throughout the OLE phase as in the double-blind phase.  
Visits should be scheduled with respect to the date of first infusion during the OLE 
phase.  The visit for the second infusion should be scheduled 14 days after the first 
infusion of the OLE dose (Dose 1).  A minimum interval of 20 weeks must be kept 
between the ocrelizumab second infusion during the OLE dose (Dose 1) and the next 
infusion at OLE dose (Dose 2).  A minimum of 22 weeks must occur between 
ocrelizumab single infusions administered from OLE Dose 2 onward. 
To verify re-treatment criteria for OLE infusion Dose 2 and subsequent doses, patients 
must attend a scheduled visit approximately 2 weeks prior to the infusion visit to have 
safety assessments performed as described in Appendix 3.  In the event that an infusion 
is delayed, additional tests or assessments, such as routine safety laboratory tests, may 
be performed by the Treating Investigator as clinically indicated.  At infusion visits, 
patients should remain in observation for at least 1 hour after the completion of the 
infusion. 
Additional unscheduled visits for the assessment of potential disease progression or MS 
relapses, new neurological symptoms, or safety events may occur at any time.  
Assessments performed at unscheduled (non-dosing) visits will be as clinically indicated.  
Patients with new neurological symptoms suggestive of MS relapse or MS worsening 
should have an EDSS and 9-HPT performed by the Examining Investigator (within 
7 days from the onset of the new neurological symptoms).  Other tests/assessments 
may be performed as appropriate. 
3.1.1.6 
Follow-Up 2 Phase 
The following patients will move into the FU2 phase (see Figure 2): 
 
Patients who are ongoing in the FU1 phase at 144 weeks from randomization for 
each patient or at the time of the primary analysis 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
39/Protocol WA40404, Version 6 
 
Patients who have either completed 144 weeks of the double-blind treatment phase 
or are ongoing in the double-blind treatment phase at the time of the primary 
analysis and will not enter the OLE phase 
 
Patients who have completed or withdrawn from the OLE phase or from PDP OCR 
treatment phase 
 
Laboratory and safety assessments for the FU2 phase will be performed during the clinic 
visit that occur 24 weeks after the last visit either in double-blind treatment phase, 
OLE, PDP OCR or FU1, whichever phase the patient is at that time  (see Appendix 4).  
All patients will continue in the FU2 phase for 24 weeks.   
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of the study will occur when the last patient completes the last scheduled visit 
at the end of the FU2 phase or discontinuation visit. 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be up to 10.5 years (assuming that the last patient randomized after 5 years 
from the start of the study has received blinded treatment for 144 weeks, followed by 
OLE phase for at least 2 years (at least 4 doses of ocrelizumab) for each patient, 
24 weeks of FU2 phase) (assuming that the number of 340 events has not been reached 
earlier).  
In addition, the Sponsor may decide to terminate the study at any time. 
3.3 
DURATION OF PARTICIPATION 
The total duration of study participation for an individual is expected to be 
approximately up to 10.5 years. 
3.4 
RATIONALE FOR STUDY DESIGN 
This study (WA40404) is a pivotal Phase III clinical trial composed of the following 
phases:  screening, double-blind treatment, an optional PDP OCR treatment, FU1, OLE, 
and FU2.  The double-blind treatment phase is designed to demonstrate the efficacy and 
safety of ocrelizumab in patients with PPMS, including those later in their disease 
course, in comparison with placebo.  The OLE phase serves to further evaluate 
long-term safety, tolerability, and efficacy of ocrelizumab treatment in patients with 
PPMS. 
3.4.1 
Rationale for Ocrelizumab Dose and Schedule 
The dose level of ocrelizumab administered in this study is 600 mg every 24 weeks. 
Ocrelizumab will be administered intravenously as dual infusions (300 mg on Days 1 
[Dose 1 Infusion 1] and 15 [Dose 1 Infusion 2]) for the first dose and subsequently as 
a single IV infusion (600 mg) every 24 weeks in 500 mL 0.9% sodium chloride.  This 
dosing regimen is consistent with the dosing regimen used in ocrelizumab Phase III/IV 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
40/Protocol WA40404, Version 6 
studies, as well as with the summary of product characteristics (SmPC) and the U.S. 
prescribing information (USPI). 
In the double-blind treatment phase, study drug for patients randomized to the placebo 
group will be administered analogously to those receiving ocrelizumab. 
3.4.2 
Rationale for Patient Population 
In comparison with the previous ocrelizumab PPMS study (WA25046), this study will 
evaluate the efficacy of ocrelizumab compared with placebo in a population that also 
includes patients with more advanced PPMS who acquired significant lower extremity 
impairment.  This study will enroll patients with PPMS with an EDSS score of 3.0-8.0 
and duration of disease less than 10 years if EDSS score  5.0 or less than 15 years if 
EDSS score 5.56.5 or less than 20 years if EDSS score 7.08.0 with an age range up 
to  65 years.  These criteria will be implemented to recruit patients with PPMS later in 
their disease course and with a higher severity of disability.  The study will also evaluate 
the efficacy of ocrelizumab on the preservation of upper limb function using the 9-HPT 
measure as a key secondary objective, and the treatment effect of ocrelizumab will be 
explored according to the presence of inflammatory activity on MRI at baseline.  
3.4.3 
Rationale for Control Group 
In this study, the control group treatment is placebo.  
PPMS is a neurologically disabling condition, without a disease-modifying treatment until 
recently.  Ocrelizumab is the first and currently the only MS treatment approved for the 
PPMS indication, and its label differs depending on the region.  Ocrelizumab was 
approved by the European Commission on 8 January 2018 for patients with early PPMS 
in terms of disease duration and level of disability, and with imaging features 
characteristic of inflammatory activity.  Additional evidence was requested by the EMA 
Committee for Medicinal Products to further elaborate the effect of ocrelizumab on the 
patient population with PPMS later in their disease course (EDSS score  6.5), in 
patients aged 5565 years, and in patients with different inflammatory profiles. 
Pursuant to the Helsinki Declaration, when standard treatment of a disease exists, 
placebo should generally not be used in clinical trials (WMA 1964).  The benefits, risks, 
burdens, and effectiveness of a new intervention must be tested against those of the 
best current proven intervention, except in the following circumstances: 
 
The use of placebo, or no treatment, is acceptable in studies where no current 
proven intervention exists, or 
 
Where, for compelling and scientifically sound methodological reasons, the use of 
placebo is necessary to determine the efficacy or safety of an intervention and the 
subjects who receive placebo, or no treatment will not be subject to any risk of 
serious or irreversible harm.  Extreme care must be taken to avoid abuse of this 
option. 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
41/Protocol WA40404, Version 6 
To better contextualize the efficacy of the various PPMS subgroups, a broader 
population needs to be investigated in a controlled trial.  Given that no standard therapy 
exists in the European Union and some other parts of the world for the treatment of 
patients with PPMS later in their disease course/without imaging features characteristic 
of inflammatory activity, a placebo-controlled trial is acceptable provided that appropriate 
patient consent and safeguards are instituted to minimize the risk of serious or 
irreversible harm resulting from exposure to placebo.  In this study, patients randomized 
to placebo who experience a DPE during the double-blind treatment phase will be given 
the option to switch to ocrelizumab (see Section 3.1.1.3). 
The Sponsor recognizes that a treatment period lasting up to 144 weeks poses risks to 
patients randomized to placebo.  For this reason, several study elements will be 
employed to protect the well-being of study participants: 
 
The Informed Consent Form clearly defines the duration of the study including the 
double-blind treatment phase, OLE phase, and follow-up phases.  The probabilities 
of assignment to placebo and ocrelizumab are indicated in easily understood terms 
in multiple sections of the Informed Consent Form.  
 
Patients who experience a DPE during the double-blind treatment phase will be 
given the option to switch to PDP OCR after they have completed at least 
120 weeks of double-blind treatment (see Section 3.1.1.3 for definition of DPE).  
Patients will have to provide their informed consent prior to switching to PDP OCR. 
 
A thorough medical monitoring plan will be implemented by the study Sponsor to 
ensure the safety of all study participants.  Moreover, an iDMC will be instituted to 
further protect the wellbeing of patients in the study. 
 
Upon withdrawal from study treatment for any reason, patients will be recommended 
to stay in the study for follow-up but may be eligible for treatment with some 
alternative therapies at the discretion of and in consultation with their Treating 
Investigator. 
 
3.4.4 
Rationale for the Use of Premedications (Methylprednisolone 
and Antihistamines)  
To reduce the frequency and severity of infusion-related reactions (IRRs), patients will 
be premedicated with 100 mg methylprednisolone IV (or equivalent oral dose of 
prednisolone or methylprednisolone, should IV methylprednisolone not be available) 
and an antihistamine approximately 30 minutes prior to administration of ocrelizumab 
(see Section 4.3.2.2).  An integrated analysis of patients with MS who were treated with 
ocrelizumab revealed that the addition of antihistamines to the pretreatment with 
methylprednisolone decreased the incidence of IRRs by 2-fold (OCREVUS U.S. 
Package Insert).  Administered infrequently at a low dose, methylprednisolone is not 
anticipated to affect the efficacy or safety outcomes of the study.  Methylprednisolone (or 
an alternative steroid in patients where methylprednisolone is contraindicated) will be 
administered to patients in both treatment groups during the treatment period to maintain 
the treatment blind. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
42/Protocol WA40404, Version 6 
3.4.5 
Rationale for Biomarker Assessments 
A blood protein biomarker sample (plasma and serum) will be taken.  Assessment of the 
sample may include, but will not be limited to, NfL, a marker of neuronal injury and/or 
other neurodegeneration/inflammatory markers.  Biomarkers of neuroinflammation, 
including NfL, an acute neuronal injury marker, has been correlated with Gd-enhancing 
MRI lesions and clinical relapses (Burman et al. 2014) and with response to drug 
treatment in PPMS and RMS (Gunnarsson et al. 2011; Axelsson et al. 2014, Kuhle et al. 
2019).  NfL can be detected in the blood, and blood levels are correlated with CSF 
levels, making NfL an attractive non-invasive biomarker to assess neuronal injury in MS 
(DiSanto et al. 2017).  In addition, NfL is prognostic for worse disability outcome in RMS 
and PPMS (Bar-Or et al. 2019; Kuhle et al. 2019).  If the patient requires a CSF sample 
to screen for IgG index or the presence of oligoclonal bands at screening, the leftover 
CSF will be stored and the assessment of the sample may include, but will not be limited 
to, NfL.  Patients for whom screening CSF was collected will have the option to 
participate in a collection of CSF at Week 48; this sample will be used for exploratory 
biomarker determination that may include, but may not be limited to, NfL.  NfL, in 
addition to other possible markers, may be used to assess the patient’s disease activity, 
and/or as a pharmacodynamic, prognostic, or predictive biomarker(s) for disease 
progression and/or to assess drug activity, efficacy, safety, or MS pathogenesis. 
Exploratory research on safety biomarkers may be conducted to support future drug 
development.  Research may include further characterization of a safety biomarker or 
identification of safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation.  
Adverse event reports will not be derived from exploratory safety biomarker data by the 
Sponsor, and safety biomarker data will not be included in the formal safety analyses for 
this study.  In addition, safety biomarker data will not inform decisions on patient 
management. 
3.4.6 
Rationale for Collection of Information on Race and 
Ethnicity  
Data pertaining to participant race and ethnicity represents a component of the broad 
demographic profile of the study population.  Collection of demographic data, including 
information on race and ethnicity, is of importance to the future interpretation of 
results from the clinical trial, including identification of potential differences in 
efficacy, safety, and pharmacokinetics among participants.  Collection of race and 
ethnicity data may enable investigation of potential relationships between biomarkers 
and race or ethnicity, including determination of whether race or ethnicity could be a 
prognostic factor.  Collection of these data may also contribute to a better 
understanding of the distribution of PPMS according to race or ethnicity. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
43/Protocol WA40404, Version 6 
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
Approximately 1000 patients will be enrolled in this study, of which at least 350 patients 
are planned to be in the MRI-active subgroup. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
Ability to provide written informed consent and be compliant with the study protocol 
 
Diagnosis of PPMS in accordance with the McDonald criteria (Thompson et al. 
2017) 
 
Age 1865 years at time of signing Informed Consent Form 
 
EDSS score at screening and baseline  3.0 to 8.0, inclusive 
 
Disease duration from the onset of MS symptoms relative to randomization date: 
Less than 20 years in patients with an EDSS score at screening 7.08.0 
Less than 15 years in patients with an EDSS score at screening 5.56.5 
Less than 10 years in patients with an EDSS score at screening  5.0 
 
Documented history or presence at screening of at least one of the following 
laboratory findings in a CSF specimen (source documentation of laboratory results 
and method must be verified) 
Elevated IgG index 
One or more IgG oligoclonal bands detected by isoelectric focusing 
 
Screening and baseline 9-HPT completed in  25 seconds (average of the 
two hands) 
 
Ability to complete the 9-HPT within 240 seconds with each hand at screening and 
baseline 
 
Neurological stability for  30 days prior to baseline 
 
Patients previously treated with immunosuppressants, immunomodulators, or other 
immunomodulatory therapies must undergo an appropriate washout period 
according to the local label of the immunosuppressant/immunomodulatory drug 
used 
Patients screened for this study should not be withdrawn from therapies for the 
sole purpose of meeting eligibility for the trial.  Patients who discontinue their 
current therapy for non-medical reasons should specifically be informed before 
deciding to enter the study of their treatment options and, that by participating in 
this study, they may be randomized to placebo for a period of 120 weeks or 
greater. 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use adequate contraceptive methods during the 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
44/Protocol WA40404, Version 6 
treatment period and for 6 or 12 months (as applicable by the Ocrevus local label) 
after the final dose of ocrelizumab. 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  Per this definition, a female participant with a tubal 
ligation is considered to be of childbearing potential.  The definition of 
childbearing potential may be adapted for alignment with local guidelines or 
requirements. 
The following contraceptive methods are considered acceptable (failure 
rate  1% [Clinical Trial Facilitation Group (CTFG)]): (1) progestogen-only oral 
hormonal contraception, where inhibition of ovulation is not the primary mode of 
action; (2) male or female condom with or without spermicide; (3) cap, 
diaphragm, or sponge with spermicide; (4) combination of male condom with 
cap, diaphragm, or sponge with spermicide (double-barrier method). 
Birth control methods that are highly effective (i.e. failure rate  1% [CTFG]) may 
also be used but are not required, and include:  (1) oral, intravaginal or 
transdermal combined hormonal contraception associated with inhibition of 
ovulation; (2) oral, injectable or implantable progestogen-only hormonal 
contraception associated with inhibition of ovulation; (3) intrauterine device; 
(4) intrauterine hormone-releasing system; (5) bilateral tubal occlusion; 
(6) vasectomised partner; (7) sexual abstinence. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the individual.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not adequate methods of contraception.  
If required per local guidelines or regulations, locally recognized adequate 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form. 
 
For female patients without reproductive potential: 
Women may be enrolled if surgically sterile (i.e., hysterectomy, complete 
bilateral oophorectomy) or post-menopausal (i.e., spontaneous amenorrhea for 
the past year confirmed by a follicle-stimulating hormone [FSH] 
level  40 mIU/mL), unless the patient is receiving a hormonal therapy for her 
menopause.  
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
History of relapsing-remitting or secondary progressive MS at screening 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
45/Protocol WA40404, Version 6 
 
Confirmed serious opportunistic infection including:  active bacterial, viral, fungal, 
mycobacterial infection or other infection, including tuberculosis or atypical 
mycobacterial disease  
 
Patients who have or have had confirmed or a high degree of suspicion of 
progressive multifocal leukoencephalopathy (PML) 
 
Known active malignancy or are being actively monitored for recurrence of 
malignancy 
 
Immunocompromised state, defined as one or more of the following: 
CD4 count  250/L 
Absolute neutrophil count  1.5  103/L 
Serum IgG  4.6 g/L 
 
Receipt of a live-attenuated vaccine within 6 weeks prior to randomization 
 
Inability to complete an MRI (contraindications for MRI, including but not restricted 
to, pacemaker, cochlear implants, intracranial vascular clips, surgery within 6 weeks 
of entry in the study, coronary stent implanted within 8 weeks prior to the time of the 
intended MRI, etc.) or contraindication to Gd administration 
 
Patients requiring symptomatic treatment of MS (e.g., fampridine) and/or 
physiotherapy who are not on a stable regimen.  Patients must not initiate 
symptomatic treatment of MS or physiotherapy within 4 weeks of randomization. 
 
Contraindications to mandatory premedications (i.e., corticosteroids and 
antihistamines) for IRRs, including: 
Uncontrolled psychosis for corticosteroids 
Closed-angle glaucoma for antihistamines 
 
Known presence of other neurologic disorders that could interfere with the diagnosis 
of MS or assessments of efficacy and/or safety during the study, including, but not 
limited to, the following: 
History of hemorrhagic or ischemic cerebrovascular disorders (e.g., stroke, 
transient ischemic attack) or hemorrhage or ischemia of the spinal cord 
History or known presence of CNS or spinal cord tumor (e.g., meningioma, 
glioma) 
History of metabolic myelopathy or known presence of untreated causes of 
metabolic myelopathy (e.g., untreated vitamin B12 deficiency) 
History or known presence of infectious myelopathy (e.g., due to syphilis, Lyme 
disease, HTLV-1, herpes zoster) 
History of genetically inherited progressive CNS degenerative disorder (e.g., 
mitochondrial myopathy, encephalopathy, lactic acidosis, stroke [MELAS] 
syndrome, and hereditary paraparesis) 
Neuromyelitis optica 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
46/Protocol WA40404, Version 6 
History or known presence of systemic autoimmune disorders potentially 
causing progressive neurologic disease (e.g., lupus, anti-phospholipid antibody 
syndrome, Sjögren syndrome, Behçet disease) 
History or known presence of sarcoidosis 
History of severe, clinically significant brain or spinal cord trauma (e.g., cerebral 
contusion, spinal cord compression) 
 
Pregnant or breastfeeding, or intending to become pregnant during the study and for 
6 or 12 months (as applicable by the Ocrevus local label) after last infusion of the 
study drug 
 
Lack of peripheral venous access 
 
Significant, uncontrolled disease, such as cardiovascular (including cardiac 
arrhythmia), pulmonary (including obstructive pulmonary disease), renal, hepatic, 
endocrine or gastrointestinal, or any other significant disease that may preclude 
patient from participating in the study 
 
Any concomitant disease that may require chronic treatment with systemic 
corticosteroids or immunosuppressants during the course of the study 
 
History of alcohol or other drug abuse 
 
History of primary or secondary (non drug-related) immunodeficiency 
 
Treatment with any investigational agent within 24 weeks prior to screening (Visit 1) 
or 5 half-lives of the investigational drug (whichever is longer), or treatment with any 
experimental procedure for MS (e.g., treatment for chronic cerebrospinal venous 
insufficiency) 
 
Previous treatment with B cell-targeting therapies (e.g., rituximab, ocrelizumab, 
atacicept, belimumab, ofatumumab, and alemtuzumab) 
 
Any previous treatment with bone marrow transplantation and hematopoietic stem 
cell transplantation 
 
Any previous history of transplantation or anti-rejection therapy 
 
Treatment with IV Ig or plasmapheresis within 12 weeks prior to randomization 
 
Systemic corticosteroid therapy within 4 weeks prior to screening 
The screening period may be extended for patients who have used systemic 
corticosteroids for MS before screening.  For a patient to be eligible, systemic 
corticosteroids should also not have been administered between screening and 
baseline. 
 
Positive serum -hCG measured at screening or positive urine -hCG at baseline 
 
Positive screening tests for hepatitis B (hepatitis B surface antigen [HBsAg] positive, 
or positive hepatitis B core antibody [total HBcAb] confirmed by a positive viral 
DNA PCR)  
 
Any additional exclusionary criterion as per ocrelizumab (Ocrevus) local label, 
if more stringent than the above 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
47/Protocol WA40404, Version 6 
 
Lack of MRI activity at screening/baseline if more than 650 patients without MRI 
activity have already been enrolled, as defined by T1 Gd lesion(s) and/or new 
and/or enlarged T2 lesion(s) in the screening, to ensure that at least 350 patients 
with MRI activity will be randomized 
 
Re-testing before baseline:  In rare cases in which the screening laboratory samples are 
rejected by the central laboratory (e.g., hemolyzed sample) or the result is not 
assessable (e.g., 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. 
4.1.3 
Eligibility Criteria for Open-Label Extension Phase 
Patients who meet the following entry criteria may participate in the OLE phase: 
 
Either completed 144 weeks of the double-blind treatment phase of the trial or are 
ongoing in the double-blind treatment phase at the time of the primary analysis and 
who, in the opinion of the investigator, may benefit from treatment with ocrelizumab 
Patients who withdrew from study treatment and received another 
disease-modifying therapy (DMT) or commercial ocrelizumab will not be 
allowed to enter in the OLE phase. 
 
Able and willing to provide written informed consent to participate in the OLE phase 
and to comply with the study protocol  
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use adequate contraceptive methods during the 
treatment period and for 6 or 12 months (as applicable by the Ocrevus local label) 
after the final dose of ocrelizumab. 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  Per this definition, a female participant with a tubal 
ligation is considered to be of childbearing potential.  The definition of 
childbearing potential may be adapted for alignment with local guidelines or 
requirements. 
The following contraceptive methods are considered acceptable (failure 
rate   1% [CTFG]):  (1) progestogen-only oral hormonal contraception, where 
inhibition of ovulation is not the primary mode of action; (2) male or female 
condom with or without spermicide; (3) cap, diaphragm, or sponge with 
spermicide; (4) combination of male condom with cap, diaphragm, or sponge 
with spermicide (double-barrier method). 
Birth control methods that are highly effective (i.e. failure rate  1% [CTFG]) may 
also be used but are not required, and include:  (1) oral, intravaginal or 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
48/Protocol WA40404, Version 6 
transdermal combined hormonal contraception associated with inhibition of 
ovulation; (2) oral, injectable or implantable progestogen-only hormonal 
contraception associated with inhibition of ovulation; (3) intrauterine device; 
(4) intrauterine hormone-releasing system; (5) bilateral tubal occlusion; 
(6) vasectomised partner; (7) sexual abstinence. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the individual.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not adequate methods of contraception.  
If required per local guidelines or regulations, locally recognized adequate 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form. 
For female patients without reproductive potential: 
Women may be enrolled if surgically sterile (i.e., hysterectomy, complete 
bilateral oophorectomy) or post-menopausal (i.e., spontaneous amenorrhea for 
the past year confirmed by a FSH level  40 mIU/mL), unless the patient is 
receiving a hormonal therapy for her menopause.  
 
4.2 
METHODS OF TREATMENT ASSIGNMENT AND BLINDING  
Randomization and blinding will be employed to minimize bias in treatment assignment 
and to provide the basis for valid statistical inference.  Eligible patients must be 
randomized through IxRS prior to receiving any study drug.  Patients who discontinue 
treatment for any reason will not be replaced.  Under no circumstances are patients who 
enroll in this study and who have completed treatment as specified, permitted to be 
re-randomized to this study. 
The randomization list will not be available to the study centers, monitors, project 
statisticians, or to the Sponsor project team.  All individuals directly involved in the study 
will remain blinded to the treatment assignment until the primary analysis.  
To maintain integrity of the trial results and to prevent potential unblinding of the 
assigned arm during the double-blind treatment phase as a result of adverse events or 
changes to laboratory results, the following additional measures will be implemented 
until the time of the primary analysis: 
 
To prevent potential unblinding as a result of adverse events or laboratory changes, 
a “dual assessor” approach will be used to evaluate efficacy and safety.  Each 
site will have two blinded investigators:  a principal or Treating Investigator 
and a rating or Examining Investigator. 
The Treating Investigator will be the safety assessor and should be a 
neurologist with experience in the care of patients with MS.  The Treating 
Investigator will have access to safety data only and will make all treatment 
decisions based on the patient’s clinical response and laboratory findings. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
49/Protocol WA40404, Version 6 
The Examining Investigator will be the efficacy assessor and should be 
a neurologist or other qualified health care practitioner trained and certified in 
administering and scoring the 9-HPT, Functional System Scores (FSS) and 
EDSS, and SDMT.  The Examining Investigator (or her/his certified 
designee) will assess the 9-HPT, EDSS scores (including 
dysphagia/bladder dysfunction assessments), and SDMT.  Until the primary 
analysis, the Examining Investigator and their qualified designees (if applicable) 
will not be involved with any aspect of medical management of the patient and 
will not be allowed access to patient data. 
The Treating Investigator and the Examining Investigator will not be allowed to 
switch roles.  Until the primary analysis, an investigator/site staff at a single site 
may not be a treating investigator for some patients and an examining 
investigator for others. 
 
