Clinical trial NCT02545868
Conditions: Multiple Sclerosis, Relapsing-Remitting
Sponsor: Hoffmann-La Roche
Start date: 2015-10-27; Completion date: 2021-09-21
Enrollment: 102 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This multicenter, randomized, open-label study will evaluate the immune response to vaccines (tetanus toxoid \[TT\]-containing adsorbed vaccine, 23-valent pneumococcal polysaccharide vaccine \[23-PPV\] either unboosted or boosted with 13-valent pneumococcal conjugate vaccine \[13-PCV\], influenza vaccine, keyhole limpet hemocyanin \[KLH\]) after administration of a dose of ocrelizumab (OCR) in participants with relapsing multiple sclerosis (RMS).

Detailed description:

Arms: arm 1: Participants will receive dual infusion of OCR 300 milligrams (mg) on Day 1 and then on Day 15, and then participants will further receive immunization course (TT-containing adsorbed vaccine, 23-PPV either unboosted or boosted with 13-PCV, influenza vaccine, and repeated administration with KLH) at 12 weeks post-OCR treatment until Week 24. Participants who complete the 24-week immunization study period will have the option for retreatment with a single infusion of 600 mg OCR on Day 169 and subsequent single infusions (600 mg OCR) at intervals of 24 weeks. Participants who have received one or more infusions of OCR will enter the 48-week safety follow-up period. arm 2: Participants will receive immunizations (TT-containing adsorbed vaccine, 23-PPV, influenza vaccine, and repeated administration with KLH) on Day 1 until Week 12 of the immunization period.
Interventions: intervention 1: 23-PPV intervention 2: 13-PCV Booster intervention 3: Influenza Vaccine intervention 4: KLH intervention 5: OCR intervention 6: TT Vaccine
Intervention descriptions: intervention 1: The 23-PPV vaccine will be given as a 0.5-milliliter (mL) intramuscular (IM) injection in the deltoid muscle on Day 112 (Group A) or Day 28 (Group B). intervention 2: The 13-PCV booster will be given as an IM injection in the deltoid muscle on Day 140 (select participants in Group A). intervention 3: The influenza vaccine will be given as an IM injection in the deltoid muscle at any time between Day 85 and Day 144 (select participants in Group A) or any time between Day 1 and Day 85 (Group B). intervention 4: KLH will be given as a 1-mg subcutaneous (SC) injection on Days 84, 112, and 140 (Group A) or Days 1, 28, and 56 (Group B). intervention 5: OCR will be given as an intravenous (IV) infusion at a dose of 600 mg, with the first dose given as two infusions of 300mg 14 days apart, according to the specifications described in the corresponding Group A and Group B arms. intervention 6: The TT-containing adsorbed vaccine will be given as a 0.5-mL IM injection in the deltoid muscle on Day 85 (Group A) or Day 1 (Group B).

Protocol documents:
Prot_002.pdf: 
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Ocrelizumab—F. Hoffmann-La Roche Ltd
Protocol BN29739, Version 8
PROTOCOL
TITLE:
A PHASE IIIb, MULTICENTER, RANDOMIZED, 
PARALLEL-GROUP, OPEN-LABEL STUDY TO 
EVALUATE THE EFFECTS OF OCRELIZUMAB ON 
IMMUNE RESPONSES IN PATIENTS WITH 
RELAPSING FORMS OF MULTIPLE SCLEROSIS
PROTOCOL NUMBER:
BN29739
VERSION NUMBER:
8
IND NUMBER:
100,593
NCT NUMBER:
NCT02545868
TEST PRODUCT:
Ocrelizumab (RO4964913)
MEDICAL MONITOR:
 M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
APPROVAL DATE:
See electronic date stamp below
 
01-Jun-2021 22:36:28
02-Jun-2021 11:41:26
Title
Approver's Name
Date and Time (UTC)


OcrelizumabF. Hoffmann-La Roche Ltd
2/Protocol BN29739, Version 8
PROTOCOL HISTORY
Protocol
Version
Date Final
8
See electronic date 
stamp on title page
7
17 December 2019
6
21 August 2018
5
18 September 2017
4
1 March 2016
3
29 October 2015
2
29 June 2015
1
17 May 2015


OcrelizumabF. Hoffmann-La Roche Ltd
3/Protocol BN29739, Version 8
PROTOCOL AMENDMENT, VERSION 8:
RATIONALE
Protocol BN29739 has been amended for the following reasons:

To clarify that patients who discontinue treatment early for any reason and patients 
who complete the study treatment period will be followed up for a maximum of 48 
weeks after the last infusion of ocrelizumab (OCR).  The requirement for continued 
B-cell monitoring for patients whose B-cells are not repleted (i.e., returned to 
baseline levels or lower limit of normal, whichever is lower) at the end of the safety 
follow-up (SFU) period has been removed as no increased safety risk was identified
in the OCR clinical development program from Week 48 post-treatment and beyond 
until B-cell repletion.