Patient education:  During the double-blind treatment phase, prior to being 
examined by the Examining Investigator, patients should be instructed not to 
discuss with the Examining Investigator what (if any) adverse effects they may be 
experiencing. 
 
Blinded, central MRI assessments:  During the double-blind treatment phase, 
a blinded, central MRI reader will assess all MRI scans performed during the study.  
Of note, screening and baseline scans will be used for the assessment of patient 
eligibility, and therefore they will not be blinded. 
 
Blinding of laboratory parameters:  Selected laboratory parameters that may lead to 
unblinding of the treatment assignment, such as flow cytometry assessment of cell 
counts including CD19 cells, lymphocyte count, and Ig levels will be blinded in all 
patients until the primary analysis.  To ensure patient safety during the study and to 
allow for assessments of the re-treatment criteria, a central laboratory will provide 
study investigators and the Medical Monitor(s) with reflex messages triggered by 
abnormal blinded laboratory results and will be instructed to suspend further 
treatment with study drug until the patient becomes eligible for ocrelizumab 
re‑treatment.  Investigators will be notified of their patient’s abnormal laboratory test 
results.  Consult the laboratory manual for additional information. 
 
Ocrelizumab and placebo treatment allocation will remain blinded until the primary 
database lock for the primary analysis. 
 
To facilitate analysis of the biological samples collected in this study, the treatment code 
will be released to the responsible analytical person when the samples have been 
received at the analytical site and are ready for assay.  The result of the analysis must 
not be released with individual identification of the patient until after the unblinding for 
the primary analysis. 
Study site personnel and patients will be blinded to treatment assignment until after the 
primary analysis.  The Sponsor and its agents will also be blinded to treatment 
assignment, with the exception of individuals who require access to patient treatment 
assignments to fulfill their job roles during a clinical trial.  These roles include the 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
50/Protocol WA40404, Version 6 
unblinding group responsible, clinical supply chain managers, sample handling staff, 
IxRS service provider, and iDMC members. 
While PK and ADA samples must be collected from patients assigned to the comparator 
arm to maintain the blinding of treatment assignment, PK and ADA assay results for 
these patients are generally not needed for the safe conduct or proper interpretation of 
this study.  Laboratories responsible for performing study drug PK and ADA assays will 
be unblinded to patients' treatment assignments to identify appropriate samples to be 
analyzed.  PK samples from patients assigned to the comparator arm will not be 
analyzed for study drug PK concentration except at baseline or by request (e.g., to 
evaluate a possible error in dosing).  ADA samples will be analyzed for all patients 
treated with study drug. 
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The investigator is not required to contact the Medical Monitor prior 
to breaking the treatment code in an emergency situation.  However, the Medical 
Monitor should be informed that the treatment code has been broken. 
The investigator will also be able to break the treatment code to determine the 
suitability of subsequent medical care for a patient.  However, approval must be 
obtained from the Medical Monitor if the investigator wants to break the treatment code 
to determine patient’s eligibility for a subsequent clinical trial testing investigational 
medicinal products or procedures.  The investigator must contact the Medical Monitor 
prior to breaking the treatment code for any reason other than a medical emergency.  
The investigator should document and provide a justification for any non-emergency 
unblinding.   
As per health authority reporting requirements, the Sponsor's Drug Safety representative 
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the investigator or Sponsor to be related to 
study drug.  The patient may continue to receive treatment, and the investigator, patient, 
and Sponsor personnel, with the exception of the Drug Safety representative and 
personnel who must have access to patient treatment assignments to fulfill their roles 
(as defined above), will remain blinded to treatment assignment. 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The investigational medicinal product (IMP) for this study is ocrelizumab and matching 
placebo used to maintain the blind. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
51/Protocol WA40404, Version 6 
4.3.1 
Study Treatment Formulation, Packaging, and Handling 
4.3.1.1 
Ocrelizumab and Placebo 
Ocrelizumab will be supplied by the Sponsor in 15 cc Type I glass vials as a sterile, 
single-use solution for IV infusion and contains no preservatives.  Each vial contains 
300 mg of ocrelizumab, at a nominal fill volume of 10 mL.  The drug product is 
formulated as 30 mg/mL ocrelizumab in 20 mM sodium acetate at pH 5.3, with 106 mM 
trehalose dihydrate and 0.02% polysorbate 20.  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 using an infusion set with an in-line, 
sterile, non-pyrogenic, low-protein-binding filter (pore size of 0.2 micrometer or less).  
For information on the formulation and handling of ocrelizumab, see the Ocrelizumab 
Investigator's Brochure, local prescribing information, and Drug Preparation Guidelines. 
In this study, ocrelizumab-matching placebo will be supplied by the Sponsor.  The 
placebo will have the same composition and configuration as the drug product but will 
not contain ocrelizumab.  Ocrelizumab placebo solutions for IV administration will be 
prepared by dilution of the ocrelizumab placebo into infusion bags containing 0.9% 
sodium chloride, using an identical procedure as for the active product. 
4.3.1.2 
Non-Investigational/Auxiliary Medicinal Products  
In this study, non-investigational/Auxiliary medicinal products will include premedication 
to the ocrelizumab infusion.  The following premedication will be used: 
 
Mandatory methylprednisolone (or an equivalent)  
 
Mandatory antihistaminic drug (e.g., diphenhydramine)  
 
Recommended oral analgesic/antipyretic (e.g., acetaminophen 1 g) 
 
Refer to Section 4.3.2.2 for further details on premedication administration. 
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.1.  Any dose modification should 
be noted on the Study Drug Administration Electronic Case Report Form (eCRF).  Cases 
of accidental overdose or medication error, along with any associated adverse events, 
should be reported as described in Section 5.4.4.  
Guidelines for treatment modification, interruption, or discontinuation for patients who 
experience adverse events are provided in Section 5.1.4.3. 
4.3.2.1 
Ocrelizumab and Placebo 
The ocrelizumab dose administered will be 600 mg every 24 weeks.  The first dose of 
ocrelizumab will be administered as two 300 mg IV infusions given 14 days apart.  For 
the subsequent doses, ocrelizumab will be administered as a single 600-mg IV infusion 
every 24 weeks.  A minimum interval of 20 weeks must be kept between the 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
52/Protocol WA40404, Version 6 
ocrelizumab second infusion during the double-blind treatment phase (Dose 1) and the 
next infusion at double-blind treatment phase (Dose 2).  A minimum interval of 22 weeks 
must be maintained between each dose of ocrelizumab.  This dosing regimen is 
consistent with the dosing regimen used in the ocrelizumab Phase III/IV studies, as well 
as with the SmPC and the USPI (see Table 4). 
Patients who experience a DPE during the double-blind treatment phase will be given 
the option to switch to PDP OCR after they completed at least 120 weeks of double-blind 
treatment (see Section 3.1.1.3 for details).  To maintain the original blind, PDP OCR will 
be offered to all patients who qualify, regardless of their original treatment assignment.  
The first dose of the PDP OCR will be administered as two 300 mg IV infusions (given 
14 days apart) 24 weeks after the last dose of blinded study drug.  A minimum interval of 
20 weeks must be kept between the ocrelizumab second infusion during the PDP OCR 
(Dose 1) and the next infusion at PDP OCR (Dose 2).  A minimum interval of 22 weeks 
must be maintained between each dose of ocrelizumab. 
Patients who are eligible (see Section 3.1.1.5) and wish to enter the OLE phase will 
receive two 300 mg IV infusions given 14 days apart for the first OLE dose (OLE 
Dose 1).  For subsequent doses, patients will continue open-label treatment with a single 
IV infusion of 600 mg ocrelizumab every 24 weeks (OLE Doses 2-N; see Appendix 3 for 
more details). 
Ocrelizumab infusions should be initiated and supervised by an experienced 
professional with access to appropriate medical support to manage severe reactions 
such as serious IRRs.  It is anticipated that the patient will need to stay at the hospital or 
clinical site for a full day at an infusion visit.  Each ocrelizumab 300 mg dose should be 
administered as a slow IV infusion over approximately 2.5 hours.  Each ocrelizumab 
600 mg dose should be administered as a slow IV infusion over approximately 3.5 hours. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
53/Protocol WA40404, Version 6 
Table 4 
Overview of Ocrelizumab or Placebo Dosing and Schedule 
 
Amount of Ocrelizumab (or 
Placebo) to Be Administered 
Infusion Instructions 
Initial dose 
(600 mg), divided 
into two infusions a 
Infusion 1 
300 mg IV in 
250 mL 
0.9% sodium 
chloride 
 Initiate the infusion at a rate of 
30 mL/hr for 30 minutes. 
 The rate can be increased in 30 mL/hr 
increments every 30 minutes to a 
maximum of 180 mL/hr. 
 Each infusion should be given over 
approximately 2.5 hours. 
Infusion 2 
(2 weeks 
later) b 
300 mg IV in 
250 mL 
0.9% sodium 
chloride 
Subsequent doses 
(600 mg), b once 
every 24 weeks 
Single 
infusion b 
600 mg IV in 
500 mL 
0.9% sodium 
chloride 
 Initiate the infusion at a rate of 
40 mL/hr for 30 minutes. 
 The rate can be increased in 40 mL/hr 
increments every 30 minutes to a 
maximum of 200 mL/hr. 
 Each infusion should be given over 
approximately 3.5 hours. 
a For patients who receive ocrelizumab at study start of the double-blind phase, start 
PDP OCR, or start OLE. 
b Prior to the next infusion, a clinical evaluation will be performed to ensure that the patient 
remains eligible for re-treatment. 
Note:  Before each infusion of ocrelizumab, 100 mg of methylprednisolone IV and an 
antihistaminic drug will be administered to reduce the potential for infusion-related reactions. 
 
Alternative Shorter Infusion of Subsequent 600 mg Ocrelizumab Doses 
If patient 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 during 
any treatment phase.  This does not apply for any initial dose (i.e., for patients who 
receive ocrelizumab at study start of the double-blind phase, start PDP OCR, or start 
OLE).  The shorter infusion should be started at a rate of 100 mL/h.  This should be 
escalated at the rates shown in Table 5. 
Table 5 
Alternative Shorter Infusions of Ocrelizumab 600 mg 
Time 
(minutes) 
Infusion Rate 
(mL/hr) 
Maximum Dose per Interval a 
(mg) 
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 Dose Preparation Guidelines for more information. 
b The shorter infusion of 600 mg ocrelizumab should be completed in approximately 
120 minutes (2 hours). 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
54/Protocol WA40404, Version 6 
 
Refer to Section 5.1.1.1 of this protocol and to current version of the IB for further details 
on the alternative shorter infusion option, including safety information. 
Ocrelizumab must not be administered as an IV push or bolus.  Well-adjusted infusion 
pumps should be used to control the infusion rate, and ocrelizumab should be infused 
through a dedicated line.  It is important not to use evacuated glass containers, which 
require vented administration sets, to prepare the infusion because this causes foaming 
as air bubbles pass through the solution. 
The patient will need to remain at the clinic at every visit for at least 1 hour after the 
completion of the infusion for observation.  After completion of the infusion, the IV 
cannula should remain in situ for at least 1 hour to allow for administration of drugs 
intravenously, 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 patient may be 
discharged. 
4.3.2.2 
Premedications 
Methylprednisolone has been shown to decrease the incidence and the severity of 
infusion reactions.  An integrated analysis of patients with MS treated with ocrelizumab 
revealed that the addition of antihistamines pretreatment with methylprednisolone 
decreased the incidence of IRRs by 2-fold. 
To reduce potential IRRs, all patients must receive mandatory prophylactic treatment 
with 100 mg of methylprednisolone administered by slow IV infusion (or equivalent oral 
dose of prednisolone or methylprednisolone, should IV methylprednisolone not be 
available), to be completed approximately 30 minutes before the start of each 
ocrelizumab (or placebo) infusion.  In the rare case when the use of methylprednisolone 
is contraindicated for the patient, use of an equivalent dose of an alternative steroid 
should be used as premedication prior to the infusion. 
Additionally, a mandatory oral or IV antihistaminic drug (such as IV diphenhydramine 
50 mg or an equivalent dose of an alternative) must be administered approximately 
3060 minutes prior to the start of each ocrelizumab (or placebo) infusion. 
Analgesic/antipyretic such as acetaminophen/paracetamol (1 g) can also be considered. 
Hypotension, as a symptom of IRR, may occur during study drug IV infusions.  
Therefore, withholding antihypertensive treatments should be considered for 12 hours 
prior to and throughout each study drug infusion. 
4.3.2.3 
Re-Treatment Criteria for Ocrelizumab 
Prior to re-treatment, the following conditions must be met: 
 
Absence of severe allergic or anaphylactic reaction to a previous ocrelizumab 
infusion 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
55/Protocol WA40404, Version 6 
 
Absence of any significant or uncontrolled medical condition or treatment-emergent, 
clinically significant laboratory abnormality 
 
Absence of active infection 
 
ANC  1.5  103/L 
 
CD4 cell count  250/L 
 
IgG  3.3 g/L 
 
Negative pregnancy test 
In the event of pregnancy, the investigator must counsel the patient as to the 
risks of continuing with the pregnancy and the possible effects on the fetus.  
Given 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 patients should continue to follow the schedule of 
activities for the study; however, no infusions will occur.  If there is a concern 
with the ability of a pregnant or breastfeeding patient to perform all scheduled 
assessments, 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 patient and investigator. 
 
If any of these are not met prior to re-dosing, further administration of ocrelizumab must 
be suspended until resolved or held indefinitely. 
4.3.3 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study will be provided by the Sponsor.  The study 
site (i.e., investigator or other authorized personnel [e.g., pharmacist]) is responsible for 
maintaining records of IMP delivery to the site, IMP inventory at the site, IMP use by 
each patient, and disposition or return of unused IMP, thus enabling reconciliation of all 
IMP received, and for ensuring that patients are provided with doses specified by the 
protocol. 
The study site should follow all instructions included with each shipment of IMP.  The 
study site will acknowledge receipt of IMPs supplied by the Sponsor, using the IxRS to 
confirm the shipment condition and content.  Any damaged shipments will be replaced.  
The investigator or designee must confirm that appropriate temperature conditions have 
been maintained during transit, either by time monitoring (shipment arrival date and 
time) or temperature monitoring, for all IMPs received and that any discrepancies have 
been reported and resolved before use of the IMPs.  All IMPs must be stored in 
a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions, with access limited to the investigator 
and authorized staff. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
56/Protocol WA40404, Version 6 
Only patients enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs. 
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor with the appropriate 
documentation.  The site's method of destroying Sponsor-supplied IMPs must be agreed 
to by the Sponsor.  The site must obtain written authorization from the Sponsor before 
any Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on 
the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the drug accountability log. 
Refer to the pharmacy manual and the effective ocrelizumab for information on IMP 
handling, including preparation and storage, and accountability. 
4.3.4 
Continued Access to Ocrelizumab 
Patients may be eligible to receive ocrelizumab as part of the OLE phase of this study, 
as described in Section 3.1.1.5. 
The Sponsor will offer continued access to Roche IMP ocrelizumab free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below. 
A patient will be eligible to receive Roche IMP ocrelizumab after completing the study 
if all of the following conditions are met: 
 
The patient has a life-threatening or severe medical condition and requires 
continued Roche IMP treatment for his or her well-being 
 
There are no appropriate alternative treatments available to the patient 
 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 
A patient will not be eligible to receive Roche IMP ocrelizumab after completing the 
study if any of the following conditions are met: 
 
The Roche IMP is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient) 
 
The patient has been treated with commercial ocrelizumab 
 
The Sponsor has discontinued development of the IMP or data suggest that the IMP 
is not effective for PPMS 
 
The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
PPMS 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
57/Protocol WA40404, Version 6 
 
Provision of the Roche IMP is not permitted under the laws and regulations of the 
patient's country 
 
The Roche IMP is no longer manufactured. 
 
In these situations, the investigator and primary care physician will transition the 
study participant to an alternative therapy in accordance with institutional or local 
guidelines.  
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website: 
https://assets.cwp.roche.com/f/176343/x/92d6b13ee6/policy_continued_access_to_invest
igational_medicines.pdf 
4.4 
CONCOMITANT THERAPY 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 7 days 
prior to initiation of study drug or ongoing therapy (e.g., physiotherapy) to the study 
completion/discontinuation visit.  All such medications and therapies (including their 
indication) should be reported to the investigator and recorded on the appropriate eCRF. 
4.4.1 
Treatment for Symptoms of Multiple Sclerosis 
The investigator should attempt to maintain therapies (e.g., physiotherapy) or treatments 
for symptoms related to MS (e.g., walking ability, spasticity, incontinence, pain, fatigue) 
reasonably constant throughout the study.  However, changes (including starting 
physiotherapy and/or symptomatic treatment) may be made if appropriate for patient’s 
well-being in the clinical judgment of the Treating Investigator. 
4.4.2 
Treatment of Relapses 
Patients who experience a relapse during study may receive treatment with IV or oral 
corticosteroids, if judged to be clinically appropriate by the investigator.  The following 
standardized treatment regimen may be used as warranted:  1 g/day IV 
methylprednisolone 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 patients should not discontinue the treatment solely based on the 
occurrence of a relapse, unless the patient or investigator feels he or she has met the 
criteria for withdrawal (see Section 4.7.1). 
4.4.3 
Prohibited Therapy and Alternative Treatment Post 
Ocrelizumab 
The following therapies for MS are not permitted during the study treatment phase:  
B cell-targeted therapies (e.g., rituximab, atacicept, belimumab, or ofatumumab), 
natalizumab, fingolimod, siponimod, alemtuzumab, daclizumab, cladribine, teriflunomide, 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
58/Protocol WA40404, Version 6 
dimethyl fumarate, interferons, glatiramer acetate, cyclophosphamide, mitoxantrone, 
azathioprine, mycophenolate mofetil, cyclosporine, methotrexate, total body irradiation, 
bone marrow transplantation, IV Ig, plasmapheresis, other approved or investigational 
therapies for MS. 
After patients have completed (or discontinued) treatment with ocrelizumab, they may 
receive alternative treatment for their MS as judged clinically appropriate by the 
investigator.  However, as sufficient data are not available regarding risks associated 
with switching to other products, the following recommendations are given: 
 
Caution is advised while patients remain B-cell depleted.  
 
Because of the unknown safety risk of administering disease-modifying treatments 
for MS after discontinuation of ocrelizumab, certain treatments for MS, such as 
lymphocyte-depleting agents or lymphocyte-trafficking blockers (alemtuzumab, 
natalizumab, fingolimod, dimethyl fumarate, cyclophosphamide, azathioprine, 
cladribine, daclizumab, etc.) are strongly discouraged for as long as the patient 
remains B-cell depleted because of unknown effects on the immune system 
(e.g., increased risk, incidence, or severity of infection). 
 
4.4.4 
Immunizations 
Physicians are advised to review the immunization status of patients who are considered 
for treatment with ocrelizumab and follow local/national guidance for adult vaccination 
against infectious disease.  Immunizations should be completed at least 6 weeks 
prior to first administration of ocrelizumab. 
Immunization with any live or live-attenuated vaccine (i.e., measles, mumps, rubella, oral 
polio vaccine, Bacille Calmette-Guerin, 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 during ocrelizumab treatment and for as long as the 
patient is B-cell depleted.  
Data from the ocrelizumab Phase II and III program currently show that over 2 years 
after treatment with ocrelizumab, the proportions of patients with positive antibody titers 
against Streptococcus pneumoniae, influenza, mumps, rubella, varicella, and tetanus 
toxoid were generally similar to the proportions at baseline. 
Of note:  for seasonal influenza vaccines, it is still recommended to vaccinate patients on 
ocrelizumab.  Refer to the current version of the Ocrelizumab Investigator’s Brochure for 
further guidance and updates on immunization.  
4.5 
STUDY ASSESSMENTS 
The schedules of activities to be performed during the study are provided in Appendix 1, 
Appendix 2, Appendix 3, and Appendix 4.  All activities must be performed and 
documented for each patient.   

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
59/Protocol WA40404, Version 6 
4.5.1 
Informed Consent Forms and Screen Failures  
All patients must sign and date the most current Institutional Review Board/Ethics 
Committee (IRB/EC) approved Informed Consent Form before any study specific 
assessments or procedures (including screening evaluations) are performed.  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a detailed record of 
all patients screened and document eligibility or record reasons for screening failure, as 
applicable. 
4.5.2 
Medical History, Concomitant Medication, and 
Demographic Data 
Medical history, including, but not limited to, clinically significant diseases, surgeries, 
cancer history (including prior cancer therapies and procedures), general cancer risk 
factors, breast cancer-specific risk factors, reproductive status, smoking history and 
smoking status, will be recorded at baseline. 
In addition, all medications (e.g., prescription drugs, over-the-counter drugs, vaccines, 
herbal or homeopathic remedies, nutritional supplements) used by the patient within 
7 days prior to initiation of study treatment and ongoing therapies (e.g., physiotherapy 
including its indication) will be recorded.  At the time of each follow-up physical 
examination, an interval medical history should be obtained, and any changes in 
medications and allergies should be recorded.   
Any previous medications taken for the treatment of MS since disease onset, including 
their start and end dates, and medications taken for the symptoms of MS in the 3-month 
period prior to the baseline visit will be recorded at the baseline visit.  
Demographic data will include age, sex, and self-reported race/ethnicity, if allowed per 
local regulations. 
4.5.3 
Physical Examinations 
A complete physical examination performed at screening should include an evaluation of 
the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF. 
Limited, symptom-directed physical examinations should be performed at specified 
postbaseline visits and as clinically indicated.  Changes from baseline abnormalities 
should be recorded in patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
60/Protocol WA40404, Version 6 
4.5.4 
Vital Signs 
Vital signs will include measurements of systolic and diastolic blood pressure while the 
patient is in a seated position, pulse rate, and temperature.  
On the infusion days, blood pressure, pulse rate, and temperature should be taken 
within 45 minutes prior to the premedication (methylprednisolone) infusion.  In addition, 
blood pressure and pulse rate should be obtained prior to start of infusion, every hour 
during the infusion, at the end of infusion, and 1 hour after the end of the infusion.  On 
non-infusion days, the vital signs may be taken at any time during the visit.  Blood 
pressure and pulse rate will be recorded on the appropriate eCRF.  Temperature should 
be measured and recorded in patient’s notes only.  Clinically significant abnormalities 
should be recorded on the Adverse Event or Infusion-Related 
Reaction/Cytokine-Release Syndrome eCRF.  In the event of an IRR or if clinically 
indicated, additional vital signs readings (e.g., blood pressure and pulse rate) should be 
taken during and post-infusion at the discretion of the investigator and should be 
recorded on a dedicated Vital Sign eCRF.  
4.5.5 
Neurological Examination 
A neurological examination will be performed by the Treating Investigator at every 
planned visit.  During an unscheduled visit, the neurological examination will be 
performed only if deemed necessary. 
In the presence of newly identified or worsening neurological symptoms at any given 
time in the study, a neurological evaluation should be scheduled promptly and performed 
within 7 days of onset of the new or worsening neurological symptom(s). 
Study investigators will screen patients for signs and symptoms of PML through 
evaluation of neurological deficits localized to the cerebral cortex, such as cortical 
symptoms/signs, behavioral and neuropsychological alteration, retrochiasmal visual 
defects, hemiparesis, and cerebellar symptoms/signs (e.g., gait abnormalities, limb 
incoordination).  A mandatory MRI scan and CSF analysis may be warranted to assist in 
the diagnosis of PML.  Refer to Appendix 5 for guidance on the diagnosis of PML. 
Patients with suspected PML, defined as a new or worsening neurological symptom that 
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 serial clinical 
evaluations and appropriate diagnostic testing (see Appendix 5).  The Medical Monitor 
should be contacted by email and should be immediately contacted by telephone. 
A patient with confirmed PML should be withdrawn from treatment.  PML should be 
reported as a serious adverse event (with all available information) with immediate 
notification of the Medical Monitor (see also Section 5.1.1.2). 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
61/Protocol WA40404, Version 6 
4.5.6 
9-Hole Peg Test 
The 9-HPT is a quantitative measure of upper extremity (arm and hand) function 
(Goodkin et al. 1988; Fischer et al. 1999b).  The test device consists of a container 
containing nine pegs and a wood or plastic block containing nine empty holes.  The 
patient is to pick up each of the nine pegs one at a time and as quickly as possible place 
them in the nine holes.  Once all the pegs are in the holes, the patient is to remove them 
again one at a time as quickly as possible and replace them into the container.  The total 
time to complete the task is recorded.  Both the dominant and non-dominant hands are 
tested twice (two consecutive trials of the dominant hand, followed immediately by two 
consecutive trials of the non-dominant hand).  
The 9-HPT will be administered by the Examining Investigator or a qualified designee at 
the timepoints indicated in the schedule of activities (see Appendix 1, Appendix 2, 
Appendix 3, and Appendix 4). 
4.5.7 
Assessment of Disability:  Expanded Disability Status Scale 
Disability in MS is commonly measured by the EDSS.  EDSS will be administered by the 
Examining Investigator at the timepoints indicated in the schedule of activities 
(see Appendix 1, Appendix 2, Appendix 3 and Appendix 4).  The EDSS will be assessed 
in all patients by the Examining Investigator at screening, baseline, and every 12 weeks 
(regularly scheduled visit) during the double-blind treatment and FU1 phases; every 
24 weeks during the OLE phase; at any unscheduled visit; and at treatment 
discontinuation, end of observation, or withdrawal from follow-up visit.  Additional EDSS 
assessments for individual patients may be requested between visits (i.e., during an MS 
relapse, neurological worsening, etc.).  All FSS and total EDSS scores will be captured 
electronically. 
EDSS CDP is 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 and  0.5 point when the baseline score is 
 5.5.  Disability progression is considered confirmed when the increase in the EDSS 
score is confirmed at a regularly scheduled visit at least 12 weeks after the initial 
documentation of the progression.  A 24-week CDP requires that the increase in EDSS 
score be confirmed at least 24 weeks after the initial documentation of the progression. 
The EDSS is based on a standard neurological examination, incorporating 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 to 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 10.0 (death) (Kurtzke 1983; Kappos 2011).  Note that the following 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
62/Protocol WA40404, Version 6 
items need not be scored: sexual dysfunction and fatigue and consequently should not 
contribute to the Cerebral FS score nor EDSS step. 
4.5.8 
Assessment of Relapse 
Although relapses are anticipated to be rare in the PPMS population, patients will be 
evaluated for relapse by the Treating Investigator at each visit throughout the study and, 
if necessary, at unscheduled visits to confirm relapse occurring between the visits. 
All new or worsening neurological events compatible with MS representing a clinical 
relapse are to be reported in the appropriate eCRF.  Patients with clinical relapses 
should be referred to the Examining Investigator who will assess the EDSS/FSS 
independently to allow confirmation as to whether or not the clinical relapse(s) meet the 
criteria for protocol defined relapse(s). EDSS should be performed within 7 days from 
the onset of the relapse. 
For this study, a 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, 
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 one of the following: 
 
Half a step (0.5 point) on the EDSS 
 
2 points on one of the selected FSS as listed below 
 
1 point on two or more of the selected FSS as listed below 
 
The change must affect the following selected FSS:  pyramidal, ambulation, cerebellar, 
brainstem, sensory, or visual.  Episodic spasms, sexual dysfunction, fatigue, mood 
change, or bladder or bowel urgency or incontinence will not suffice to establish 
a relapse.  Note that the following items need not be scored:  sexual dysfunction and 
fatigue. 
It should be noted that all patients with new neurological symptoms defined at a visit or 
over the telephone should be referred to the Examining Investigator unless the Treating 
Investigator considers the symptoms consistent with an intensification of neurological 
symptoms from a transient systemic infection. 
Clinical relapses (i.e., regardless of whether they meet criteria for a protocol-defined 
relapse) will be recorded in the eCRF. 
4.5.9 
Symbol Digit Modalities Test 
The SDMT (Smith 1982) has demonstrated sensitivity in detecting not only the presence 
of cognitive impairment but also changes in cognitive functioning over time and in 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
63/Protocol WA40404, Version 6 
response to treatment.  The SDMT is recognized as being particularly sensitive to 
slowed processing of information that is commonly seen in MS (Benedict et al. 2017).  
The SDMT is brief, is 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 will be 
collected orally, and administration time is approximately 5 minutes.  
SDMT will be administered by the Examining Investigator or a qualified designee at the 
timepoints indicated in the schedules of activities (see Appendix 1, Appendix 2, 
Appendix 3, and Appendix 4). 
4.5.10 
Mandatory and Optional MRI Sequences  
MRI will be used to monitor CNS lesions in patients with MS and potentially other 
pathophysiology, such as inflammation and neurodegeneration.  Mandatory MRI scans 
(formally known as ‘brain MRI’) will be obtained in all patients at study visits as indicated 
in Appendix 1, Appendix 2, Appendix 3, and Appendix 4. 
During the screening phase, two mandatory MRI scans (performed at least 6 weeks 
apart, but not more than 24 weeks apart) or one MRI with the mandatory sequences that 
can be compared with a historical MRI acquired in the previous 1 year will be performed 
to assess the patient’s MRI activity level.  MRI activity is defined as the presence of any 
T1 Gd lesion(s) and/or new and/or enlarging T2 lesion(s) during the screening period 
(see also Section 3.1).  If the presence of new or enlarging lesions is ascertained, the 
patient will be stratified to the MRI-active subgroup.  The MRI performed closer to 
randomization (i.e., either the second MRI scan at screening or the [only] screening MRI 
scan in the case where a historical scan was used for the assessment of MRI activity) 
will be considered as baseline MRI for the study analyses and will be captured under the 
baseline visit in the eCRF.  Note that this baseline scan should be obtained maximum 
6 weeks before but at least 10 days prior to performing the baseline visit to allow time for 
the centralized reading center to assess its quality and for potential re-scans if needed. 
Postbaseline, the mandatory MRI scans will be obtained in all patients at Weeks 24, 48, 
and 72.  From Week 72 onward, MRI scans will be performed every 48 weeks (i.e., at 
Week 120, 168, etc.).  In addition, mandatory MRI scans will be obtained in patients who 
withdraw from study treatment (at withdrawal visit) if one was not performed during the 
prior 4 weeks.  Mandatory MRI scans should occur within a window of 4 weeks of the 
scheduled visit, as per the schedules of activities (see Appendix 1, Appendix 2, 
Appendix 3, and Appendix 4).  At the Week 120 visit for patients switching to PDP OCR 
treatment, mandatory MRI scans should be obtained within 4 weeks before the 
Week 120 visit. 
The mandatory MRI sequences are comprised of both brain and axial cervical spinal 
sequences if site technology is available, and data from these scans will contribute 
measurements for the key MRI secondary endpoints as well as novel exploratory 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
64/Protocol WA40404, Version 6 
endpoints.  For details of the mandatory MRI sequences, refer to the MRI Acquisition 
Procedures Manuals.  Axial cervical spine sequences are not required for the first 
mandatory MRI at screening MRI nor are expected to be included in a historical MRI 
used for screening (if applicable), but these axial cervical spine sequences should be 
included in second mandatory MRI scan (considered the baseline MRI). 
If site technology is available, in addition to the mandatory MRI sequences, optional, 
additional sagittal cervical spinal cord MRI sequences may be acquired for baseline, 
Weeks 24 and 120, at treatment discontinuation, and every 48 weeks in the OLE 
(according to the yearly schedule as carried over from the double-blind treatment 
phase).  These sagittal cervical spine sequences provide further information on cervical 
spinal cord lesions and atrophy. Additional optional sagittal cervical spinal cord MRI 
sequences are not required to accompany the first mandatory MRI at screening MRI nor 
are expected to be included in a historical MRI used at screening, but these sequences 
should be included in the second mandatory MRI (considered the baseline MRI) scan.  
Subjects who choose to participate, an additional signed Informed Consent Form (ICF – 
denoted as ‘Consent for optional cervical spinal cord MRI scans’ in the master ICF), 
dedicated to the sagittal cervical spine is required.  For details of the additional optional 
sagittal cervical spine MRI sequences, refer to the MRI Acquisition Procedures Manuals. 
During the OLE, MRI mandatory and additional optional sagittal cervical spinal cord 
scans will be performed every 48 weeks (according to the yearly schedule as carried 
over from the double-blind treatment phase). 
MRI assessments will include, but may not be limited to, T1-weighted scans before and 
after injection of Gd contrast, fluid-attenuated inversion recovery, proton 
density-weighted, and T2-weighted scans. 
MRI scans will be read by a centralized reading center for efficacy endpoints.  The 
centralized reading center will be blinded to treatment assignment, and the reading will 
be 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 will be described in a separate 
MRI Acquisition Procedures Manual. 
All MRI scans will also be reviewed locally by a radiologist for safety, and the MRI scan 
report containing only non-MS pathology will be provided to the Treating Investigator.  
During the double-blind treatment phase, only the local radiologist/technician at the 
investigational site who is assigned to this study may have access to the MRI scans, 
except at screening and baseline when the Treating Investigator may view the MRI scan.  
To protect the blind, the Treating Investigator must not review the MRI scans (including 
additional optional cervical MRIs) obtained after randomization unless a safety concern 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
65/Protocol WA40404, Version 6 
arises.  In the event that the Treating Investigator becomes aware of these MRI results, 
this should be documented in the eCRF, indicating the reason. 
Note:  the treating investigator may have access to MRI scans performed during the 
OLE phase after the primary analysis. 
If patients receive corticosteroids for an MS relapse, every effort should be made to 
obtain an MRI scan prior to the first corticosteroid dose if the pre-corticosteroid scan is 
within 1 week of the scheduled visit.  In patients receiving corticosteroids for an MS 
relapse, there should be an interval of 3 weeks between the last dose of corticosteroids 
and the MRI scan.  
4.5.11 
Laboratory, Biomarker, and Other Biological Samples 
Samples for the following laboratory tests will be sent to the central laboratory for 
analysis unless otherwise indicated (further details will be provided in the laboratory 
manual). 
 
Hematology:  hemoglobin, hematocrit, RBC, WBC (absolute and differential:  
neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells), and 
quantitative platelet count 
 
Blood chemistry:  AST, ALT, gamma-glutamyl transferase, total bilirubin, creatinine, 
amylase, potassium, sodium 
 
Flow cytometry:  Analysis will include, but is not limited to, the determination of the 
duration of B-cell depletion and recovery (CD19), B-cell subsets (e.g., CD19, 
CD27, IgD, CD38 markers to assess naive, memory, plasmablasts and/or other 
populations), and T-cell counts (CD3, CD4, CD8). 
 
Quantitative Ig:  Ig levels (IgG, IgM, and IgA) 
 
ADA:  Serum samples will be collected for determination of antibodies against 
ocrelizumab.  Because ocrelizumab concentrations affect the ADA assay, the 
concentration of ocrelizumab will be measured as well at all timepoints with 
ADA assessment to enable interpretation of the results.  Refer to Appendix 1, 
Appendix 2, Appendix 3, and Appendix 4 for details. 
 
Urinalysis:  A urine dipstick will be performed at the site (pH, specific gravity, 
glucose, protein, ketones, blood), and a microscopic examination if abnormal and 
clinically significant will be performed at the site (local laboratory). 
 
Pregnancy test:  All women of childbearing potential will have a serum pregnancy 
test at screening. 
 
All women of childbearing potential must have regular pregnancy tests.  A urine 
pregnancy test (sensitivity of at least 25 mU/mL -hCG) will be performed locally at the 
timepoints shown in Appendix 1, Appendix 2, Appendix 3, and Appendix 4.  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 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
66/Protocol WA40404, Version 6 
the central laboratory prior to any further dosing with study drug.  If a urine pregnancy 
test is positive, the patient will not receive the scheduled dose, and a confirmatory serum 
pregnancy test will be performed by the central laboratory. 
 
Viral serology and detection:  All patients must have negative HBsAg test result at 
screening prior to enrollment.  If total HBcAb is positive at screening, hepatitis B 
virus (HBV) DNA measured by PCR must be negative to be eligible. 
For patients enrolled with negative HBsAg and positive total HBcAb, HBV 
DNA (PCR) must be repeated every 12 weeks during the double-blind phase.  
Retests will continue in OLE phase on a 24-week basis as per the scheduled 
visits.  Patients 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.  Patients found to have a confirmed viral 
DNA-positive test should be referred to a hepatologist for immediate 
assessment.  These patients will not receive further infusions of study drug and 
will enter the follow-up phase. 
Liver function (i.e., ALT/SGPT, AST/SGOT, gamma-glutamyl transferase, total 
bilirubin) should be reviewed throughout the study.  Patients who develop 
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.  Patients who develop hepatitis B should be withdrawn from the 
treatment and should enter the follow-up phase.  Should treatment be 
prescribed, this will be recorded in the eCRF.  Patients with viral hepatitis due 
to other agents, such as hepatitis A, may resume treatment after recovery. 
 
Biomarker sample:  A plasma and a serum sample will be collected, and analysis 
may include, but will not be limited to, NfL.  The sample may be shipped to the 
Sponsor, or one or more laboratories designated by the Sponsor for analysis.  
 
CSF:  If the patient does not have documented history or presence at screening of 
at least one laboratory finding of either elevated IgG index or one or more IgG 
oligoclonal bands detected by isoelectric focusing on a prior CSF specimen, a CSF 
specimen will be collected to test for these parameters during the screening phase.  
The remainder of this CSF sample will be retained as a biomarker sample, and 
analysis may include, but will not be limited to, NfL.  The sample may be shipped to 
the Sponsor, or one or more laboratories designated by the Sponsor for these 
analyses.  Patients for whom screening CSF was collected will have the option to 
participate in a collection of CSF at Week 48; this sample will be used for 
exploratory biomarker determination that may include, but may not be limited to, 
NfL.   
 
All laboratory samples collected during the study will be shipped to a central laboratory, 
with the exception of urine dipsticks/urine probes, which will be analyzed locally unless 
otherwise indicated. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
67/Protocol WA40404, Version 6 
Laboratory samples will be taken at the study visit as described in the schedules of 
activities (see Appendix 1, Appendix 2, Appendix 3, and Appendix 4). 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
At participating sites, screening blood and CSF samples collected from patients who do 
not enroll in the study (screen-fail samples) may be used for research related to the 
disease under study and the development of disease-related tests or tools. 
Biological samples will be destroyed when the final Clinical Study Report has been 
completed, with the following exceptions: 
 
Plasma and/or serum samples collected for biomarker research will be destroyed no 
later than 5 years after the final Clinical Study Report has been completed 
 
Any leftover CSF samples that were collected for IgG index/OCB analysis to 
determine eligibility for patients who did not have historical data and the optional 
Week 48 CSF sample will be destroyed no later than 5 years after the final Clinical 
Study Report has been completed or until exhausted, or earlier depending on local 
regulations. 
 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed, or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data, unless more stringent local requirements apply. 
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4. 
4.5.12 
Patient-Reported Outcomes 
Patient-reported outcome (PRO) data will be collected via questionnaires to characterize 
the treatment benefit of ocrelizumab.  The questionnaires, translated and culturally 
validated into the local language as appropriate, will be completed in their entirety at 
specified timepoints during the study.  To ensure instrument validity and that data 
standards meet health authority requirements, questionnaires will be self-administered 
before the patient receives any information on disease status, prior to the performance 
of non-PRO assessments, and prior to the administration of study treatment, unless 
otherwise specified. 
In the event that the patient is unable to complete PROs on his or her own (e.g., due to 
problems with eyesight or dexterity), appropriate site personnel (except the Examining 
Investigator) may administer the PRO to the patient; however, staff should not influence 
responses in any way and questions and response options should be read out verbatim. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
68/Protocol WA40404, Version 6 
Patients will use an electronic device to capture PRO data.  The electronic device and/or 
instructions for completing the questionnaires electronically will be provided by site staff.  
The data will be transmitted to a centralized database maintained by the electronic 
device vendor.  The data will be available for access by appropriate study personnel. 
4.5.12.1 
EQ-5D-5L 
The EQ-5D-5L is a validated self-report health status questionnaire that is used to 
calculate a health status utility score for use in health economic analyses (EuroQol 
Group 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013).  There are two 
components to the EQ-5D-5L:  a five-item health state profile that assesses mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression, as well as a visual 
analogue scale that measures health state (see Appendix 6).  Published weighting 
systems allow for creation of a single composite score of the patient's health status.  The 
EQ-5D-5L takes approximately 5 minutes to complete.  It will be used in this study for 
informing pharmacoeconomic evaluations. 
4.5.12.2 
Multiple Sclerosis Impact Scale, Version 2 
The MSIS, v2 is a 29-item patient-reported measure of the physical and psychological 
impacts of MS (Hobart et al. 2001).  Patients are asked to rate how much their 
functioning and well-being has been impacted over the past 14 days on a 4-point scale, 
from “Not at all” (1) to “Extremely” (4) (see Appendix 7).  The physical score is the sum 
of items 120, which is then transformed onto a 0100 scale.  The psychological score is 
the sum of items 2129, transformed onto a 0100 scale.  Higher scores indicate a 
greater impact of MS.  A change of 7.5 points on the physical scale is considered to be 
clinically meaningful.  
4.5.12.3 
Modified Fatigue Impact Scale 
The MFIS is a 21-item instrument that asks patients to rate the impact of fatigue over the 
past 4 weeks on a 5-point Likert scale, from “Never” (0) to “Almost always” (4) (Fischer 
et al. 1999a) (see Appendix 8).  The total score is the sum of all items from 0 to 84, with 
higher scores indicating greater impacts of fatigue.  Physical, cognitive, and 
psychosocial domain scores can also be calculated. 
4.5.12.4 
ABILHAND 
The ABILHAND measures the ability to measure everyday activities that use upper 
limbs.  It was originally developed for rheumatoid arthritis (Penta et al. 1998) and has 
since been used in MS (Cano et al. 2015; Mikol et al. 2015; see Appendix 9).  Each item 
is scored on a 4-point scale, using "Impossible" (0), "Very Difficult" (1), "Difficult" (2), 
and "Easy" (3). 
4.5.12.5 
Quality of Life in Neurological Disorders Upper Extremity 
Function 
The Neuro-QoL-UE (fine motor, activities of daily living [ADL]) domain is a 20-item 
questionnaire used to assess upper limb function, which involves people with MS 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
69/Protocol WA40404, Version 6 
through each stage of its development (Gershon et al. 2012; see Appendix 10).  Items 
include assessments of dressing, cooking, eating, cleaning, and writing from which the 
patient uses a 5-point Likert scale to rate his or her performance ranging from “without 
any difficulty” (5) to “unable to do” (1).  Item scores are summed, multiplied by 100, and 
divided by 80; a higher score (range: 0100) indicates better health reported function. 
4.5.12.6 
Patient Global Impression of Change for Fatigue 
The Patient Global Impression of Change for Fatigue is a single item completed by the 
patient to assess changes in fatigue over the last 6 months (see Appendix 11).  Patients 
will be asked to respond on a 7-point Likert scale from “very much better” (1) to “very 
much worse” (7). 
4.5.12.7 
Patient Global Impression of Change for Upper Limb Function 
The PGIC-UL is a single item questionnaire completed by the patient to assess upper 
limb function compared with the function over the last 6 months (see Appendix 12).  The 
patient will be asked to rate their upper limb function using a 7-point Likert scale ranging 
from “very much better” (1) to “very much worse” (7).  The PGIC-UL is used as an 
anchor to determine what is a clinically meaningful change in ABILHAND and the 
Neuro-QoL-UE.  
4.5.13 
Samples for Whole Genome Sequencing 
At participating sites, blood samples will be collected for DNA extraction to enable whole 
genome sequencing (WGS) or other genotype analysis to assess the patient’s germline 
genotype for allelic variations or mutations that are predictive of response to study drug, 
are associated with progression to a more severe disease state, are associated with 
acquired resistance to study drug, are associated with susceptibility to developing 
adverse events, or can increase the knowledge and understanding of disease biology.  
The blood samples may be sent to one or more laboratories for analysis. 
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS and whole exome sequencing (WES) provide a comprehensive characterization of 
the genome and exome, respectively, and, along with clinical data collected in this study, 
may increase the opportunity for developing new therapeutic approaches.  Data will be 
analyzed in the context of this study but will also be explored in aggregate with data from 
other studies.  The availability of a larger dataset will assist in identification of important 
pathways, guiding the development of new targeted agents. 
Collection and submission of WGS samples is contingent upon the review and approval 
of the exploratory research by each site's IRB/EC and, if applicable, an appropriate 
regulatory body.  If a site has not been granted approval for WGS sampling, this section 
of the protocol (Section 4.5.13) will not be applicable at that site. 
Candidate genes of MS susceptibility or progression that have been identified will be 
assessed in DNA from the study patients and may include, but will not be limited to, 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
70/Protocol WA40404, Version 6 
those in the human leukocyte antigen locus (IMSGC and WTCCC 2011; IMSGC 2013; 
Patsopoulos et al. 2013; Didonna and Oksenberg 2015).  The genotype will also be 
assessed to identify potential new markers that may be prognostic of MS progression or 
disease worsening or to assess predictive value of markers for enhanced ocrelizumab 
response.  The DNA genotype may be assessed for genes that have been associated 
with increased risk for MS or otherwise used to further understand the pathogenesis of 
MS (IMSGC and WTCCC 2011; IMSGC 2013). 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Blood samples collected for WGS are to be stored until they are no longer needed or 
until they are exhausted.  However, the storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
Patient medical information associated with WGS specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Given the complexity and exploratory nature of the WGS analyses, data derived from 
these analyses will generally not be provided to study investigators or patients unless 
required by law.  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication. 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.  
4.5.14 
Optional Samples for Research Biosample Repository 
4.5.14.1 
Overview of the Research Biosample Repository 
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection, 
storage, and analysis of RBR specimens will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
71/Protocol WA40404, Version 6 
Specimens for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR specimens will be used to achieve the 
following objectives: 
 
To study the association of biomarkers with efficacy, adverse events, or disease 
progression 
 
To increase knowledge and understanding of disease biology 
 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.14.2 
Approval by the Institutional Review Board or 
Ethics Committee 
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the Informed 
Consent Form by each site's IRB/EC and, if applicable, an appropriate regulatory body.  
If a site has not been granted approval for RBR sampling, this section of the protocol 
(Section 4.5.14) will not be applicable at that site. 
4.5.14.3 
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 or diseases: 
 
A single sample for DNA collected as indicated in the schedule of activities 
 
Plasma samples collected over time as indicated in the schedule of activities 
 
RNA samples collected over time as indicated in the schedule of activities 
 
Leftover samples from the main trial 
 
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic mutations via whole genome sequencing (WGS), whole exome sequencing 
(WES), next-generation sequencing, or other genomic analysis methods. 
Genomics is increasingly informing researchers understanding of disease pathobiology.  
WGS and WES provide a comprehensive characterization of the genome and exome, 
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches.  Data will be analyzed in the 
context of this study but will also be explored in aggregate with data from other studies.  
The availability of a larger dataset will assist in identification of important pathways, 
guiding the development of new targeted agents. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
72/Protocol WA40404, Version 6 
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
4.5.14.4 
Confidentiality 
Specimens and associated data will be labeled with a unique patient identification 
number. 
Patient medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Given the complexity and exploratory nature of the analyses of RBR specimens, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication. 
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
4.5.14.5 
Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR specimens.  
Patients who decline to participate will not provide a separate signature. 
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the Sample Informed 
Consent/Withdrawal eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
73/Protocol WA40404, Version 6 
4.5.14.6 
Withdrawal from the Research Biosample Repository 
Patients who give consent to provide RBR specimens have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  However, if RBR samples 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 
his or her RBR samples during the study, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and must enter the date of withdrawal on the Sample Informed 
Consent/Withdrawal eCRF.   
If a patient wishes to withdraw consent to the testing of his or her RBR samples after 
closure of the site, the investigator must inform the Sponsor by emailing the study 
number and patient number to the following email address: 
global.rcr-withdrawal@roche.com 
A patient's withdrawal from Study WA40404 does not, by itself, constitute withdrawal of 
specimens from the RBR.  Likewise, a patient's withdrawal from the RBR does not 
constitute withdrawal from Study WA40404. 
4.5.14.7 
Monitoring and Oversight 
RBR specimens will be tracked in a manner consistent with Good Clinical Practice by 
a quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Sponsor monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RBR for the purposes 
of verifying the data provided to the Sponsor.  The site will permit monitoring, audits, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples. 
4.5.15 
Optional Smartphone-Based Digital Outcome Assessment 
Floodlight RPM digital outcome data collection encompasses active tests that have been 
developed to be self-administered by patients via smartphone devices.  The Floodlight 
RPM assessment in this study may include, but may not be limited to, the following tests:  
information processing speed test; active gait and posture tests (only for patients with 
a baseline EDSS score  7.0), including a static balance test, a U-turn test, and 
a 2-minute walk test; hand motor function tests, including the "Draw a Shape" and 
"Pinching" test; daily mood questions; a MS symptom tracker; and the continuous 
analysis of mobility through passive monitoring.  Patient participation in this data 
collection is optional.  Only patients, who consent to Floodlight RPM self-assessments at 
screening will be asked to begin performing the digital assessment.  The patient 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
74/Protocol WA40404, Version 6 
adherence data from the 4 weeks prior to baseline will be used to determine if the 
patient can continue to use Floodlight RPM for 144 weeks from randomization or until 
the primary analysis, whichever occurs earlier.  Screening for Floodlight RPM 
participation will close in November 2022 in order for the last Floodlight RPM patient 
enrollment to occur by the end of December 2022. 
4.5.16 
Optional CSF Collection 
Patients for whom screening CSF was collected will have the option to participate in 
a collection of CSF at Week 48 of the double-blind treatment phase; this sample will be 
used for exploratory biomarker determination that may include, but may not be limited to, 
NfL (see Section 3.4.5).  The CSF sample should be collected prior to the ocrelizumab 
(or placebo) infusion at Week 48 (within a window of 14 days prior to the actual 
scheduled visit Week 48; see Appendix 1). 
4.6 
OVERVIEW OF CLINICAL VISITS 
After the screening, patients who fulfill the entry criteria will be scheduled for baseline 
assessments.  Visits will take place as described in Appendix 1, Appendix 2, Appendix 3, 
and Appendix 4. 
Visits should be scheduled with reference to the date of the baseline visit (Day 1).  
A minimum interval of 20 or 22 weeks, depending if the previous dose was administered 
in one or two infusions as per Section 3.1.1.2, Section 3.1.1.3, and Section 3.1.1.5, 
respectively, should be maintained between each infusion. 
At infusion visits, it is anticipated that the patients will have to stay at the hospital or clinic 
for a full day.  Patients treated with ocrelizumab should remain in observation for at least 
1 hour after the completion of the infusion.  If for logistical reasons the infusion cannot be 
administered on the same study visit day, the infusion should be given within the next 
24 hours provided that the patient still meets re-treatment criteria. 
Patients 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 4.6.1).  Additional 
unscheduled visits for the assessment of disease worsening, new neurological 
symptoms, or safety events may occur at any time. 
Patients who are pregnant and breastfeeding should continue to follow the schedule of 
activities; however, no infusions will occur.  If there is a concern with the ability of 
a pregnant or breastfeeding patient to complete all scheduled assessments, or if 
assessments are contraindicated with pregnancy, the investigator must contact the 
Medical Monitor for further discussion. 
4.6.1 
Delayed Dosing Visit 
Delayed dosing visits may be scheduled only if the infusion cannot be administered at 
the timepoints defined in the schedules of activities (see Appendix 1, Appendix 2, 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
75/Protocol WA40404, Version 6 
Appendix 3, and Appendix 4).  Thus, a patient who had all assessments of a dosing visit 
performed, but could not receive the infusion, should be rescheduled for the infusion on 
another day.  At the delayed dosing visit, additional tests or assessments, such as 
routine safety laboratory tests, may be performed as clinically indicated. 
4.6.2 
Unscheduled Visits 
Patients 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 and regardless of the study period.  The EDSS assessment 
should be performed for any suspected neurological worsening.  If an MS relapse is 
diagnosed or suspected, EDSS assessment should be performed within 7 days, in 
addition to completing the appropriate eCRF. 
Other assessments performed at unscheduled (non-dosing) visits will depend on the 
clinical needs of the patient.  The primary reason for performing an unscheduled visit will 
be reported in the eCRF. 
4.7 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.7.1 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment if they experience any of the 
following: 
 
Any medical condition that the investigator determines may jeopardize the patient’s 
safety if he or she continues to receive study treatment 
 
Investigator determines it is in the best interest of the patient 
 
Additionally, patients must be withdrawn from treatment under the following 
circumstances: 
 
Life-threatening (National Cancer Institute Common Terminology Criteria for 
Adverse Events [NCI CTCAE] Grade 4) infusion-related event that occurred during 
a previous ocrelizumab infusion 
 
Demonstrate active hepatitis B infection, either new onset or reactivation 
 
PML 
 
Patients who decide to discontinue the treatment 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
An excessive rate of treatment withdrawals can render the study non-interpretable; 
therefore, unnecessary treatment withdrawal of patients should be avoided. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
76/Protocol WA40404, Version 6 
If a patient meets any of the treatment withdrawal criteria (see above), the patient must 
be withdrawn from treatment.  Patients who prematurely withdraw from study drug 
treatment will need to return to the clinic for a treatment discontinuation visit 
(see Appendix 1, Appendix 2, and Appendix 3 for additional details).  After treatment 
discontinuation, every effort should be made to have the patient enter the follow-up 
phase of the study (FU1 or FU2). 
For patients who have withdrawn from study drug treatment, the investigator should 
decide as to further treatment of the underlying disease (see Section 4.4.3 for 
recommendations on alternative treatments for MS post-ocrelizumab). 
4.7.2 
Patient Discontinuation from Study 
Patients will return to the clinic for an end of observation or withdrawal from follow-up 
visit. 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following: 
 
Patient withdrawal of consent 
 
Study termination or site closure 
 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  Patients 
who withdraw from the study will not be replaced. 
Patients who withdraw from study drug treatment during any study period, for any 
reason, are encouraged to enter and complete the applicable follow-up phase 
(see Section 4.7.1).  Patients who withdraw from FU1 or FU2 will return to the clinic for 
a withdrawal from follow-up visit (see Appendix 2 and Appendix 4 for additional details).  
If a patient discontinues from the study, the patient should be asked if he or she can still 
be contacted for further information, unless otherwise specified by the local 
requirements.  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 
patient 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 patient’s withdrawal should be made with 
an explanation of why the patient withdrew from the study. 
When applicable, patients should be informed of circumstances under which their 
participation may be terminated at the medical discretion of the investigator without their 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
77/Protocol WA40404, Version 6 
consent.  Any administrative or other reasons for withdrawal must be documented and 
explained to the patient. 
An excessive rate of withdrawals can render the study non-interpretable; therefore, 
unnecessary withdrawal of patients should be avoided.  Should a patient decide to 
withdraw, all efforts will be made to complete and report the observations prior to 
withdrawal as thoroughly as possible. 
4.7.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
 
The incidence or severity of adverse events in this or other studies indicates 
a potential health hazard to patients 
 
Patient enrollment is unsatisfactory 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study. 
4.7.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
The safety plan for patients in this study is based on clinical experience with ocrelizumab 
in completed and ongoing studies.  The anticipated important safety risks for 
ocrelizumab are outlined below.  Refer to the ocrelizumab local labels and the 
Ocrelizumab Investigator's Brochure for a complete summary of safety information.  
Several measures will be taken to ensure the safety of patients participating in this 
study.  Eligibility criteria have been designed to exclude patients at higher risk for 
toxicities.  Patients will undergo safety monitoring during the study, including 
assessment of the nature, frequency, and severity of adverse events.  In addition, 
guidelines for managing adverse events, including criteria for dosage modification and 
treatment interruption or discontinuation, are provided below. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
78/Protocol WA40404, Version 6 
5.1.1 
Risks Associated with Ocrelizumab 
Important, identified, and potential risks associated with ocrelizumab are described in the 
approved risk management plan and provided below.  Refer to the most recent version 
of the Ocrelizumab Investigator’s Brochure for updates on risks associated with 
ocrelizumab treatment. 
5.1.1.1 
Identified Risks and Adverse Drug Reactions 
Infusion-Related Reactions 
All CD20-depleting agents administered via the intravenous 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 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 patients that IRRs can occur within 24 hours of the 
infusion.  Across the RMS and PPMS trials, symptoms associated with IRRs included, 
but are not limited to the following:  pruritus, rash, urticaria, erythema, throat irritation, 
oropharyngeal pain, dyspnea, pharyngeal or laryngeal edema, flushing, hypotension, 
pyrexia, fatigue, headache, dizziness, nausea, tachycardia and anaphylaxis. 
Patients should be observed for at least 1 hour after the completion of the infusion for 
any symptom of IRR.  Patients will be informed about delayed post-infusion symptoms 
and instructed to contact the study physician if he or she develops such symptoms.   
Hypotension, as a symptom of IRR, may occur during ocrelizumab infusions.  Therefore, 
withholding of antihypertensive treatments should be considered for 12 hours prior to 
and throughout each study drug infusion.  
For further guidance on how to manage IRRs refer to the current Ocrelizumab 
Investigator’s Brochure. 
Alternative Shorter Infusion of Subsequent Doses 
In a study (MA30143, ENSEMBLE Plus) designed to characterize the safety profile of 
shorter ocrelizumab infusions in patients with RRMS, no differences were found in the 
frequency and severity of IRRs associated with shorter (2 hour) infusions compared with 
conventional infusions (3.5 hours).  For further details, refer to the current version of the 
Investigator’s Brochure. 
Infections 
Infection is an identified risk associated with ocrelizumab treatment, predominantly 
involving mild to moderate respiratory tract infections.  Non-disseminated herpes 
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%). 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
79/Protocol WA40404, Version 6 
During the controlled period of the pivotal trials, the proportion of patients with serious 
infections in RMS was lower in the ocrelizumab group (1.3%) than in the 
interferon -1a group (2.9%); in PPMS, the proportion of patients 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 patients with lupus and 
rheumatoid arthritis treated with ocrelizumab in Phase III clinical trials.  Data from 
completed studies regarding infection risks with ocrelizumab treatment in these patient 
populations are provided in the Ocrelizumab Investigator’s Brochure.  
No opportunistic infections were reported by any patient 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 
patients with MS treated with ocrelizumab, but it had been reported in 1 patient with 
rheumatoid arthritis treated with ocrelizumab.  HBV screening should be performed in all 
patients before initiation of treatment with ocrelizumab as per local guidelines.  Patients 
with active HBV should not be treated with ocrelizumab.  Patients 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. 
Delay ocrelizumab administration in patients with an active infection until the infection is 
resolved. 
For PML, see Section 5.1.1.2 below. 
Impaired Response to Vaccination 
After treatment with ocrelizumab for over 2 years in pivotal clinical trials, the proportion 
of patients with positive antibody titers against Streptococcus pneumoniae, mumps, 
rubella, and varicella were generally similar to the proportions at baseline. 
The results of the randomized, open-label Phase IIIb study (BN29739) that assessed if 
ocrelizumab recipients with RMS raised adequate humoral responses to selected 
vaccines indicate that patients treated with ocrelizumab were able to mount humoral 
responses, albeit decreased, to tetanus toxoid; 23-valent pneumococcal polysaccharide; 
keyhole limpet hemocyanin neoantigen; and seasonal influenza vaccines.  The results 
are summarized in the current version of the Ocrelizumab Investigator’s Brochure. 
Investigators should review the immunization status of patients being considered for 
treatment with ocrelizumab.  Patients who require vaccination should complete it at least 
6 weeks prior to initiation of ocrelizumab.  For seasonal influenza vaccines, it is still 
recommended to vaccinate patients who are on ocrelizumab.  Vaccination with live or 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
80/Protocol WA40404, Version 6 
live-attenuated vaccines are not recommended during the treatment with ocrelizumab 
and until B cells have returned to normal levels. 
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 with 
live or live-attenuated vaccines should be delayed until B cells have recovered; 
therefore, measuring CD19-positive B-cell level in neonates and infants prior to 
vaccination is recommended. 
It is recommended that all vaccinations other than live or live-attenuated should follow 
the local immunization schedule, and measurement of vaccine-induced response titers 
should be considered to check whether individuals can mount a protective immune 
response because the efficacy of the vaccination may be decreased. 
Decrease in Immunoglobulins 
Treatment with ocrelizumab resulted in a decrease in total Ig over the controlled period 
of the studies, mainly driven by reduction in IgM.  The proportion of patients with 
decrease in Igs below LLN increased over time and with successive dosing.  Based on 
additional patient exposure, in cases of continuous decrease over time, a higher risk of 
serious infection cannot be ruled out. 
Serious Infections Related to Decrease in Immunoglobulins (Patients 
Previously Exposed to Immunosuppressive/Immunomodulatory Drugs or 
with Preexisting Hypogammaglobulinemia) 
Based on additional patient exposure, an association between decrease in Igs and 
serious infections with ocrelizumab treatment was observed and was most apparent with 
IgG.  There was no difference in the pattern (e.g., type of infections, latency, duration, 
outcome) of the serious infections reported in this subset of patients compared to the 
overall serious infections profile.  In addition, risk factors for a subset of patients at 
higher risk of serious infections could not be identified. Refer to the Ocrelizumab 
Investigator’s Brochure for more details. 
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) as an expected pharmacologic 
effect.  This was sustained throughout the treatment period.  The longest follow-up 
duration after the last ocrelizumab infusion from Phase II Study WA21493 in 51 patients 
indicates that the median time to repletion (returned to baseline/LLN, whichever 
occurred first) of B cells was 72 weeks (range 27175 weeks).   
5.1.1.2 
Potential Risks 
Malignancies (including Breast Cancer) 
An increased risk of malignancy with ocrelizumab may exist.  In controlled trials in MS, 
malignancies, including breast cancer, occurred more frequently in ocrelizumab-treated 
patients.  Breast cancer occurred in 6 of 781 females treated with ocrelizumab and none 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
81/Protocol WA40404, Version 6 
of 668 females treated with interferon -1A or placebo.  Patients should follow standard 
breast cancer screening guidelines. 
Refer to the current Ocrelizumab Investigator’s Brochure for more details. 
If a malignant event is reported, key available information on cancer will be collected for 
this study and reported as a serious adverse event on the eCRF.  Further explorations 
and detailed cancer information will be solicited via a questionnaire (e.g., further details 
on tumor diagnostics, grade/staging, and available histopathologic and genetic testing 
results). 
Progressive Multifocal Leukoencephalopathy  
John Cunningham (JC) virus infection resulting in PML has been reported very rarely in 
patients treated with anti-CD20 antibodies, including ocrelizumab, and mostly associated 
with risk factors such as patient population or polytherapy with immunosuppressants.  
The reporting rate with ocrelizumab has been approximately 1 case per 100,000 
patients.  Since the risk of PML cannot be ruled out, 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 
scans preferably with contrast (compared with pretreatment MRI scans), confirmatory 
CSF testing for JC viral DNA, and repeat neurological assessments should be 
considered.  If PML is confirmed, ocrelizumab must be discontinued permanently. 
Refer to Appendix 5 for diagnosis guidance of PML.  See the Ocrelizumab Investigator’s 
Brochure for more details.  
Hypersensitivity Reactions  
Hypersensitivity may be difficult to distinguish from IRRs in terms of symptoms.  
A hypersensitivity reaction may present during any infusion, although typically would not 
present 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 
infusion, the infusion must be stopped immediately and permanently.  Patients with 
known IgE-mediated hypersensitivity to ocrelizumab must not be treated. 
Neutropenia 
During the controlled treatment period, decreased neutrophils were observed in 12% 
and 15% of MS patients treated with ocrelizumab in PPMS and RMS, respectively.  Most 
were mild to moderate in severity, approximately 1% of the patients had Grade 3 or 4 
neutropenia; and no temporal association with infections was identified.  On the basis of 
additional patient exposure, an association between neutropenia and serious infections 
with ocrelizumab treatment was not observed.  Refer to the Ocrelizumab Investigator’s 
Brochure for more details. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
82/Protocol WA40404, Version 6 
5.1.2 
Risks Associated with Corticosteroids 
The adverse reactions of corticosteroids may result from unwanted glucocorticoid 
actions or from inhibition of the hypothalamic-pituitary-adrenal axis.  Refer to local 
prescribing information. 
5.1.3 
Risks Associated with 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.  Refer to local prescribing information. 
5.1.4 
Management of Patients Who Experience Adverse Events 
5.1.4.1 
Dose Modifications 
Study drug dose modifications are not foreseen. 
5.1.4.2 
Treatment Interruption 
Study drug treatment may be temporarily suspended in patients who experience relevant 
adverse events considered to be related to study drug and prevent the patient from 
re-treatment with the study drug (see Section 4.3.2.3 for details on re-treatment criteria). 
For female patients who become pregnant during the study, study drug treatment must 
be withheld for the duration of the pregnancy and breastfeeding.  Study drug may be 
restarted following the delivery/end of breastfeeding, after discussing the risks and 
benefits of continuing the treatment (see Section 5.4.3). 
5.1.4.3 
Management Guidelines 
Infusion-Related Reactions 
Slowing of the infusion rate or interruption of the infusion may be necessary in the event 
of an infusion reaction.  In rare cases, ocrelizumab treatment may need to be 
discontinued.  Follow ocrelizumab local label for further guidelines. 
Handling of IRRs will depend on the intensity of symptoms (see also Table 6 for grading 
of intensity of IRRs). 
For a mild to moderate (Grade 1 or 2) non-allergic, 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 mL/hr to 25 mL/hr or from 100 mL/hr to 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 patient’s infusion schedule and the rate increments resumed. 
For a severe infusion-related event (Grade 3) or a complex of flushing, fever, and 
throat pain symptoms, the infusion should be interrupted immediately, and the patient 
should receive aggressive symptomatic treatment.  The infusion should be restarted only 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
83/Protocol WA40404, Version 6 
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. 
For a life-threatening infusion-related event (Grade 4) during an infusion, the infusion 
should be immediately stopped, and the patient should receive appropriate treatment 
(including use of resuscitation medications and equipment that must be available and 
used as clinically indicated).  The patient will be withdrawn from treatment and should 
enter the follow-up phase. 
The above examples of dose interruption and slowing (for mild/moderate and severe 
IRRs) will result in a change in the infusion rate and increase the total duration of the 
infusion but not the total dose. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered 
a pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.9 
and 5.3.5.10 for more information) 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
84/Protocol WA40404, Version 6 
Clinical relapses will be recorded only on the appropriate eCRF.  IRRs will be recorded 
only on a pre-specified Infusion-Related Reaction/Cytokine-Release Syndrome eCRF. 
B-cell depletion is the expected outcome of ocrelizumab treatment and is not an adverse 
event.  However, patients 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 patients reporting signs or symptoms 
of infection, to take appropriate specimens for identification of the pathogen, and to treat 
infections aggressively.  Prior to enrollment in the study, it is recommended that the 
investigator review and, if warranted, update each patient’s immunizations in accordance 
with country medical immunization guidelines (see Section 4.4.4). 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
 
Is fatal (i.e., the adverse event actually causes or leads to death) 
 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death. 
 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.11) 
 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions) 
 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
85/Protocol WA40404, Version 6 
The exception to this definition of a serious adverse event is in the rare event that a 
patient is hospitalized following an MS relapse and the reason for hospitalization is to 
receive standard treatment with IV methylprednisolone.  The rationale for this exception 
is that some countries and/or clinical sites routinely hospitalize patients who require 
administration of methylprednisolone in the event of an MS relapse.  Thus, the serious 
adverse event criteria for “hospitalization” would be met on the basis of local practice 
and would not reflect the seriousness of the event. 
If the MS relapse results in hospitalization for any reason other than for routine treatment 
of the relapse (e.g., for a treatment course beyond the standard treatment; see 
Section 5.3.5.11) or when hospitalization is prolonged, the MS relapse should be 
considered a serious adverse event. 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows: 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.7) 
 
Suspected transmission of an infectious agent by the study drug, as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.4.15.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4). 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
86/Protocol WA40404, Version 6 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events will be reported throughout the study 
duration. 
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?" 
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 6 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
87/Protocol WA40404, Version 6 
Table 6 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
Table 7):  
 
Temporal relationship of event onset to the initiation of study drug 
 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
 
Known association of the event with the study drug or with similar treatments 
 
Known association of the event with the disease under study 
 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
88/Protocol WA40404, Version 6 
Table 7 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.   
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
  
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Infusion-Related Reactions 
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug infusion should be captured as a diagnosis 
(e.g., “infusion-related reaction”) on the Adverse Event eCRF.  If possible, avoid 
ambiguous terms such as “systemic reaction.”  Associated signs and symptoms should 
be recorded on the dedicated Infusion-Related Reaction/Cytokine-Release Syndrome 
eCRF.  If a patient experiences both a local and systemic reaction to the same dose of 
study drug, each reaction should be recorded separately on the Adverse Event eCRF, 
with signs and symptoms also recorded separately on the dedicated Infusion-Related 
Reaction/Cytokine-Release Syndrome eCRF.  Report a local IRR for any symptoms 
affecting only the skin and localized to only one place. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
For adverse events other than IRRs (see Section 5.3.5.1), a diagnosis (if known) should 
be recorded on the Adverse Event eCRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases).  However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded on the Adverse Event eCRF.  If a diagnosis is 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
89/Protocol WA40404, Version 6 
subsequently established, all previously reported adverse events based on signs and 
symptoms should be nullified and replaced by one adverse event report based on the 
single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; 
see Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be 
updated by changing the event from "non-serious" to "serious," providing the date that 
the event became serious, and completing all data fields related to serious adverse 
events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as 
a separate event on the Adverse Event eCRF. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
90/Protocol WA40404, Version 6 
5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
 
Is clinically significant in the investigator’s judgment 
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5  upper limit of normal [ULN] associated with cholestasis), only 
the diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with 
a descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
Is clinically significant in the investigator’s judgment 
 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
91/Protocol WA40404, Version 6 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  ULN) in combination with either an elevated 
total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy’s Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
 
Treatment-emergent ALT or AST  3  ULN in combination with total bilirubin 
 2  ULN 
 
Treatment-emergent ALT or AST  3  ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2). 
5.3.5.8 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period 
(see Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of MS. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
If the death is attributed to progression of MS, "multiple sclerosis progression" should be 
recorded on the Adverse Event eCRF. 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
92/Protocol WA40404, Version 6 
5.3.5.9 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.10 
Lack of Efficacy or Worsening of MS 
Events that are clearly consistent with expected pattern of progression of the underlying 
disease should not be recorded as adverse events; however, clinical MS relapses will be 
recorded on eCRF.  These data will be captured as effectiveness assessment data only.  
In most cases, the expected pattern of progression will be based on EDSS scores and/or 
9-HPT times.  In rare cases, the determination of clinical progression will be based on 
symptomatic deterioration.  However, every effort should be made to document 
progression through use of objective criteria.  If there is any uncertainty as to whether an 
event is due to disease progression, it should be reported as an adverse event. 
Occasional isolated symptoms that according to the investigator are caused by MS, but 
do not constitute a full MS relapse, should be reported as an adverse event, with the 
causality “Disease under study" (see Section 5.3.4). 
5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below. 
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Elective hospitalizations or surgical procedures that are a result of a patient’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 eCRF. 
 
Hospitalization to receive study medication, such as infusions of ocrelizumab unless 
this is prolonged. 
 
Hospitalization following an MS relapse as long as the reason for hospitalization is 
to receive standard treatment with IV methylprednisolone. 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
93/Protocol WA40404, Version 6 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.12 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  Sites are not expected to review the 
PRO data for adverse events. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
 
Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements) 
 
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements) 
 
Pregnancies (see Section 5.4.3 for details on reporting requirements) 
 
Accidental overdoses or medication errors see Section 5.4.4 for details on reporting 
requirements) 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 
 
Change in causality based on new information 
 
Change in the event’s outcome, including recovery 
 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
To ensure the safety of study participants, access to the Medical Monitors is available 
24 hours per day, 7 days per week.  Details will be provided separately.  To ensure the 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
94/Protocol WA40404, Version 6 
safety of study patients, 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 a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators. 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Adverse Event/Special Situations Form provided to investigators 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the event), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators. 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported throughout the study duration.  Investigators should record all 
case details that can be gathered immediately (i.e., within 24 hours after learning of the 
event) on the Adverse Event eCRF and submit the report via the electronic data capture 
(EDC) system.  A report will be generated and sent to Roche Safety Risk Management. 
In the event that the EDC system is unavailable, the paper Clinical Trial Adverse 
Event/Special Situations Form provided to investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the event), either by faxing or by scanning and emailing the form using the 
fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system. 
Instructions for reporting post-study adverse events are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study.  
A paper Clinical Trial Pregnancy Reporting Form should be completed and submitted to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number 
or email address provided to investigators.  Pregnancy should not be recorded on the 
Adverse Event eCRF.  The investigator should discontinue study drug and counsel the 
patient, discussing the risks of the pregnancy and the possible effects on the fetus.  

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
95/Protocol WA40404, Version 6 
Monitoring of the patient should continue until conclusion of the pregnancy.  Any serious 
adverse events associated with the pregnancy (e.g., an event in the fetus, an event in 
the mother during or after the pregnancy, or a congenital anomaly/birth defect in the 
child) should be reported on the Adverse Event eCRF.  In addition, the investigator will 
submit a Clinical Trial Pregnancy Reporting Form when updated information on the 
course and outcome of the pregnancy becomes available.  Information regarding child 
health up to 1 year should be collected on the infant health questionnaire 
(see Appendix 13). 
5.4.3.2 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
5.4.3.3 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2). 
5.4.4 
Reporting Requirements for Cases of Accidental Overdose or 
Medication Error 
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows: 
 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
 
Medication error:  accidental deviation in the administration of a drug  
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
 
Special situations are not in themselves adverse events but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
96/Protocol WA40404, Version 6 
seriousness criteria or qualifies as an adverse event of special interest, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).  For ocrelizumab or matching placebo, adverse events 
associated with special situations should be recorded as described below for each 
situation: 
 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
 
In addition, all special situations associated with ocrelizumab or matching placebo, 
regardless of whether they result in an adverse event, should be recorded on the 
Adverse Event eCRF as described below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details. 
 
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details. 
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
97/Protocol WA40404, Version 6 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed with a Pregnancy Outcome 
and Infant Health Information on First Year of Life questionnaire provided by the 
Sponsor. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or 
a monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case. 
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. 
All adverse events must be collected and reported during the study through the end of 
the FU2 phase. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
48 weeks after the last dose of study drug), if the event is believed to be related to prior 
study drug treatment.  These events should be reported through use of the Adverse 
Event eCRF.  However, if the EDC system is not available, the investigator should report 
these events directly to the Sponsor or its designee, either by faxing or by scanning and 
emailing the paper Clinical Trial Adverse Event/Special Situations Form using the fax 
number or email address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor has a legal responsibility to notify regulatory authorities about the safety 
of a study treatment under clinical investigation.  The Sponsor will comply with 
regulatory requirements for expedited safety reporting to regulatory authority (which 
includes the use of applicable systems, such as EudraVigilance), IRBs, ECs, and 
investigators.   
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through the use of the reference safety 
information in the Ocrelizumab Investigator's Brochure. 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
98/Protocol WA40404, Version 6 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
For a list of serious adverse drug reactions that are considered expected, refer to the 
current Ocrelizumab Investigator’s Brochure. 
An iDMC will monitor the incidence of the above-listed anticipated events until primary 
analysis is performed.  An aggregate report of any clinically relevant imbalances that do 
not favor the test product will be submitted to health authorities. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
Full details of all statistical issues and planned statistical analyses will be specified in 
a separate Statistical Analysis Plan, which will be finalized prior to the database lock and 
unblinding of the study database.  The SAP will include a more technical and detailed 
description of the statistical analyses described in this section. This section is a 
summary of the planned statistical analyses of the most important endpoints, including 
primary and key secondary endpoints. The analyses specified in the SAP supersede 
those specified here. 
6.1 
DETERMINATION OF SAMPLE SIZE 
The primary objective for this study is to evaluate the efficacy of ocrelizumab compared 
with placebo on the composite 12-week CDP  of EDSS and 9-HPT in all randomized 
patients and in patients with MRI activity.  The sample size was estimated on the basis 
of data from Study WA25046 (ORATORIO).   
A two-group test of equal exponential survival is used to determine the sample size for 
the composite 12-week CDP of EDSS and 9-HPT.  With a sample size of 1000 patients 
(of which at least 350 patients are expected in the MRI-active population), a double-blind 
treatment phase of 144 weeks, an annual dropout rate of 10%, and a randomization ratio 
of 1:1, it is expected that approximately 340 events will be observed in all randomized 
patients (placebo progression rate: 40%), which will provide approximately 80% power to 
detect a hazard ratio of 0.70 at a type I error rate of 0.0146 and approximately 75.5% 
power to detect a hazard ratio of 0.75 at a type I error rate of 0.05.  Likewise, it is 
expected that approximately 122 events will be observed in the MRI-active subgroup 
(placebo progression rate: 44%), which will provide approximately 78% power to detect 
a hazard ratio of 0.60 at a type I error rate of 0.04. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
99/Protocol WA40404, Version 6 
Operating characteristics (power and expected total number of events) for true 
underlying hazard ratio values of 0.60, 0.70, and 0.75 are provided in Table 8 for all 
randomized patients and the MRI-active subgroup. 
Table 8 
Operating Characteristics for Possible True Underlying Hazard 
Ratio Values 
 
MRI-Active 
Subgroup 
All Patients 
Randomized 
All Patients 
Randomized 
Expected number of events 
122 
340 
340 
Expected proportion of placebo patients with 
composite events at Week 120  
44% 
40% 
40% 
2-sided alpha for the log-rank test 
0.04 
0.0146 
0.05 
Power 
78% 
80% 
75.5% 
Detectable hazard ratio 
0.60 
0.70 
0.75 
MRI  magnetic resonance imaging. 
Note:  Operating characteristics are based on the following assumptions:  event times are 
exponentially distributed, and patients are followed for 144 weeks. 
 
It should be noted that the type I error rate to be used for the testing in all randomized 
patients will be adjusted depending of the proportion of events in the MRI-active 
subgroup (see Section 6.4.1.3 for control of type I error). 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
The number of patients who enroll, discontinue treatment or study, or complete the study 
will be summarized.  Reasons for premature treatment and study withdrawal will be 
listed and summarized.  Enrollment and major protocol deviations will be listed and 
evaluated for their potential effects on the interpretation of study results. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics (including age, sex, history of MS, 
stratification factors) will be summarized using means, standard deviations, medians, 
and ranges for continuous variables and proportions for categorical variables, as 
appropriate.  Summaries will be presented overall and by treatment group, for the 
MRI-active subgroup and all randomized patients as allocated. 
6.4 
EFFICACY ANALYSES 
The analysis population for the efficacy analyses will consist of all randomized patients, 
with patients grouped according to their assigned treatment. 
6.4.1 
Primary Analysis 
The primary analysis will compare the time to onset of composite 12-week CDP between 
ocrelizumab and placebo in all randomized patients and in the MRI-active subgroup.  

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
100/Protocol WA40404, Version 6 
If at least one of the two co-primary analyses is statistically significant, then the trial is 
considered positive.  Type I error will be controlled using a fallback and loop-back 
procedure (see Section 6.4.1.3). 
There are two co-primary analyses: 
 
In all randomized patients 
 
In the MRI-active subgroup 
 
The MRI-active subgroup is defined as patients with any T1 Gd lesion and/or new and/or 
enlarging T2 lesion during the screening period or at baseline. 
Time to onset of composite 12-week CDP is defined as the time from randomization to 
the first occurrence of at least one of the following progression events: 
 
12-week CDP in 9-HPT, defined as a worsening of 20% from baseline in 9-HPT 
confirmed for at least 12 weeks 
 
12-week CDP in EDSS, defined as an increase of  1.0 point from baseline EDSS 
score in patients with a baseline EDSS score   5.5 or an increase of   0.5 point in 
patients with a baseline EDSS score of   5.5 that is confirmed for at least 12 weeks 
 
The EDSS is a disability scale that ranges in 0.5-point steps from 0 (normal) to 
10.0 (death) (Kurtzke 1983; Kappos 2011).  The most recent EDSS measured before 
first dose administration (or randomization for non-treated patients) will be considered 
as baseline EDSS.   
The 9-HPT time is the reciprocal of the score for the 9-HPT as described in the MS 
functional composite guide (National Multiple Sclerosis Society 2001).  The score for the 
9-HPT is an average of the four trials (2 for the dominant hand and 2 for the 
non-dominant hand), calculated as follows:  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.  The most recent 9-HPT measured before first dose 
administration (or randomization for non-treated patients) will be considered as baseline 
9-HPT. 
In each component (EDSS and 9-HPT), CDP is considered confirmed when the increase 
is sustained at the next regularly scheduled visit at least 12 weeks after the initial 
disability progression.  Assessments occurring within 30 days after a protocol-defined 
relapse will not be used for confirmation of a disability progression. The non-
confirmatory assessments (if any) should be at least equal to the minimum change 
required for progression.   
For each component (EDSS and 9-HPT), missing assessments at scheduled visits prior 
to the last assessment of a patient, i.e. intermediate missing data, will not be replaced; 
progression detection or confirmation will be delayed to the next available assessment. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
101/Protocol WA40404, Version 6 
The hazard ratio will be estimated from a Cox regression, stratified by the 
randomization factors.  The p-value will be calculated from a log-rank test, stratified by 
the randomization stratification factors. 
In addition, a sensitivity analysis that adjusts for sex and other prognostic factors will be 
performed to assess the impact of these prognostic factors.  
The handling of intercurrent events and missing data is described in Section 6.4.1.1. 
6.4.1.1 
Estimands for the Primary Analysis 
The primary analysis has two co-primary estimands (see ICH E9 [R1] addendum on 
estimands and sensitivity analysis in clinical trials to the guideline on statistical principles 
for clinical trials; EMA 2017). 
Co-primary estimand 1 follows a combination of treatment-policy and hypothetical 
strategies and estimates the treatment effect in the MRI-active subgroup of ocrelizumab 
versus placebo, regardless of adherence to the randomized treatment had the patients 
not initiated another MS DMT or commercial ocrelizumab on the basis of the following 
attributes: 
a) 
Population:  Patients with PPMS, including patients later in their disease course, 
as defined by the study inclusion and exclusion criteria (See Sections 4.1.1 and 
4.1.2 of the protocol), with magnetic resonance imaging (MRI) activity (See 
Section 2.1.1 of the protocol). 
b) Treatment:  Ocrelizumab IV 300mg administered at Day 1 and Day 14, followed by 
Ocrelizumab IV 600 mg administered every 24 weeks versus matching placebo. 
c) 
Variable:  The variable will be time to onset of composite 12-week CDP. 
d) Intercurrent events will be handled as follows:  
 
Withdrawal from treatment and no initiation of another MS DMT or commercial 
ocrelizumab:  Patients will be followed regardless of adherence to study 
treatment or reason for withdrawal, and data will be collected and included in the 
analysis, following a treatment-policy strategy. 
 
Withdrawal from treatment and initiation of another MS DMT or commercial 
ocrelizumab:  Future disease progression in the hypothetical scenario as if no 
other therapy had been initiated is predicted on the basis of previously 
observed data and the preceding reason for withdrawal from study treatment.  
The following strategies will be used: 
– 
If the patient withdraws from study treatment due to lack of efficacy, 
a disability progression event will be imputed at the time of initiation of 
another treatment. 
– 
Withdrawal from study treatment due to another reason will be: 
Imputed as a disability progression event if the patient had an initial 
disability progression at the date of his or her last EDSS or 9-HPT 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
102/Protocol WA40404, Version 6 
assessment prior to the initiation of another treatment, whichever is the 
earliest 
Censored in all other cases at the date of the last EDSS or 9-HPT 
assessment prior to the initiation of another treatment,whichever is the 
earliest  
 
Withdrawal from study (missing data): 
– 
If the patient withdraws from study treatment due to lack of efficacy, 
a disability progression event will be imputed at the time of withdrawal from 
the study. 
– 
Withdrawal from study treatment due to another reason will be: 
Imputed as a disability progression event if the patient had an initial 
disability progression at the date of his or her last EDSS or 9-HPT 
assessment, whichever is the earliest 
Censored in all other cases at the date of the last EDSS or 9-HPT 
assessment, whichever is the earliest 
 
The switch to PDP OCR has no impact on this efficacy endpoint because it can 
only occur after a confirmed disability progression in 9-HPT and EDSS 
(see Section 3.1.1.3).  Patients who experience a DPE during the double-blind 
treatment phase will be given the option to switch to PDP OCR after they 
completed at least 120 weeks of double-blind treatment. 
e) Population-level-summary estimator:  The hazard ratio will be calculated from 
a Cox-regression to estimate the treatment-benefit, and the log-rank p-value will be 
used to test the statistical significance.  Both will be stratified by the stratification 
factors from the randomization.  
Patients without any disability progression events (including imputed events) during 
the double-blind treatment period will be censored at the date of the last EDSS or9-HPT 
assessment during the double-blind treatment period, whichever is the earliest. 
 
Sensitivity analyses for co-primary estimand 1: 
 
A tipping-point analysis will be performed to assess the impact of the assumptions 
for patients who had an initial progression just before initiation of another MS DMT 
or commercial ocrelizumab, or withdrawal from study.  In this analysis, the impact of 
different disability progression probabilities between 0 and 100% by randomized 
treatment arm will be assessed.  
 
Sensitivity analysis will be performed where the observed profile of patients in the 
placebo group is used to impute time to event for patients experiencing censoring 
because of the following:  
– 
Initiation of another MS DMT or commercial ocrelizumab  
– 
Withdrawal from study (missing data) 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
103/Protocol WA40404, Version 6 
Supplementary estimand applying treatment-policy strategy to withdrawal 
from study treatment and to initiation of other treatments: 
This supplementary estimand will use a treatment-policy strategy to estimate the 
treatment effect of ocrelizumab versus placebo on disability progression, on the basis of 
initial treatment, regardless whether patients adhered to randomized treatment or 
initiated other treatments (e.g., discontinued treatment or switched to another MS DMT 
or commercial ocrelizumab). 
Supplementary estimand to estimate the treatment effect had the patient 
not withdrawn from study treatment: 
The supplementary estimand will use a hypothetical strategy to estimate the treatment 
effect of ocrelizumab versus placebo on disability progression had the patient not 
withdrawn from study treatment as follows: 
 
The same estimand as the primary analysis for the Oratorio study (WA25046):  
If the patient withdraws from treatment without any prior events, an event is 
imputed as if the patient had an initial disability progression at the date of his or her 
last EDSS or 9-HPT assessment prior to withdrawal from treatment, whichever is the 
earliest, and no follow-up data are available, otherwise the patient is censored in all 
other cases at the  date of the last EDSS or 9-HPT assessment prior to withdrawal 
from treatment, whichever is the earliest. 
 
Estimand counting withdrawal due to lack of efficacy as treatment failure: 
This estimand will estimate the treatment effect measured as time to disease 
progression or discontinuation from the randomized treatment due to lack of efficacy 
(composite endpoint).  Same as the estimand above (Study WA25046); however, 
patients who withdrew from treatment due to lack of efficacy will also have an 
imputed event. 
 
Estimand counting withdrawal due to lack of efficacy or due to adverse events as 
treatment failure: 
This estimand will estimate the treatment effect measured as time to disease 
progression or discontinuation from the randomized treatment due to lack of efficacy 
or due to an adverse event (composite endpoint).  Same as the estimand above 
(Study WA25046); however, patients who withdrew from treatment due to lack of 
efficacy or due to an adverse event will also have an imputed event. 
 
Co-primary estimand 2 will be similar to the co-primary estimand 1 except the 
population will be patients with PPMS, including patients later in their disease course, 
as defined by the study inclusion and exclusion criteria (See Sections 4.1.1 and 4.1.2 of 
the protocol). 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
104/Protocol WA40404, Version 6 
6.4.1.2 
Estimands for the Key Secondary Endpoint of Time to 
Confirmed Disability Progression 
6.4.1.2.1 
Estimands for the Key Secondary Endpoint of Time to 12-
week Confirmed Disability Progression in 9-HPT 
The estimand for the key secondary endpoint of time to 12-week CDP in 9-HPT follows 
the same combination of treatment-policy and hypothetical strategies as for the primary 
endpoint but using the variable time to 12-week CDP in 9-HPT.  This will estimate the 
treatment effect of ocrelizumab versus placebo, regardless of adherence to the 
randomized treatment, had the patients not initiated another MS DMT or commercial 
ocrelizumab on the basis of the following attributes: 
a) Population:  Patients with PPMS, including patients later in their disease course, 
as defined by the study inclusion and exclusion criteria (See Sections 4.1.1 
and 4.1.2). 
b) Treatment:  Ocrelizumab IV 300mg administered at Day 1 and Day 14, followed by 
Ocrelizumab IV 600 mg administered every 24 weeks versus matching placebo. 
c) 
Variable:  The variable will be time to 12-week CDP in 9-HPT. 
d) Intercurrent events will be handled as below:  
 
Withdrawal from treatment and no initiation of another MS DMT or 
commercial ocrelizumab:  Patients will be followed regardless of adherence to 
study treatment or reason for withdrawal, and data will be collected and 
included in the analysis, following a treatment-policy strategy. 
 
Withdrawal from treatment and initiation of another MS DMT or commercial 
ocrelizumab:  Future disease progression in the hypothetical scenario as if no 
other therapy had been initiated is predicted on the basis of previously 
observed data and the preceding reason for withdrawal from study treatment.  
The following strategies will be used:   
– 
If the patient withdraws from study treatment due to lack of efficacy, 
a disability progression event will be imputed at the time of initiation of 
another treatment. 
– 
Withdrawal from study treatment due to another reason will be: 
Imputed as an event if the patient had an initial increase of 20% in 9-
HPT time at the date of his or her last 9-HPT assessment prior to the 
initiation of another treatment  
Censored in all other cases at the date of the last 9-HPT assessment 
prior to the initiation of another treatment 
 
Withdrawal from study (missing data): 
– 
If the patient withdraws from study treatment due to lack of efficacy, a 
disability progression event will be imputed at the time of withdrawal from 
study. 
– 
Withdrawal from study treatment due to another reason will be: 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
106/Protocol WA40404, Version 6 
 MRI  magnetic resonance imaging. 
a The a level indicated for estimand 2 is an example assuming that 36% (122 of 340) of all 
events in all randomized patients have occurred in the MRI-active subgroup.  The actual alpha 
level for the primary analysis will be determined based on the actually observed events based 
on the Spiessens-Debois method. 
  
Calculation of 1 and 2 will be as follows: 
1 is arbitrarily chosen as 0.04, to maximize the power of the analysis for the 
MRI-active subgroup. 
2: calculated according to the Spiessens-Debois method (2010).  For example of 2 
calculated assuming 122 events in MRI-active subgroup and 340 events in the ITT, 
2  0.0146.  a2 will be calculated at the primary analysis, with the proportion of 
information in the MRI-active subgroup. 
 
Fallback:  If the analysis of the co-primary estimand 1 has a p-value  0.04, then the 
analysis for the co-primary estimand 2 will be tested with   0.05. 
Loop-back:  If the analysis of the co-primary estimand 2 has a p-value  0.0146, then the 
co-primary estimand 1 will be tested with   0.05. 
If at least one of the two co-primary estimands is statistically significant, then the trial is 
positive. 
If only one of the co-primary estimands is positive, the secondary endpoints will be 
tested for all randomized patients and the MRI-active subgroup but the p-value will not 
be formally controlled. 
If both co-primary estimands are statistically significant, then the secondary endpoints 
will be tested with   0.05. 
The secondary endpoints will be tested in a hierarchical gatekeeping procedure for all 
randomized patients, and as exploratory in the MRI-active subgroup. 
6.4.2 
Secondary Efficacy Endpoints 
The secondary efficacy objective for this study is to evaluate the efficacy of ocrelizumab 
compared with placebo for all randomized patients on the basis of the following 
endpoints, in hierarchical order: 
 
Time to 12-week CDP in 9-HPT  
 
Time to 12-week CDP in EDSS 
 
Time to 24-week CDP in 9-HPT  
 
Time to 24-week CDP in EDSS 
 
Differences in the annual rate of percent change from baseline in total volume of 
T2 lesions on MRI scans will be analyzed using a random coefficient regression 
model (RCRM) 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
107/Protocol WA40404, Version 6 
 
Differences in the annual rate of percent change from Week 24 in total brain volume 
on MRI scans will be analyzed using an RCRM analysis 
 
The estimand for the secondary endpoint of time to 12-week CDP in 9-HPT and time to 
12-week CDP in EDSS is described in Sections 6.4.1.2.1 and 6.4.1.2.2, respectively. 
6.4.3 
Exploratory Efficacy Endpoints 
The secondary efficacy endpoints will also be evaluated as exploratory analyses for the 
MRI-active subgroup. 
An exploratory efficacy objective for this study is to evaluate the efficacy of ocrelizumab 
compared with placebo on the primary and secondary endpoints in the subgroup of 
patients ages  55 versus  55, patients with EDSS score  6.5 versus  6.5, males and 
females (all randomized patients, MRI-active subgroup and MRI-inactive subgroup), and 
in the MRI-inactive subgroup versus MRI-active subgroup.  Because the above 
subgroups of patients ages  55 and with EDSS score  6.5 were not enrolled in the 
previous PPMS study (WA25046), there is a special interest in analyzing these 
subgroups.  An MRI-active subgroup is a co-primary endpoint; therefore, the 
complementary MRI-inactive subgroup will also be analyzed. 
Other exploratory analyses for all randomized patients and MRI-active subgroup are on 
the basis of the following endpoints: 
 
Change from baseline to Week 120 in fatigue as measured by MFIS 
 
Annual rate of percent change from baseline and from Week 24 in cervical spinal 
cord volume on MRI scans  
 
Change from baseline to Week 120 in ABILHAND 
 
Change from baseline to Week 120 in the upper limb domain of a life quality 
measure for patients with neurological disorders (Neuro-QoL-UE) 
 
Change from baseline to Week 120 in the PGIC-UL function 
 
Change from baseline to Week 120 in the PGIC-F 
 
Change from baseline to Week 120 in the MSIS-29 physical score 
 
Proportion of patients at Week 120 with a pre-specified, clinically meaningful decline 
on the MSIS-29 
 
Change from baseline to Week 120 in the SDMT 
 
Rate of decline in fine motor skills of upper extremities and manual/finger dexterity 
as measured by smartphone-based digital outcome assessment (Floodlight RPM) 
 
The number of Gd-enhancing T1 lesions and number of new or enlarging T2 
hyperintense lesions as detected by mandatory MRI 
 
Annual rate of percent change from baseline in total non-enhancing T1 lesion 
volume on MRI scan of the brain. 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
108/Protocol WA40404, Version 6 
6.5 
SAFETY ANALYSES 
The safety analysis population will consist of all randomized patients who received at 
least one infusion (partial or complete) of study drug (ocrelizumab or placebo), with 
patients grouped according to treatment received. 
All verbatim adverse event terms will be mapped to MedDRA thesaurus terms, and 
adverse event severity will be graded according to NCI CTCAE v5.0. 
The main safety objective for this study is to evaluate the safety of ocrelizumab 
compared with placebo until when patients receive any PDP OCR, commercial 
ocrelizumab treatment, or other MS DMT in all patients who receive at least one infusion 
(partial or complete) of study drug (ocrelizumab or placebo). 
The safety endpoints considered are as follows: 
 
Adverse events leading to study treatment withdrawal 
 
Adverse events in patients previously treated with an another DMT for MS 
 
Proportion of patients with adverse events and serious adverse events 
 
Incidence rates per 100 PY for infections, serious infections, death, and 
malignancies, including breast cancer 
 
Vital signs (blood pressure and pulse rate) during and 1 hour after infusion 
 
Change from baseline in laboratory test results for hematology and chemistry 
 
Change from baseline in laboratory test results for immunoglobulins (IgA, IgM, IgG) 
and T-cell subtype (CD3, CD4, CD8):  MMRM analyses will be performed.  Fixed 
effects in the model will include treatment arm, visit, treatment by visit interaction, 
stratification factors, baseline value of the immunoglobulin or T-cell, and baseline by 
visit interaction.  Visits 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.  
Appropriate variance stabilizing transformations of the laboratory measurements 
(e.g., log-transformation) may be applied. 
 
Association of decrease in each immunoglobulin (IgA, IgM, IgG) and serious 
infections:  incidence rate of serious infections per 100 PY during the episodes of 
confirmed drop of immunoglobulin levels below LLN versus the incidence rate of 
serious infections per 100 PY in the remaining exposure (before or after a confirmed 
drop, and during the overall exposure for the patients without any confirmed drop of 
immunoglobulin) for each treatment arm.  The exposure of a confirmed episode is 
counted from the day the immunoglobulin first decreased below LLN until the day it 
is normalized above LLN, and the serious infections with onset date in between are 
counted.  The 95% confidence interval will be calculated using Poisson distribution 
methods. 
 
Association of decrease in each T-cell subtype (CD3, CD4, CD8) and serious 
infections will be analyzed as for the immunoglobulin described above. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
109/Protocol WA40404, Version 6 
 
Additional safety objectives for this study will include evaluation of the following: 
 
Subgroup analyses:  patients with MRI-active versus MRI-inactive, patients 
aged  55 versus  55 years, patients with a baseline EDSS score of  6.5 versus 
 6.5, females and males, and patients previously treated (prior to randomization) 
with another DMT for MS 
 
Incidence rates per 100 PY for infections, serious infections, death, and 
malignancies, including breast cancer  
 
Pharmacodynamics, as measured by B-cell levels in blood 
 
The ocrelizumab pool for long-term safety analysis will consist of all randomized patients 
who received at least one infusion (partial or complete) of ocrelizumab (study drug, 
PDP OCR, or commercial ocrelizumab) until when patients receive any other MS DMT 
as follows: 
 
Adverse events leading to withdrawal of ocrelizumab treatment 
 
Adverse events in patients previously treated with another DMT for MS 
 
Proportion of patients with adverse events and serious adverse events 
 
Incidence rates per 100 PY for infections, serious infections, death, and 
malignancies, including breast cancer 
 
Change from first administration of ocrelizumab in laboratory test results for 
hematology and chemistry 
 
Change from first dose of ocrelizumab in immunoglobulins (IgA, IgM, IgG) and T-cell 
subtype (CD3, CD4, CD8) 
 
Associations of decrease in each immunoglobulin (IgA, IgM, IgG) and serious 
infections 
 
Associations of decrease in each T-cell subtype (CD3, CD4, CD8) and serious 
infections 
 
In an exploratory analysis, all safety analyses will be conducted on data collected from 
the first ocrelizumab dose until the end of the study. 
6.6 
PHARMACOKINETIC ANALYSES 
PK analysis of ocrelizumab serum concentration versus time data will be conducted 
using a population PK approach.  Nonlinear mixed effects modeling (with software 
NONMEM) will be used to analyze the sparse sampling dose-concentration-time data of 
ocrelizumab.  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 would interfere with PK 
evaluation.  The PK data of this study may be pooled with data from other studies.  
Population PK parameters (e.g., clearances and volumes) will be estimated and the 
influence of covariates, such as sex, body weight, and baseline CD19 lymphocytes, on 
these parameters will be investigated.  Exposure (area under the concentration-time 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
110/Protocol WA40404, Version 6 
curve) to ocrelizumab will be estimated.  The selection of other parameters will depend 
on the final PK model used for this analysis.  Additional PK analyses will be conducted 
as appropriate. 
6.7 
IMMUNOGENICITY ANALYSES 
The immunogenicity analysis population will consist of all patients with at least one 
ADA assessment.  Patients will be grouped according to treatment received or, if no 
treatment is received prior to study discontinuation, according to treatment assigned. 
The numbers and proportions of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after drug administration (postbaseline incidence) 
will be summarized by treatment group.  When determining postbaseline incidence, 
patients are considered to be ADA positive if they are ADA negative or have missing 
data at baseline but develop an ADA response following study drug exposure 
(treatment-induced ADA response), or if they are ADA positive at baseline and the titer 
of one or more postbaseline samples is at least 0.60 titer unit greater than the titer of the 
baseline sample (treatment-enhanced ADA response).  Patients are considered to be 
ADA negative if they are ADA negative or have missing data at baseline and all 
postbaseline samples are negative, or if they are ADA positive at baseline but do not 
have any postbaseline samples with a titer that is at least 0.60 titer unit greater than the 
titer of the baseline sample (treatment unaffected). 
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
will be analyzed and reported via descriptive statistics. 
6.8 
BIOMARKER ANALYSES 
Biomarkers will be assessed at baseline and subsequent timepoints following 
administration of ocrelizumab.  Pharmacodynamic biomarkers will be presented as 
absolute value over time and/or percent change relative to baseline over time and/or 
proportion of participants with biomarker levels within a defined threshold over time.  
Biomarker levels at baseline or over time may be compared with efficacy or safety 
measurements to assess prognostic or predictive properties.  Descriptive or summary 
statistics will be used to describe biomarker assessments. 
NfL treatment response will be presented as absolute values over time, percent change 
relative to baseline over time, and/or proportion of participants with NfL levels below a 
pre-defined threshold over time. 
Baseline NfL levels or NfL levels on treatment determined by the appropriate assay and 
to be determined pre-defined cutoffs will be used to assess the relationship of baseline or 
on-treatment NfL to future efficacy, imaging, or other outcomes. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
111/Protocol WA40404, Version 6 
6.9 
INTERIM ANALYSIS 
6.9.1 
Planned Interim Analysis 
There is no planned interim analysis. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory, central imaging, 
electronic PRO, and IxRS data will be sent directly to the Sponsor, using the Sponsor's 
standard procedures to handle and process the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures. 
PRO data will be collected through the use of an electronic device provided by a vendor 
(see Section 7.3 for details). 
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in 
a readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required. 
7.3 
ELECTRONIC PATIENT REPORTED OUTCOME DATA 
Patients will use an electronic device to capture PRO data.  The device is designed for 
entry of data in a way that is attributable, secure, and accurate, in compliance with U.S. 
FDA regulations for electronic records (21 CFR Part 11).  The data will be transmitted to 
a centralized database maintained by the electronic device vendor. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
112/Protocol WA40404, Version 6 
The electronic data will be available for view access only, via a secure web server.  Only 
identified and trained users may view the data, and their actions will become part of the 
audit trail.  The Sponsor will have view access only.  System backups for data stored by 
the Sponsor and records retention for the study data will be consistent with the 
Sponsor’s standard procedures. 
Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived.  The investigator will receive patient data for the site in both human- and 
machine-readable formats on an archival-quality compact disc that must be kept with the 
study records as source data.  Acknowledgement of receipt of the compact disc is 
required.  In addition, the Sponsor will receive all data in a machine-readable format on 
a compact disc. 
7.4 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6. 
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities. 
7.5 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
113/Protocol WA40404, Version 6 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PRO data (if applicable), Informed Consent 
Forms, laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for at least 15 years after completion or discontinuation of the 
study or for the length of time required by relevant national or local health authorities, 
whichever is longer.  After that period of time, the documents may be destroyed, subject 
to local regulations. 
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
The Sponsor will retain study data for 25 years after the final study results have been 
reported or for the length of time required by relevant national or local health authorities, 
whichever is longer. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the Clinical Trials Regulation (536/2014) and 
applicable local, regional, and national laws. 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in 
a certified translation of the local language.  The Sponsor or its designee must review 
and approve any proposed deviations from the Sponsor's sample Informed Consent 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
114/Protocol WA40404, Version 6 
Forms or any alternate consent forms proposed by the site (collectively, the "Consent 
Forms") before IRB/EC submission.  The final IRB/EC-approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to 
a significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes 
a separate Authorization Form for patient authorization for use and disclosure of 
personal health information under the HIPAA regulations, the review, approval, 
and other processes outlined above apply except that IRB review and approval may not 
be required per study site policies. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
115/Protocol WA40404, Version 6 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments 
(see Section 9.7). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC and 
archived in the site’s study file. 
8.4 
CONFIDENTIALITY 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or access.  
In the event of a data security breach, appropriate mitigation measures will be 
implemented. 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Roche policy on study data publication 
(see Section 9.6). 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
116/Protocol WA40404, Version 6 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
Study data, which may include data on germline mutations, may be submitted to 
government or other health research databases or shared with researchers, government 
agencies, companies, or other groups that are not participating in this study.  These data 
may be combined with or linked to other data and used for research purposes, to 
advance science and public health, or for analysis, development, and commercialization 
of products to treat and diagnose disease.  In addition, redacted clinical study reports 
and other summary reports will be provided upon request. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.3 
MANAGEMENT OF STUDY QUALITY 
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  Prior 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
117/Protocol WA40404, Version 6 
to study initiation, the Sponsor will identify potential risks associated with critical trial 
processes and data and will implement plans for evaluating and controlling these risks.  
Risk evaluation and control will include the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters prior to study initiation.  Detection of deviations 
from quality tolerance limits will trigger an evaluation to determine if action is needed.  
Details on the establishment and monitoring of quality tolerance limits will be provided in 
a Quality Tolerance Limit Management Plan. 
9.4 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.5 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring. 
At least 220 sites globally are estimated to participate to enroll approximately 
1000 patients, of which at least 350 patients are planned to be in the MRI-active 
subgroup.  Enrollment will occur through an IxRS. 
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in Section 4.5. 
An iDMC will be employed to monitor and evaluate patient safety throughout the study, 
until the primary analysis is performed.  Monitoring details will be described in the iDMC 
Charter. 
An external Steering Committee will provide general guidance, assist with liaison to 
investigators and oversee any external communication of the results of the study.  The 
external Steering Committee will stay blinded to all data until the primary analysis. 
9.6 
PUBLICATION OF DATA AND PROTECTION OF 
TRADE SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and/or other summaries of clinical study results may be 
available in health authority databases for public access, as required by local regulation, 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
118/Protocol WA40404, Version 6 
and will be provided upon request.  For more information, refer to the Roche Global 
Policy on Sharing of Clinical Study Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/ 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.7 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
119/Protocol WA40404, Version 6 
10. 
REFERENCES 
Andersson PB, Waubant E, Gee L, et al. Multiple sclerosis that is progressive from the 
time of onset: clinical characteristics and progression of disability. Arch Neurol 
1999;56:1138−42. 
Axelsson M, Malmeström C, Gunnarsson M, et al. Immunosuppressive therapy reduces 
axonal damage in progressive multiple sclerosis. Mult Scler 2014;20:4350. 
Banchereau J, Rousset F. Human B lymphocytes: phenotype, proliferation, and 
differentiation. Adv Immunol 1992;52:125−262. 
Bar-Or A, Thanei GA, Harp CT, et al. Blood neurofilament light levels are lowered to 
a healthy donor range in patients with RMS and PPMS following ocrelizumab 
treatment [abstract on the Internet]. 2019 Sept [cited 2020 April 21]. Available from 
https://onlinelibrary.ectrims-congress.eu/ectrims/2019/stockholm/279451/amit.bar-
or.blood.neurofilament.light.levels.are.lowered.to.a.healthy.donor.html. 
Belafsky PC, Mouadeb DA, Rees CJ, et al. Validity and reliability of the Eating 
Assessment Tool (EAT-10). Ann Otol Rhinol Laryngol 2008;117:919–24. 
Benedict RHB, DeLuca J, Phillips G, et al. Validity of the Symbol Digit Modalities Test as 
a cognition performance outcome measure for multiple sclerosis. Mult Scler 
2017;23:721–33.  
Brooks R. EuroQol: the current state of play. Health Policy 1996;37:5372. 
Burman J, Zetterberg H, Fransson M, et al. Assessing tissue damage in multiple 
sclerosis: a biomarker approach. Acta Neurol Scand 2014;130:819. 
Cano S, Cleanthous S, Marquis P, et al. Measuring upper limb function in multiple 
sclerosis: Enhancing the ABILHAND’s performance. Value in Health 2015;18:A24. 
Compston A, Coles A. Multiple sclerosis. Lancet 2008;372:150217. 
Correale J, Fiol M, Gilmore W. The risk of relapses in multiple sclerosis during systemic 
infections. Neurology 2006;67:652–9. 
Cottrell DA, Kremenchutzky M, Rice GPA, et al. The natural history of multiple sclerosis: 
a geographically based study. 5. The clinical features and natural history of 
primary progressive multiple sclerosis. Brain 1999;122:625−39. 
Didonna A, Oksenberg JR. Genetic determinants of risk and progression in multiple 
sclerosis. Clinica Chimica Acta 2015;449:1622. 
DiSanto G, Barro C, Benkert P, et al. Serum Neurofilament light: A biomarker of 
neuronal damage in multiple sclerosis. Ann Neurol 2017;81:85770. 
Earhart GM, Cavanaugh JT, Ellis T, et al. The 9-hole PEG test of upper extremity 
function: average values, test-retest reliability, and factors contributing to 
performance in people with Parkinson disease. J Neurol Phys Ther 
2011;35:15763. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
120/Protocol WA40404, Version 6 
[EMA] European Medicines Agency. Annex I: Ocrevus (ocrelizumab) summary of product 
characteristics. [resource on the Internet]. 2018 [updated January 2018; cited 
April 2018]. Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/004043/WC500241124.pdf. 
[EMA] European Medicines Agency. ICH E9 (R1) addendum on estimands and 
sensitivity analysis in clinical trial to the guideline on statistical principles for clinical 
trials. 2017 [updated August 2017; cited February 2018]. Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/201
7/08/WC500233916.pdf. 
[EMA] European Medicines Agency. Guideline on clinical investigation of medicinal 
products for the treatment of multiple sclerosis [resource on the Internet]. 2015 
[updated March 2015; cited February 2018]. Available from: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_c
ontent_001169.jsp&mid=WC0b01ac0580034cf5. 
Erasmus L-P, Sarno S, Albrecht H, et al. Measurement of ataxic symptoms with 
a graphic tablet: standard values in controls and validity in multiple sclerosis 
patients. J Neurosci Methods 2001;108:2537. 
EuroQol Group. EuroQol: a new facility for the measurement of health-related quality of 
life. Health Policy 1990;16:199208. 
Feys P, Lamers I, Francis G, et al. The Nine-Hole Peg Test as a manual dexterity 
performance measure for multiple sclerosis. Mult Scler 2017;23:71120. 
Fischer JS, LaRocca NG, Miller DM, et al. Recent developments in the assessment of 
quality of life in multiple sclerosis (MS). Mult Scler 1999a;5:2519. 
Fischer JS, Rudick RA, Cutter GR, et al. The Multiple Sclerosis Functional Composite 
Measure (MSFC): an integrated approach to MS clinical outcome assessment. 
Mult Scler 1999b;5:244–50. 
Frischer JM, Bramow S, Dal-Bianco A, et al. The relation between inflammation and 
neurodegeneration in multiple sclerosis brains. Brain 2009;132:117589.  
Frischer JM, Weigand SD, Guo Y, et al. Clinical and pathological insights into the 
dynamic nature of the white matter multiple sclerosis plaque. Ann Neurol 
2015;78:71021. 
Gershon RC, Lai JS, Bode R, et al. Neuro-QOL: quality of life item banks for adults with 
neurological disorders: item development and calibrations based upon clinical and 
general population testing. Qual Life Res 2012;21(3):47586. 
Goodkin DE, Hertsgaard D, Seminary J. Upper extremity function in multiple sclerosis: 
improving assessment sensitivity with Box-and-Block and Nine-Hole Peg Tests. 
Arch Phys Med Rehabil 1988;69:850–54. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
121/Protocol WA40404, Version 6 
Gunnarsson M, Mameström C, Axelsson M, et al. Axonal damage in relapsing multiple 
sclerosis is markedly reduced by natalizumab. Ann Neurol 2011;69:839. 
Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus interferon beta-1a in relapsing 
multiple sclerosis. N Engl J Med 2017;376:22134. 
Hennessey A, Robertson NP, Swingler R, et al. Urinary, faecal and sexual dysfunction in 
patients with multiple sclerosis. J Neurol 1999;246:102732. 
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new 
five-level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011;20:172736. 
Hobart JC, Lamping D, Fitzpatrick R, et al. The Multiple Sclerosis Impact Scale 
(MSIS-29); a new patient-based outcome measure. Brain 2001;124:962–73. 
Hughes R, Whitley L, Fitovski K, et al. COVID-19 in ocrelizumab-treated people with 
multiple sclerosis. Mult Scler Relat Disord 2021;49:102725. 
[IMSGC] International Multiple Sclerosis Genetics Consortium. Analysis of 
immune-related loci idintifies 48 new susceptibility variants for multiple sclerosis. 
Nature Gent 2013;45:135362. 
[IMSGC and WTCCC] International Multiple Sclerosis Genetics Consortium and the 
Wellcome Trust Case Control Consortium. Genetic risk and a primary role for 
cell-mediated immune mechanisms in multiple sclerosis. Nature 2011;476:2149. 
Janssen MF, Pickard AS, Golicki D, et al. Measurement properties of the EQ-5D-5L 
compared to the EQ-5D-3L across eight patient groups: a multi-country study. 
Qual Life Res 2013;22:171727. 
Kappos L. Standardised neurological examination and assessment of Kurtzke's 
functional systems and expanded disability status scale. Slightly modified from J.F. 
Kurtzke, Neurology 1983:33,1444-52. Neurology, University Hospital Basel, 
Switzerland: Neurostatus Scoring Definitions, 2011. 
Kraft GH, Amtmann D, Bennett SE, et al. Assessment of upper extremity function in 
multiple sclerosis: review and opinion. Postgrad Med 2014;126:1028. 
Kuhle J, Kropshofer H, Haering DA, et al. Blood neurofilament light chain as a biomarker 
of MS disease activity and treatment response. Neurology 2019;92:e1007–15.  
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability 
status scale (EDSS). Neurol 1983;33:144452. 
Leray E, Yaouanq J, Le Page E, et al. Evidence for a two-stage disability progression 
in multiple sclerosis. Brain 2010;133(Pt 7):190013. 
Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple 
sclerosis: the 2013 revisions. Neurology 2014;83:27886. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
122/Protocol WA40404, Version 6 
Mikol D, Goldman M, Hartung HP.et al. The 9-Hole Peg Test (9-HPT) has a stronger 
correlation than the Expanded Disability Status Scale (EDSS) with patient-reported 
upper extremity impairment as assessed using ABILHAND in patients with 
secondary progressive multiple sclerosis (SPMS): Analysis of baseline data from 
the ASCEND Study (P7.222). Neurology 2015;84(14 Supp):P7.222. 
Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus placebo in primary 
progressive multiple sclerosis. N Engl J Med 2017;376:20920. 
[MSIF] Multiple Sclerosis International Federation. Atlas of MS 2013. Mapping multiple 
sclerosis around the world [resource on the Internet]. 2013 [cited March 2018]. 
Available from: https://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf.  
National Multiple Sclerosis Society. 9-Hole-Peg-Test-(9-HPT) [resource on the Internet]. 
2001 [updated October 2001; cited February 2018]. Available from: 
https://www.nationalmssociety.org/For-Professionals/Researchers/Resources-for-
Researchers/Clinical-Study-Measures/9-Hole-Peg-Test-(9-HPT). 
Nicholas R, Young C, Friede T. Bladder symptoms in multiple sclerosis: a review of 
pathophysiology and management. Expert Opin Drug Saf 2010;9:905–15. 
OCREVUS® (ocrelizumab) INJECTION, Genentech. March 2017 [cited 27 March 2018]. 
Available from: https://www.gene.com/download/pdf/ocrevus_prescribing.pdf. 
Parker VM, Wade DT, Langton Hewer R. Loss of arm function after stroke: 
measurement, frequency, and recovery. Int Rehabil Med 1986;8:6973. 
Patsopoulos NA, Barcellos LF, Hintzen RQ, et al. Fine-mappin the genetic association of 
the major histocompatibilitiy complex in muliple sclerosis: HLA and non-HLA 
effects. PLoS Genet 2013;9:e1003926. 
Penta M, Ing, Thonnard J-L, et al. ABILHAND: a Rasch-built measure of manual ability. 
Arch Phys Med Rehabil 1998;79:1038–42. 
Prosiegel M, Schelling A, Wagner-Sonntag E. Dysphagia and multiple sclerosis. Int MS J 
2004;11:22–31. 
Smith A. Symbol digit modalities test: manual. Los Angeles: Western Psychological 
Services, 1982. 
Spiessens B, Debois M. Adjusted significance levels for subgroup analyses in clinical 
trials. Contemp Clinical Trials 2010;31:647–56. 
Tassorelli C, Bergamaschi R, Buscone S, et al. Dysphagia in multiple sclerosis: from 
pathogenesis to diagnosis. Neurol Sci 2008;29(Suppl 4):S360–3. 
Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 
revisions of the McDonald criteria. Lancet Neurol 2018;17:162–73. 
Tullman MJ. Overview of the epidemiology, diagnosis, and disease progression 
associated with multiple sclerosis. Am J Manag Care 2013;19(2 Suppl):S1520. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
123/Protocol WA40404, Version 6 
Wang YC, Bohannon RW, Kapellusch J, et al. Dexterity as measured with the 9-hole 
peg test (9-HPT) across the age span. J Hand Ther 2015;28:539;quiz 60. 
[WMA] World Medical Association. WMA declaration of Helsinkiethical principles for 
medical research involving human subjects [resource on the Internet]. 1964 
[updated March 2017; cited February 2018]. Available from: 
https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-
for-medical-research-involving-human-subjects/. 

Appendix 1:  Schedule of Activities:  Double-Blind Treatment (cont.) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
127/Protocol WA40404, Version 6 
d The assessments required for N represent the typical schedule of assessments for the double-blind treatment phase with Week 144 being the last 
visit.  If the study ends for any reason or the patient must be withdrawn from treatment, a treatment discontinuation visit should be performed. 
e Must be obtained and documented in written form before any study-specific screening procedure and initiation of study treatment and PDP OCR 
(if applicable).  
f Questionnaires will be self-administered prior to the administration of study treatment.  The questionnaires should be completed before the 
patient receives any information on disease status, prior to the administration of non-PRO assessments, and in the following order each time, 
whenever possible:  ABILHAND, Neuro-QoL-UE, PGIC-UL, MFIS, PGIC-F, MSIS-29, and EQ-5D-5L.  Questionnaires will be completed every 
6 months during the double-blind treatment phase.  EQ-5D-5L will not be completed at screening.  PGIC-UL and PGIC-F will not be completed at 
screening and baseline. 
g Includes pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, and temperature.  Temperature should be 
measured and recorded in patient’s notes only.  Blood pressure and pulse rate will be recorded on the appropriate eCRF.  On ocrelizumab (or 
placebo) infusion visits, vital signs should be taken within 45 minutes prior to the methylprednisolone infusion. In addition, blood pressure and 
pulse rate should be obtained prior to start of infusion, every hour during the infusion, at the end of infusion and 1 hour after the end of the 
infusion.  On non-infusion days, the vital signs may be taken at any time during the visit.  Record abnormalities observed at baseline on the 
General Medical History and Baseline Conditions eCRF page.  At subsequent visits, record new or worsened clinically significant abnormalities 
on the Adverse Event eCRF. 
h At screening, perform a complete physical examination that should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  Any abnormality identified at 
baseline should be recorded on the General Medical History and Baseline Conditions eCRF.  During the study conduct, perform a limited, 
symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically significant abnormalities on 
the Adverse Event eCRF. 
i Neurological examinations will be used to distinguish relapse in MS from another neurological (non-MS) disorder.  Potential relapses should be 
recorded throughout the treatment period.  All patients with new neurological symptoms suggestive of MS worsening should have EDSS 
assessment performed by Examining Investigator.  Investigators will also screen patients 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).  Patients with suspected 
PML should be withheld from ocrelizumab treatment until PML is ruled out by complete clinical evaluation and appropriate diagnostic testing.  
A patient with confirmed PML should be withdrawn from the study treatment permanently. 
j Both the dominant and non-dominant hands are tested twice (two consecutive trials of the dominant hand, followed immediately by two 
consecutive trials of the non-dominant hand) (National Multiple Sclerosis Society 2001). 
k EDSS including functional system scores will be assessed and collected.  

Appendix 1:  Schedule of Activities:  Double-Blind Treatment (cont.) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
128/Protocol WA40404, Version 6 
l Hematology includes hemoglobin, hematocrit, RBC, WBC (absolute and differential:  neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, other cells), and quantitative platelet count.  Chemistry includes AST, ALT, gamma-glutamyl transferase, total bilirubin, creatinine, 
amylase, potassium, sodium.  Urinalysis includes dipstick (pH, specific gravity, glucose, protein, ketones, blood), and a microscopic examination 
if abnormal and clinically significant will be performed at the site (local laboratory).  
m B cells and other cell types and/or B-cell subsets will be assessed in fresh whole blood using flow cytometry. 
n CSF sample will only be required at screening for patients who do not have documented history of elevated IgG index and/or one or more IgG 
oligoclonal bands detected by isoelectric focusing.  The CSF specimen will be sent out to the central laboratory to verify presence of elevated IgG 
index and IgG oligoclonal bands.  Leftover CSF will be stored by the central laboratory for biomarker use.  Patients for whom screening CSF was 
collected will have the option to participate in a collection of CSF at Week 48.  The CSF sample should be collected prior to the ocrelizumab 
(or placebo) infusion at Week 48 (within a window of 14 days prior to the actual scheduled visit Week 48).  This sample will be used for 
exploratory biomarker determination. 
o All women of childbearing potential will have a serum pregnancy test at screening.  Urine pregnancy tests will be performed at specified 
subsequent visits.  If a urine pregnancy test is positive, the patient will not receive the scheduled dose, and a confirmatory serum pregnancy test 
will be performed.  Urine -hCG (sensitivity of at least 25 mU/mL) will be performed locally. 
p Testing of the FSH level is only applicable to female patients to confirm the post-menopausal status at screening.  The sample will be analyzed 
by the central laboratory. 
q Patients will receive prophylactic treatment with 100 mg of methylprednisolone IV (or equivalent oral dose of prednisolone or 
methylprednisolone should IV methylprednisolone not available) and an oral or IV antihistamine (e.g., IV 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 (or placebo) 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 patient, use of an equivalent dose of an alternative 
steroid should be used as premedication prior to the infusion.  It is also recommended that patients receive an analgesic/antipyretic such as 
acetaminophen/paracetamol (1 g) 3060 minutes prior to ocrelizumab (or placebo) infusion. 
r The investigator must review the clinical and laboratory re-treatment criteria prior to subsequent infusion of ocrelizumab.  The patient will need to 
remain under observation at the clinical site for at least 1 hour after infusion.  At infusion visits, it is anticipated that the patient will need to stay at 
the hospital or clinical site for a full day. 
s Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by 
a patient in addition to protocol-mandated treatment. 
t All adverse events will be reported for as long as the patient remains in the study.  The investigator should follow each adverse event until the 
event has resolved to baseline grade or better, the event is assessed as stable by the investigator, the patient is lost to follow up, or the patient 
withdraws consent.  Every effort should be made to follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported. 

Appendix 1:  Schedule of Activities:  Double-Blind Treatment (cont.) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
129/Protocol WA40404, Version 6 
u At screening, two mandatory MRI scans will be performed at least 6 weeks apart or one mandatory MRI that can be compared with a historical 
MRI performed in the previous 1 year to be used for eligibility determination. The mandatory MRI performed closer to randomization will be 
considered the baseline MRI for the study analyses and should be obtained from 6 weeks up to 10 days prior to randomization.  During the study 
conduct, mandatory MRI scans should occur within  4 weeks of the scheduled visit.  In addition, mandatory MRI scans will be obtained in 
patients who withdraw from study treatment (at treatment discontinuation visit) if one was not performed during the prior 4 weeks.  From 
Week 72 onward, mandatory MRI scans will be performed every 48 weeks.  The mandatory MRI sequences are comprised of both brain and 
upper cervical spinal sequences if site technology is available.  Cervical spinal sequences are not required for the first mandatory MRI at 
screening MRI nor are expected to be included in a historical MRI used for screening (if applicable), but these sequences should be included in 
second mandatory MRI scan (considered the baseline MRI).  Additional optional, cervical spinal cord MRI sequences may be acquired for 
baseline, Weeks 24 and 120, and at treatment discontinuation.  Additional optional MRI sequences are not required to accompany the first 
mandatory MRI at screening MRI, nor are expected to be included in a historical MRI used at screening (if applicable), but these sequences 
should be included in the second mandatory MRI (considered the baseline MRI) scan.  At the Week 120 visit for patients switching to PDP OCR 
treatment, mandatory MRI scans should be obtained within 4 weeks before the Week 120 visit. 
v Serum sample, to be taken prior to the IV methylprednisolone infusion. 
w On study drug infusion days, two serum samples (one prior to the IV methylprednisolone infusion and one within 30 minutes after completion of 
study drug infusion) will be collected.  On visits without study drug infusion, PK sample may be collected at any time.  At study drug infusion visits, 
PK samples will be collected from the arm opposite to the infusion. 
x Plasma and serum samples will be collected before the initial study drug dose at Visit 2 as well as Visits 3, 4, and 5; and every 6 months 
following for biomarkers during double-blind treatment, as indicated. 
y A single mandatory DNA sample will be collected for patient genotyping at the baseline visit.  If the DNA sample is not collected at the baseline 
visit, it may be collected at any subsequent visit.  Collection and submission of this sample is contingent upon the review and approval of the 
exploratory research by each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not been granted approval for WGS 
sampling (see Section 4.5.13), collection of this sample will not be applicable at that site. 
z These sample types to be collected for research purposes if patient agrees to separate optional RBR consent—a single RBR DNA sample at 
baseline visit (or any subsequent visit if missed), and an RBR RNA and a RBR plasma sample collected at all indicated visits. 
aa Digital outcome assessments are optional only.  Patients who choose to and consent to the optional digital outcome assessments at screening 
will be asked to begin performing digital assessments 4 weeks prior to baseline (i.e., Days 28 to 1; see Section 4.5.15). 
bb All patients must have negative HBsAg test result at screening prior to enrollment.  If total HBcAb is positive at screening, HB virus DNA measured 
by PCR must be negative to be eligible.  For those patients enrolled with negative HBsAg and positive total HBcAb, HB virus DNA (PCR) must be 
repeated every 12 weeks during double-blind treatment phase. 
 

Appendix 2:  Schedule of Activities:  Follow-Up 1 (and PDP OCR) (cont.) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
132/Protocol WA40404, Version 6 
a The FU1 phase will run in parallel with the double-blind treatment phase until 144 weeks from randomization for each patient or until the 
primary analysis.  Scheduled visits will be performed every 12 weeks and will include both efficacy and safety assessments.  For patients 
receiving PDP OCR, patients must sign the optional PDP OCR informed consent form.  Patients who experience a double-progression event 
during the double-blind treatment phase will be given the option to switch to PDP OCR after they have completed at least 120 weeks of double-
blind treatment.  PDP OCR treatment phase will continue until the end of the OLE phase. Assessments in FU1 and PDP OCR phases that only 
need to be performed annually are marked in brackets (x). 
b A delayed dosing visit will be performed and recorded in the Delayed Dosing Visit eCRF when dosing cannot be administered at the scheduled 
dosing visit.  Other tests or assessments may be performed as appropriate. 
c Assessments at unscheduled (non-dosing) visits may be performed as clinically appropriate. 
d Patients who discontinue study drug prematurely from the PDP OCR treatment phase will return to the clinic for a treatment discontinuation visit. 
e The PDP OCR can be terminated at any time up to the date at which the last data point is collected for the primary analysis (see Section 3.1.1.3).  
The assessments required for N represent the typical schedule of assessments for the PDP OCR phase.  If the study ends for any reason or the 
patient must be withdrawn from treatment, a treatment discontinuation visit should be performed. 
f Must be obtained and documented in written form before any study-specific screening procedure and initiation of study treatment and PDP OCR 
(if applicable).  
g Questionnaires will be self-administered prior to the administration of study treatment.  The questionnaires should be completed before the 
patient receives any information on disease status, prior to the administration of non-PRO assessments, and in the following order each time, 
whenever possible:  ABILHAND, Neuro-QoL-UE, PGIC-UL, MFIS, PGIC-F, MSIS-29, and EQ-5D-5L.  During FU1 and PDP OCR they will be 
completed every 48 weeks, starting Week 0 of FU1.  EQ-5D-5L will only be completed during PDP OCR. 
h Includes pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, and temperature.  Temperature should be 
measured and recorded in patient’s notes only.  Blood pressure and pulse rate will be recorded on the appropriate eCRF.  On ocrelizumab 
infusion visits, vital signs should be taken within 45 minutes prior to the methylprednisolone infusion.  In addition, blood pressure and pulse rate 
should be obtained prior to start of infusion, every hour during the infusion, at the end of infusion and 1 hour after the end of the infusion.  On 
non-infusion days, the vital signs may be taken at any time during the visit.  Record abnormalities observed at baseline on the General Medical 
History and Baseline Conditions eCRF page.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse 
Event eCRF. 
i Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF. 

Appendix 2:  Schedule of Activities:  Follow-Up 1 (and PDP OCR) (cont.) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
133/Protocol WA40404, Version 6 
j Neurological examinations will be used to distinguish relapse in MS from another neurological (non-MS) disorder.  Potential relapses should be 
recorded throughout the treatment period.  All patients with new neurological symptoms suggestive of MS worsening should have EDSS 
assessment performed by Examining Investigator.  Investigators will also screen patients 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).  Patients with suspected 
PML should be withheld from ocrelizumab treatment until PML is ruled out by complete clinical evaluation and appropriate diagnostic testing.  
A patient with confirmed PML should be withdrawn from the study treatment permanently. 
k Both the dominant and non-dominant hands are tested twice (two consecutive trials of the dominant hand, followed immediately by two 
consecutive trials of the non-dominant hand) (National Multiple Sclerosis Society 2001). 
l EDSS including functional system scores will be assessed and collected. 
m Hematology includes hemoglobin, hematocrit, RBC, WBC (absolute and differential:  neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, other cells), and quantitative platelet count.  Chemistry includes AST, ALT, gamma-glutamyl transferase, total bilirubin, creatinine, 
amylase, potassium, sodium.  Urinalysis includes dipstick (pH, specific gravity, glucose, protein, ketones, blood), and a microscopic examination 
if abnormal and clinically significant will be performed at the site (local laboratory).  
n B cells and other cell types and/or B-cell subsets will be assessed in fresh whole blood using flow cytometry. 
o Urine pregnancy tests will be performed at specified subsequent visits.  If a urine pregnancy test is positive, the patient will not receive the 
scheduled dose, and a confirmatory serum pregnancy test will be performed.  Urine -hCG (sensitivity of at least 25 mU/mL) will be performed 
locally. 
p Patients will receive prophylactic treatment with 100 mg of methylprednisolone IV (or equivalent oral dose of prednisolone or 
methylprednisolone should IV methylprednisolone not available) and an oral or IV antihistamine (e.g., IV 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 patient, use of an equivalent dose of an alternative steroid should 
be used as premedication prior to the infusion.  It is also recommended that patients receive an analgesic/antipyretic such as 
acetaminophen/paracetamol (1 g) 3060 minutes prior to ocrelizumab (or placebo) infusion. 
q The investigator must review the clinical and laboratory re-treatment criteria prior to subsequent infusion of ocrelizumab.  The patient will need to 
remain under observation at the clinical site for at least 1 hour after infusion.  At infusion visits, it is anticipated that the patient will need to stay at 
the hospital or clinical site for a full day.  
r Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by 
a patient in addition to protocol-mandated treatment. 

Appendix 2:  Schedule of Activities:  Follow-Up 1 (and PDP OCR) (cont.) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
134/Protocol WA40404, Version 6 
s All adverse events will be reported for as long as the patient remains in the study.  The investigator should follow each adverse event until the 
event has resolved to baseline grade or better, the event is assessed as stable by the investigator, the patient is lost to follow up, or the patient 
withdraws consent.  Every effort should be made to follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported. 
t During the study conduct, mandatory MRI scans should occur within  4 weeks of the scheduled visit and will be performed every 48 weeks.   
In addition, mandatory MRI scans will be obtained in patients who withdraw from study treatment (at Tx Discon, WD from FU or EOO visit) if one 
was not performed during the prior 4 weeks.  
u Serum sample, to be taken prior to the IV methylprednisolone infusion. 
v On study drug infusion days, two serum samples (one prior to the IV methylprednisolone infusion and one within 30 minutes after completion of 
study drug infusion) will be collected.  On visits without study drug infusion, PK sample may be collected at any time.  At study drug infusion visits, 
PK samples will be collected from the arm opposite to the infusion. 
w Plasma and serum samples will be collected as indicated.  Only to be collected for WD from FU visits performed before start of OLE. 
x These sample types to be collected for research purposes if patient agrees to separate optional RBR consent—a single RBR DNA sample at 
baseline visit (or any subsequent visit if missed), and an RBR RNA and a RBR plasma sample collected at all indicated visits.  Only to be 
collected for WD from FU visits performed before start of OLE. 
y Digital outcome assessments are optional only. 
z For those patients enrolled with negative HBsAg and positive total HBcAb, HB virus DNA (PCR) must be repeated every 12 weeks during FU1 and 
PDP OCR. 

Appendix 3:  Schedule of Activities:  Open-Label Extension (cont.) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
137/Protocol WA40404, Version 6 
d Each patient will remain in the OLE phase for at least 2 years (at least 4 doses of ocrelizumab).  The assessments required for N represent the 
typical schedule of assessments for the OLE phase.  If the study ends for any reason or the patient must be withdrawn from treatment, a 
treatment discontinuation visit should be performed. 
e Must be obtained and documented in written form before any study-specific screening procedure and initiation of study treatment.  
f Questionnaires will be self-administered prior to the administration of study treatment.  The questionnaires should be completed before the 
patient receives any information on disease status, prior to the administration of non-PRO assessments, and in the following order each time, 
whenever possible:  ABILHAND, Neuro-QoL-UE, PGIC-UL, MFIS, PGIC-F, MSIS-29, and EQ-5D-5L. 
g Includes pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, and temperature.  Temperature should be 
measured and recorded in patient’s notes only.  Blood pressure and pulse rate will be recorded on the appropriate eCRF.  On ocrelizumab 
infusion visits, vital signs should be taken within 45 minutes prior to the methylprednisolone infusion.  In addition, blood pressure and pulse rate 
should be obtained prior to start of infusion, every hour during the infusion, at the end of infusion and 1 hour after the end of the infusion.  On 
non-infusion days, the vital signs may be taken at any time during the visit.  At subsequent visits, record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF. 
h Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF. 
i Neurological examinations will be used to distinguish relapse in MS from another neurological (non-MS) disorder.  Potential relapses should be 
recorded throughout the treatment period.  All patients with new neurological symptoms suggestive of MS worsening should have EDSS 
assessment performed by Examining Investigator.  Investigators will also screen patients 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).  Patients with suspected 
PML should be withheld from ocrelizumab treatment until PML is ruled out by complete clinical evaluation and appropriate diagnostic testing.  
A patient with confirmed PML should be withdrawn from the study treatment permanently. 
j Both the dominant and non-dominant hands are tested twice (two consecutive trials of the dominant hand, followed immediately by two 
consecutive trials of the non-dominant hand) (National Multiple Sclerosis Society 2001). 
k EDSS including functional system scores will be assessed and collected.  
l Hematology includes hemoglobin, hematocrit, RBC, WBC (absolute and differential:  neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, other cells), and quantitative platelet count.  Chemistry includes AST, ALT, gamma-glutamyl transferase, total bilirubin, creatinine, 
amylase, potassium, and sodium.  Urinalysis includes dipstick (pH, specific gravity, glucose, protein, ketones, blood), and a microscopic 
examination if abnormal and clinically significant will be performed at the site (local laboratory). 
m B cells and other cell types and/or B-cell subsets will be assessed in fresh whole blood using flow cytometry. 
n Urine pregnancy tests will be performed at specified visits.  If a urine pregnancy test is positive, the patient will not receive the scheduled dose, 
and a confirmatory serum pregnancy test will be performed.  Urine -hCG (sensitivity of at least 25 mU/mL) will be performed locally. 

Appendix 3:  Schedule of Activities:  Open-Label Extension (cont.) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
138/Protocol WA40404, Version 6 
o Patients will receive prophylactic treatment with 100 mg of methylprednisolone IV (or equivalent oral dose of prednisolone or 
methylprednisolone should IV methylprednisolone not available) and an oral or IV antihistamine (e.g., IV 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 patient, use of an equivalent dose of an alternative steroid should 
be used as premedication prior to the infusion.  It is also recommended that patients receive an analgesic/antipyretic such as 
acetaminophen/paracetamol (1 g) 3060 minutes prior to ocrelizumab infusion. 
p The investigator must review the clinical and laboratory re-treatment criteria prior to subsequent infusion of ocrelizumab.  The patient will need to 
remain under observation at the clinical site for at least 1 hour after infusion.  At infusion visits, it is anticipated that the patient will need to stay at 
the hospital or clinical site for a full day. 
q Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by 
a patient in addition to protocol-mandated treatment. 
r All adverse events will be reported for as long as the patient remains in the study.  The investigator should follow each adverse event until the 
event has resolved to baseline grade or better, the event is assessed as stable by the investigator, the patient is lost to follow up, or the patient 
withdraws consent.  Every effort should be made to follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported. 
s MRI scans should occur within a window of  4 weeks of the scheduled visit.  In addition, mandatory MRI scans and additional optional cervical 
spinal MRI scans (if applicable) will be obtained in patients who withdraw from study treatment (at treatment discontinuation visit) if one was not 
performed during the prior 4 weeks.  During the OLE, mandatory MRI scans and additional optional sagittal cervical spinal cord scans will be 
performed every 48 weeks indicated by (x) (according to the yearly schedule as carried over from the double-blind treatment phase).  
t Serum sample, to be taken prior to the IV methylprednisolone infusion.  
u On study drug infusion days, two serum samples (one prior to the IV methylprednisolone infusion, and one within 30 minutes after completion of 
study drug infusion) will be collected.  On visits without study drug infusion, PK sample may be collected at any time.  During study drug infusion 
visits, PK samples will be collected from the arm opposite to the infusion.  
v For those patients enrolled with negative HBsAg and positive total HBcAb, HB virus DNA (PCR) must be repeated every 24 weeks. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
139/Protocol WA40404, Version 6 
Appendix 4  
Schedule of Activities:  Follow-Up 2  
 
FU2 a 
EOO or WD from FU 
Study week 
Week 24 (24 wks after the 
last visit in DBT, OLE, 
PDP OCR or FU1 
phases)  
 
(Window in days) 
( 7 d) 
 
Physical examination c 
x 
x 
Neurological examination d 
x 
x 
Hematology, chemistry, urinalysis e 
x 
x 
Flow cytometry (including 
CD3/4/8/19 count) f 
x 
x 
IgG, IgA, IgM 
x 
 
Concomitant medications g 
x 
x 
Adverse events h 
x 
x 
MRI i 
 
x 
ADA sample (serum) j 
x 
 
PK sample (serum) k 
x 
 
Hepatitis B virus DNA (if required) l 
x 
x 
 
ADA  anti-drug antibody; DBT  double-blind treatment; eCRF  electronic Case Report Form; 
EOO  end of observation; FU  follow up; FU1  follow-up 1; HBcAb  hepatitis B core antibody; 
HBsAg  hepatitis B surface antigen; MRI  magnetic resonance imaging; MS  multiple sclerosis; 
OLE  open-label extension; PDP OCR  post-double-progression ocrelizumab; 
PK  pharmacokinetic; PML  progressive multifocal leukoencephalopathy; WD  withdrawal; 
Wk  week. 
Notes:  All assessments should be performed on the day of the scheduled visit, unless otherwise 
specified.  For more information regarding FU2, see Section 3.1.1.6.  See Figure 2 for 
information regarding how a patient proceeds through the different study phases (including FU2). 
 
a Laboratory and safety assessments performed during clinical visit at 24 weeks.  All patients 
will continue in the FU2 for 24 weeks after the last visit either in DBT, OLE, PDP OCR or 
FU1 phases wherever patient was at that time.  For information regarding FU2 duration and 
eligibility, refer to Section 3.1.1.6. 
b At the end of FU2 phase the patient will complete the study. 
c Perform a limited, symptom-directed examination at specified timepoints or as clinically 
indicated.  Record new or worsened clinically significant abnormalities on the Adverse Event 
eCRF. 

Appendix 4:  Schedule of Activities:  Follow-Up 2 (cont.) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
140/Protocol WA40404, Version 6 
d Neurological examinations will be used to distinguish relapse in MS from another neurological 
(non-MS) disorder.  Potential relapses should be recorded throughout the treatment period.  All 
patients with new neurological symptoms suggestive of MS worsening should have EDSS 
assessment performed by Examining Investigator.  Investigators will also screen patients 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).  Patients with suspected PML should be withheld from ocrelizumab treatment 
until PML is ruled out by complete clinical evaluation and appropriate diagnostic testing.  
A patient with confirmed PML should be withdrawn from the study treatment permanently. 
e Hematology includes hemoglobin, hematocrit, RBC, WBC (absolute and differential:  
neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells), and quantitative 
platelet count.  Chemistry includes AST, ALT, gamma-glutamyl transferase, total bilirubin, 
creatinine, amylase, potassium, and sodium.  Urinalysis includes dipstick (pH, specific gravity, 
glucose, protein, ketones, blood), and a microscopic examination if abnormal and clinically 
significant will be performed at the site (local laboratory). 
f B cells and other cell types and/or B-cell subsets will be assessed in fresh whole blood using 
flow cytometry. 
g Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic 
remedies, nutritional supplements) used by a patient in addition to protocol-mandated 
treatment. 
h All adverse events will be reported for as long as the patient remains in the study.  The 
investigator should follow each adverse event until the event has resolved to baseline grade or 
better, the event is assessed as stable by the investigator, the patient is lost to follow up, or the 
patient withdraws consent.  Every effort should be made to follow all serious adverse events 
considered to be related to study drug or trial-related procedures until a final outcome can be 
reported. 
i Mandatory MRI scans will be obtained in patients who withdraw from study (at WD from FU or 
EOO visit) if one was not performed during the prior 4 weeks. 
j Serum samples may be collected at any time. 
k PK sample may be collected at any time during the visit. 
l For those patients enrolled with negative HBsAg and positive total HBcAb, HB virus DNA (PCR) 
must be repeated every 24 weeks. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
141/Protocol WA40404, Version 6 
Appendix 5  
Progressive Multifocal Leukoencephalopathy:  Guidance for 
Diagnosis of Progressive Multifocal Leukoencephalopathy 
 
ACTION STEPS IF PML IS SUSPECTED 
 
If the clinical presentation is suggestive of progressive multifocal 
leukoencephalopathy (PML) (see Table 1), further investigations should include 
brain magnetic resonance imaging (MRI) evaluation as soon as possible. If MRI 
evaluation reveals lesions suspicious for PML (Berger et al. 2013; Figure 1) 
a lumbar puncture with evaluation of the cerebrospinal fluid (CSF) should be 
undertaken for the detection of JC virus (JCV) DNA by polymerase chain reaction 
using a validated sensitive assay. For details, refer to the most up to date laboratory 
manual providing storage conditions and shipment instructions.  A diagnosis of PML 
can potentially be made by evaluating clinical and MRI findings plus the 
identification of JCV in the CSF.  This sample will be stored for 1 year after the last 
patient, last visit. 
 
There is no known treatment or cure for PML.  Treatment considerations are 
discussed in the medical literature (Calabrese et al. 2007). 
 
MRI ASSESSMENT 
 
Although there are no pathognomonic findings that differentiate PML from multiple 
sclerosis (MS), a mandatory MRI scan that includes fluid-attenuated inversion 
recovery and T2-weighted and T1-weighted sequences, with and without 
gadolinium, should be performed to assess patients with neurological changes 
suggestive of PML (see Figure 1). 
 
Comparison with a baseline scan may assist with interpretation of the findings on 
the newly acquired MRI (see Table 2) 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 patient 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. 
 

 
 
 
Appendix 5:  Progressive Multifocal Leukoencephalopathy:  Guidance for 
Diagnosis of Progressive Multifocal Leukoencephalopathy 
(cont.) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
144/Protocol WA40404, Version 6 
Table 2 
MRI Lesion Characteristics Typical of PML and MS 
Feature 
Multiple Sclerosis 
PML 
Location of new 
lesions 
Mostly focal; may affect entire brain 
and spinal cord, in white and possibly 
gray matter; posterior cranial fossa 
lesions are rarely seen 
Diffuse lesions, mainly subcortical and 
rarely periventricular, located almost 
exclusively in white matter, although 
occasional extension to gray 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; infiltrating; irregular in 
shape; confined to white matter, sparing 
gray 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 
With 
enhancement 
 Acute lesions:  dense homogeneous 
enhancement, sharp edges  
 Subacute lesions:  ring enhancement  
 Chronic lesions:  no enhancement 
Usually no enhancement even in large 
lesions; in patients with HIV, some 
peripheral enhancement is possible, 
especially under therapy 
Atrophy 
Focal atrophy possible, due to focal 
white-matter degeneration; no 
progression 
No focal atrophy 
FLAIR  fluid-attenuated inversion recovery; MRI  magnetic resonance imaging; 
PML  progressive multifocal leukoencephalopathy. 
Adapted from Yousry et al. 2006. 
 
 

 
 
 
Appendix 5:  Progressive Multifocal Leukoencephalopathy:  Guidance for 
Diagnosis of Progressive Multifocal Leukoencephalopathy 
(cont.) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
145/Protocol WA40404, Version 6 
REFERENCES 
Berger JR, Aksamit AJ, Clifford DB, et al. PML diagnostic criteria: consensus statement 
from the AAN Neuroinfectious Disease Section. Neurology 2013;80:14308. 
Calabrese LH, Molloy ES, Huang D, et al. Progressive multifocal leukoencephalopathy in 
rheumatic diseases: evolving clinical and pathologic patterns of disease. Arthritis 
Rheum 2007;56:211628. 
Kappos L, Bates D, Hartung HP, et al. Natalizumab treatment for multiple sclerosis: 
recommendations for patient selection and monitoring. Lancet Neurol 
2007;6:43141. 
Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation of patients treated with 
natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 
2006;354:92433. 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
151/Protocol WA40404, Version 6 
Appendix 8  
Modified Fatigue Impact Scale 
 
Patient’s Name: 
 
 
Date:     ______/_____/_____ 
 
month 
day 
year 
 
ID#: 
 
 
Test#:  
1    2    3    4 
 
MODIFIED FATIGUE IMPACT SCALE (MFIS) 
 
Following is a list of statements that describe how fatigue may affect a person.  
Fatigue is a feeling of physical tiredness and lack of energy that many people 
experience from time to time.  In medical conditions like MS, feelings of fatigue can 
occur more often and have a greater impact than usual.  Please read each statement 
carefully, and then circle the one number that best indicates how often fatigue has 
affected you in this way during the past 4 weeks.  (If you need help in marking your 
responses, tell the interviewer the number of the best response.)  Please answer 
every question.  If you are not sure which answer to select, please choose the one 
answer that comes closest to describing you.  The interviewer can explain any words 
or phrases that you do not understand. 
 
Because of my fatigue 
during the past 4 weeks… 
 
 
 
 
 
Never 
Rarely Sometimes
Often 
Almost 
always 
1. 
I have been less alert. 
0 
1 
2 
3 
4 
 
 
 
 
 
2. 
I have had difficulty  
paying attention for  
long periods of time. 
0 
1 
2 
3 
4 
 
 
 
 
 
3. 
I have been unable to  
think clearly. 
0 
1 
2 
3 
4 
 
 
 
 
 
4. 
I have been clumsy  
and uncoordinated. 
0 
1 
2 
3 
4 
 
 
 
 
 
5. 
I have been forgetful. 
0 
1 
2 
3 
4 
 
 
 
 
 
6. 
I have had to pace myself  
in my physical activities. 
0 
1 
2 
3 
4 
 
 
 
 
 
7. 
I have been less 
motivated  
to do anything that 
requires physical effort. 
0 
1 
2 
3 
4 
 
 

Appendix 8:  Modified Fatigue Impact Scale (cont.) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
152/Protocol WA40404, Version 6 
Because of my fatigue 
during the past 4 weeks… 
 
 
 
 
 
Never 
Rarely Sometimes
Often 
Almost 
always 
8. 
I have been less 
motivated  
to participate in social 
activities. 
0 
1 
2 
3 
4 
 
 
 
 
 
9. 
I have been limited in my 
ability to do things away 
from home. 
0 
1 
2 
3 
4 
 
 
 
 
 
10. 
I have had trouble 
maintaining physical 
effort for long periods. 
0 
1 
2 
3 
4 
 
 
 
 
 
11. 
I have had difficulty  
making decisions. 
0 
1 
2 
3 
4 
 
 
 
 
 
12. 
I have been less 
motivated to do anything 
that requires thinking. 
0 
1 
2 
3 
4 
 
 
 
 
 
13. 
My muscles have felt 
weak. 
0 
1 
2 
3 
4 
 
 
 
 
 
14. 
I have been physically 
uncomfortable. 
0 
1 
2 
3 
4 
 
 
 
 
 
15. 
I have had trouble 
finishing tasks that 
require thinking. 
0 
1 
2 
3 
4 
 
 
 
 
 
16. 
I have had difficulty 
organizing my thoughts 
when doing things at 
home or at work. 
0 
1 
2 
3 
4 
 
 
 
 
 
17. 
I have been less able to 
complete tasks that 
require physical effort. 
0 
1 
2 
3 
4 
 
 
 
 
 
18. 
My thinking has been  
slowed down. 
0 
1 
2 
3 
4 
 
 
 
 
 
19. 
I have had trouble 
concentrating. 
0 
1 
2 
3 
4 
 
 

Appendix 8:  Modified Fatigue Impact Scale (cont.) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
153/Protocol WA40404, Version 6 
Because of my fatigue 
during the past 4 weeks… 
 
 
 
 
 
Never 
Rarely Sometimes
Often 
Almost 
always 
 
 
 
 
 
20. 
I have limited my  
physical activities. 
0 
1 
2 
3 
4 
 
 
 
 
 
21. 
I have needed to rest 
more often or for longer 
periods. 
0 
1 
2 
3 
4 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
158/Protocol WA40404, Version 6 
Appendix 11  
Patient Global Impression of Change for Fatigue 
 
Over the last 6 months, my fatigue is (please tick one box): 
☐ Very much better 
☐ Much better 
☐ A little better 
☐ The same 
☐ A little worse 
☐ Much worse 
☐ Very much worse 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
159/Protocol WA40404, Version 6 
Appendix 12  
Patient Global Impression of Change for Upper Limb Function 
Some people with MS have problems with their hands and arms (e.g., weakness, 
stiffness, or numbness in fingers).  These problems can make it difficult to do everyday 
tasks (e.g., doing up buttons, using cutlery, carrying a heavy box, or taking a book off a 
high shelf). 
Over the last 6 months, how has your ability to do tasks involving your arms/hands 
changed? (please tick a box):  
☐ Very much better 
☐ Much better 
☐ A little better 
☐ The same 
☐ A little worse 
☐ Much worse 
☐ Very much worse 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
160/Protocol WA40404, Version 6 
Appendix 13  
Pregnancy Outcome and Infant Health Information on First Year 
of Life  
 
Pregnancy Outcome and Infant Health Information on First Year of Life 
 
If twin or  multi-gestational pregnancy, this questionnaire has to be filled out separately for 
each baby born in the multi-gestational pregnancy. 
Please check all that apply and provide detailed information on complications in infant on 
last page. 
Table 1: Parent’s (or person with parental responsibility in law) consent to data collection 
 
Has parent’s (or person’s with 
parental responsibility in law) data 
authorization form been signed? 
☐Yes 
☐No 
Date signed 
 
____________________ 
Other – comment 
 
___________________ 
 
Date consent 
 withdrawn: 
(if applicable) 
 
 
 
 
 
Table 2: Information on birth 
Mode of birth 
☐Vaginal delivery 
Forceps / vacuum: 
- Yes ☐ 
- No ☐ 
☐Cesarean section (CS) 
- scheduled CS ☐ 
- emergency CS ☐ 
Reason for assisted delivery/Cesarean 
section  
 
Gestational age at 
birth 
 
 weeks 
- since conception ☐ 
- since LMP ☐ 
Induced labor 
- Yes ☐ 
- No   ☐ 
 
 
 

Appendix 13:  Pregnancy Outcome and Infant Health Information on First 
Year of Life (cont.) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
161/Protocol WA40404, Version 6 
 
Table 3: Growth alteration, congenital anomalies and functional deficits 
Date of Assessment 
Growth alteration 
- Yes ☐ 
- No  ☐ 
☐Small for gestational age 
(SGA) 
☐Low birth weight 
☐Short birth length 
If Growth alteration 
present: 
Specify weight:  
 
Specify length:   
   
Contributing factors: 
Congenital anomalies 
- Yes ☐ 
- No ☐ 
☐ Major structural 
malformation 
A defect that has either 
cosmetic or functional 
significance to the child 
Specify:   
 
  
 
Contributing factors: 
☐ Minor structural 
malformation 
A defect that occurs 
infrequently but has neither 
cosmetic nor functional 
significance to the child 
Specify:   
 
  
 
 
☐ Deformation 
A defect attributable to 
deformation of a structure, 
which had previously formed 
normally (usually due to 
mechanical force) 
Specify:   
 
  
 
 
☐ Disruption 
A defect due to destruction of 
a structure, which has 
previously formed normally 
(may be of vascular, 
infectious, or mechanical 
origin) 
Specify:   
 
  
 
 
Functional deficit 
(except for 
infections, which 
should be 
described in 
separate table 
below) 
- Yes ☐ 
- No  ☐ 
☐Functional deficit 
Specify:   
 
 
 
 
 
 
Contributing factors: 
 
__________________
__________________ 
 
 
 
 

Appendix 13:  Pregnancy Outcome and Infant Health Information on First 
Year of Life (cont.) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
162/Protocol WA40404, Version 6 
Status of infant at the time of latest follow-up (at birth, 3 months, 
6 months, 12 months) 
 
Table 4: Status of infant 
Date of Assessment 
Contributing factors/ 
Comments 
Status of infant 
☐Normal 
☐Abnormal, specify abnormality:   
 
☐Neonatal/infant death, specify cause and date of death:  
__________________________________________________ 
______________
______________ 
Nursing status 
☐Exclusive breastfeeding 
☐Mixed feeding (partial breastfeeding along with infant formula 
and/or baby food), specify date since when:   
 
☐Fully weaned, specify date since when:   
 
______________ 
 
Infections in neonate and infant during first year of life 
 
Any infection detected at birth? 
Yes 
No 
Unknown 
 
If infection detected at birth then Tables 5 and 6 should to be filled out and additional 
detailed information may be provided on last page. 
If no infection detected at birth, however an infection developed later during the first year of 
live, please move directly to Table 7. 
If no infection detected at birth, and if also no infection developed during the first 12 months 
then move directly to Table 8. 
 
Table 5: Information on infection in neonate at birth 
 
Specify the event term: 
Event number 
Location of infection present in neonate at birth? 
Site of infection (specify):  
Outcome of 
infection? 
Duration of 
infection? 
☐Resolved 
☐Improving 
☐Fatal  
☐Persisting  
☐Unknown 
Duration:  
 

Appendix 13:  Pregnancy Outcome and Infant Health Information on First 
Year of Life (cont.) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
163/Protocol WA40404, Version 6 
Intensity of infection (Grade 1-5 NCI 
CTCAE)? 
Seriousness of 
infection? 
Treatment with anti- 
infective? 
Pathogen causing 
infection known? 
Severity: ☐Mild (Grade 1) 
 
☐Moderate (Grade 2) 
 
☐Severe (Grade 3) 
 
Serious: 
☐Yes 
☐No 
☐Yes, specify: 
 
 
 
 
☐No 
 
☐Yes, specify: 
 
 
 
 
☐No 
 
☐Life-threatening (Grade 4)  
 
☐Death (Grade 5)  
 
☐Unknown 
☐Unknown 
Relevant laboratory test results (in newborn infant): 
CD19 count 
☐normal 
☐abnormal  
☐unknown 
If abnormal, specify 
test result: 
If abnormal, date of 
test:   
 
IgG levels 
☐normal 
☐abnormal  
☐unknown 
If abnormal, specify test 
result: 
If abnormal, date of 
test:   
 
White blood cell count 
☐normal 
☐abnormal  
☐unknown 
If abnormal, specify test 
result: 
If abnormal, date of 
test:   
 
Neutrophil count 
☐normal 
☐abnormal  
☐unknown 
If abnormal, specify test 
result: 
If abnormal, date of 
test:   
 
Lymphocyte count 
☐normal 
☐abnormal  
☐unknown 
If abnormal, specify test 
result: 
If abnormal, date of 
test:   
 
Other, specify: 
☐normal 
☐abnormal  
☐unknown 
If abnormal, specify 
test result: 
If abnormal, date of 
test:   
 
 
 

Appendix 13:  Pregnancy Outcome and Infant Health Information on First 
Year of Life (cont.) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
164/Protocol WA40404, Version 6 
Table 6:  Maternal risk factors for neonatal infection (during most recent pregnancy, if infant 
developed neonatal infection at birth)  
Maternal risk factors for neonatal 
infection 
Date of diagnosis 
If diagnosed, was pregnant 
mother 
treated with anti-infective prior to 
delivery? 
☐Maternal intrapartum colonization or 
infection with group B streptococcus (GBS) 
☐Maternal listeriosis 
☐Premature rupture of membranes (PROM)  
☐Meconium in amniotic fluid 
(meconium-stained liquid) 
 
☐Active genital herpes infection 
☐CMV 
☐HPV (papilloma virus) 
 
Other, specify 
  
 
 
 
 
 
 
 
 
________________  
 
 
________________
________________
________________ 
 
 
 
 
 
 
 
 
 
_____________________________ 
 
 
_____________________________ 
_____________________________
_____________________________ 
Relevant laboratory test results in pregnant mother: 
CD19 count 
☐normal 
☐abnormal  
☐unknown 
If abnormal, 
specify test 
result: 
If abnormal, date of 
test:   
 
IgG levels 
☐normal 
☐abnormal  
☐unknown 
If abnormal, 
specify test 
result: 
If abnormal, date of 
test:   
 
White blood cell count 
☐normal 
☐abnormal  
☐unknown 
If abnormal, 
specify test 
result: 
If abnormal, date of 
test:   
 
Neutrophil count 
☐normal 
☐abnormal  
☐unknown 
If abnormal, 
specify test 
result: 
If abnormal, date of 
test:   
 
Lymphocyte count 
☐normal 
☐abnormal  
☐unknown 
If abnormal, 
specify test 
result: 
If abnormal, date of 
test:   
 
Other, specify: 
(e.g., any specific antibodies and their titers) 
☐normal 
☐abnormal  
☐unknown 
If abnormal, 
specify test 
result: 
If abnormal, date of 
test:   
 
 
 
 
 

Appendix 13:  Pregnancy Outcome and Infant Health Information on First 
Year of Life (cont.) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
165/Protocol WA40404, Version 6 
Any infection detected during first year of infant’s life? 
Yes 
No 
Unknown 
 
If infection detected during first year of infant’s life, then Table 7 should be filled out and 
additional detailed information may be provided on last page.  If no infection developed during 
first 12 months of life, then please move directly to Table 8. 
 
Table 7: Information on infection detected during first year of infant’s life 
Specify the event term: 
Event number 
(automatically 
populated by the
system?) 
 
 
Location of infection? 
Infant’s age on 
day of onset of 
infection? 
Outcome of 
infection? 
Duration of 
infection? 
Site of infection (specify):   
 
 
 
Age:
 
☐Resolved 
☐Improving  
☐Fatal  
☐Persisting  
☐Unknown 
Duration:  
 
Intensity of infection (Grade 1-5 
NCI CTCAE)? 
Seriousness of 
infection? 
Treatment with 
anti- infective? 
Pathogen causing 
infection known? 
Severity: ☐Mild (Grade 1) 
☐Moderate (Grade 2)  
☐Severe (Grade 3)  
☐Life-threatening (Grade 4)  
☐Death (Grade 5) 
Serious:  
 
☐Yes 
 
☐No 
☐Yes, specify: 
 
 
 
☐No 
☐Unknown 
☐Yes (specify): 
 
 
 
☐No  
☐Unknown 
Relevant laboratory test results (in infant): 
CD19 count 
☐normal 
☐abnormal  
☐unknown 
If abnormal, 
specify test result: 
If abnormal, date of 
test:   
 
IgG levels 
☐normal 
☐abnormal  
☐unknown 
If abnormal, 
specify test result: 
If abnormal, date of 
test:   
 
White blood cell count 
☐normal 
☐abnormal  
☐unknown 
If abnormal, 
specify test result: 
If abnormal, date of 
test:   
 
Neutrophil count 
☐normal 
☐abnormal  
☐unknown 
If abnormal, 
specify test result: 
If abnormal, date of 
test:   
 
Lymphocyte count 
☐normal 
☐abnormal  
☐unknown 
If abnormal, 
specify test result: 
If abnormal, date of 
test:   
 
Other, specify: 
☐normal 
☐abnormal  
☐unknown 
If abnormal, 
specify test result: 
If abnormal, date of 
test:   
 
 

Appendix 13:  Pregnancy Outcome and Infant Health Information on First 
Year of Life (cont.) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
166/Protocol WA40404, Version 6 
Table 8:  Vaccinations administered to infant at birth and during first year of age 
 
Vaccinations administered at 
birth and during first year of 
age 
Date 
administered 
Infant’s age 
on day of 
vaccination 
Comments (abnormal outcome, 
reason for postponing vaccination, 
etc.) 
☐Hepatitis B 
☐Rotavirus 
☐Diphtheria, tetanus, and 
pertussis 
☐Hemophilus influenza type b 
☐Pneumococcal 
☐Poliovirus 
☐Attenuated oral polio 
vaccine 
☐Inactivated polio vaccine 
☐Meningococcal group B 
bacteria 
☐Tuberculosis (Bacille Calmette
Guérin, BCG) bacteria 
☐Other vaccination, specify: 
 
 
 
 
Table 9:  Fetal/neonatal abnormalities in previous pregnancies 
Fetal/neonatal abnormalities (in previous 
pregnancies) 
Please, provide specifics including 
contributing factors 
None  ☐ 
Yes  ☐ 
Unknown  ☐ 
 
Infection; if yes, specify 
 
Death in utero; if yes, specify reason 
Birth defects; if yes, specify 
Family history of birth defects; if yes, specify 
 
Small for gestational age at birth (or Intrauterine 
growth retardation) 
 
Premature delivery (before 37 weeks) 
 
Other; specify 
 
Detailed information on health-related findings in infant during first year 
of life 
 
Please enter text in the free text box below. 
 
 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
167/Protocol WA40404, Version 6 
Appendix 14  
Investigational and Auxiliary Medicinal Product Designations 
for use in European Economic Area and United Kingdom 
Table 1 
Investigational, Authorized Auxiliary, and Unauthorized 
Auxiliary Medicinal Product Designations for European 
Economic Area 
Product Name 
IMP/AxMP 
Designation 
Marketing 
Authorization 
Status in EEA  
Used within 
Marketing 
Authorization 
Ocrelizumab  
IMP (test product)a  
Authorized 
Nob 
Ocrelizumab-matched 
placebo 
IMP (placebo) 
Not authorized 
Not applicable 
Methylprednisolone 
AxMP 
(Premedication) 
Authorized 
Yes 
Antihistamine (e.g. 
diphenhydramine) 
AxMP 
(Premedication) 
Authorized 
Yes 
Analgesic/antipyretic 
(e.g. acetaminophen) 
AxMP 
(Premedication) 
Authorized 
Yes 
AxMP    auxiliary medicinal product; EEA  European Economic Area; IMP  investigational 
medicinal product. 
a Ocrelizumab is considered to be an IMP test product as well as an IMP comparator. 
b Ocrelizumab is approved for the treatment of PPMS at a dose of 600 mg but not at the higher dose 
of 1200 mg (patient’s body weight < 75 kg at baseline) or 1800 mg (patient’s body weight ≥ 75 kg at 
baseline) 
 
 
 

Appendix 14:  Investigational and Auxiliary Medicinal Product 
Designations for use in European Economic Area and United 
Kingdom (cont.) 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
168/Protocol WA40404, Version 6 
Table 2 
Investigational and Non-Investigational Medicinal Product 
Designations for the United Kingdom 
Product Name 
IMP/NIMP 
Designation 
Marketing 
Authorization 
Status in U.K.  
Used within 
Marketing 
Authorization 
Ocrelizumab  
IMP (test product)a 
Authorized 
Nob 
Ocrelizumab-matched 
placebo 
IMP (placebo) 
Not authorized 
Not applicable 
Methylprednisolone 
NIMP 
(Premedication) 
Authorized 
Yes 
Antihistamine (e.g. 
diphenhydramine) 
NIMP 
(Premedication) 
Authorized 
Yes 
Analgesic/antipyretic 
(e.g. acetaminophen) 
NIMP 
(Premedication) 
Authorized 
Yes 
IMP  investigational medicinal product; NIMP  non-investigational medicinal product. 
a Ocrelizumab is considered to be an IMP test product as well as an IMP comparator. 
b Ocrelizumab is approved for the treatment of PPMS at a dose of 600 mg but not at the higher dose of 
1200 mg (patient’s body weight < 75 kg at baseline) or 1800 mg (patient’s body weight ≥ 75 kg at 
baseline) 
 

Signature Page for Protocol - WA40404 - OCREVUS - v6 - Global/Core - Published
System identifier: RIM-CLIN-542024
Approval Task
Deputy EU QPPV
04-Jul-2024 15:22:27 GMT+0000
Approval Task
04-Jul-2024 15:37:43 GMT+0000