To clarify that after entering SFU and upon treatment initiation with another disease-
modifying therapy (DMT), patients will be discontinued from the SFU and from the 
study. The rationale for this change is that, given the low numbers of patients in the 
clinical development program who have switched to alternative DMTs, and data 
consisting of several different DMTs with various treatment durations, the Sponsor 
considers that such data would not allow any meaningful interpretation and it is 
unlikely that prolonged data collection would facilitate this.  Patients who switch to 
commercial OCR after entering SFU, will also be discontinued from the SFU and the 
study.
Changes to the protocol that address the above reasons are summarized below:

Language has been added to clarify that patients who discontinue treatment early 
for any reason and patients who complete the study treatment period will be 
followed up for 48 weeks after the last infusion of OCR (Sections 3.1, 4.7.4, and 
4.8.2; Appendix 1).

Text related to continued B-cell monitoring has been removed (Sections 3.1, 3.2, 
3.3.5, 4.6.3.1, 4.7.4, 4.7.7, 4.7.8.7, 4.8.2, 5.1.1.5, 5.3.1, 5.4.2.2, 5.6 and 8.5; Figures 
1 and 2; Appendices 1 and 2).

Language has been added to clarify that when patients begin an alternative 
treatment for multiple sclerosis or start treatment with commercial OCR, they will be 
discontinued from the SFU and from the study (Sections 3.1, 4.6.3.1, 4.7.4, 4.7.7, 
4.8.2; Appendix 1).
Additional changes to the protocol, along with a rationale for each change, are 
summarized below:

Language regarding post-trial access to OCR has been amended to indicate that 
continued access to OCR will be offered (Section 4.5).

The safety risks for ocrelizumab have been updated and clarifications have been 
added to the section.  These changes will be or were implemented across the 
ocrelizumab clinical program for consistency and do not reflect a change in the 
benefitrisk assessment for ocrelizumab (Section 5.1).


OcrelizumabF. Hoffmann-La Roche Ltd
4/Protocol BN29739, Version 8

Guidance for pregnancy reporting has been updated to remove the requirement for 
reporting within 6 months after the last dose of OCR (Section 5.4.3.1).

Language has been added to clarify that adverse events associated with a special 
situation that also qualify as adverse events of special interest should be reported 
within 24 hours (Section 5.3.5.11).

Language has been added to indicate that the Informed Consent Form will instruct 
female patients to inform the investigator if they become pregnant (Section 5.4.3.1).

Language regarding investigator reporting of pregnancies has been clarified
(Section 5.4.3.1).

The name of a Roche policy on data sharing has been corrected (Section 9.5).
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


OcrelizumabF. Hoffmann-La Roche Ltd
5/Protocol BN29739, Version 8
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 12
PROTOCOL SYNOPSIS .................................................................................... 13
1.
BACKGROUND .......................................................................................... 25
1.1
Background on Multiple Sclerosis.......................................... 26
1.1.1
Multiple Sclerosis................................................................... 26
1.1.2
Ocrelizumab .......................................................................... 26
1.1.3
Sponsor Experience with Anti-CD20 Compounds 
in Multiple Sclerosis............................................................... 26
1.1.3.1
Ocrelizumab in Relapsing Forms of Multiple 
Sclerosis (RMS)..................................................................... 27
1.1.3.2
Safety in Multiple Sclerosis.................................................... 28
1.1.4
Vaccine Response with Ocrelizumab .................................... 29
1.2
Study Rationale and Benefit-Risk Assessment...................... 29
2.
OBJECTIVES.............................................................................................. 30
2.1
Primary Objective .................................................................. 30
2.2
Secondary Objectives............................................................ 30
2.3
Safety Objectives................................................................... 31
3.
STUDY DESIGN......................................................................................... 31
3.1
Description of Study .............................................................. 31
3.2
End of Study.......................................................................... 36
3.3
Rationale for Study Design.................................................... 36
3.3.1
Rationale for Specific Antigens.............................................. 36
3.3.2
Rationale for Timing of Vaccinations ..................................... 36
3.3.2.1
Tetanus Toxoid Adsorbed Vaccine........................................ 36
3.3.2.2
23-Valent Pneumococcal Polysaccharide 
Vaccine.................................................................................. 37
3.3.2.3
Keyhole Limpet Hemocyanin................................................. 37
3.3.2.4
Influenza Vaccine .................................................................. 37
3.3.2.5
Conjugate Pneumococcal Vaccine Booster (13-
PCV)...................................................................................... 37
3.3.3
Rationale for Ocrelizumab Dose Selection ............................ 38


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3.3.4
Rationale for Group B............................................................ 38
3.3.5
Rationale for the Safety Follow-Up Period............................. 38
3.4
Outcome Measures ............................................................... 38
3.4.1
Primary Immunization Outcome Measure.............................. 38
3.4.2
Secondary Outcome Measures ............................................. 39
3.4.3
Immunophenotyping Outcome Measures.............................. 40
3.4.4
Safety Outcome Measures .................................................... 40
4.
MATERIALS AND METHODS .................................................................... 41
4.1
Patients.................................................................................. 41
4.1.1
Inclusion Criteria.................................................................... 41
4.1.2
Exclusion Criteria................................................................... 42
4.1.3
Eligibility for the Optional Ocrelizumab Extension 
Period .................................................................................... 45
4.1.4
Re-treatment Criteria ............................................................. 45
4.2
Method of Treatment Assignment and Blinding..................... 46
4.3
Study Treatment.................................................................... 46
4.3.1
Formulation, Packaging, and Handling.................................. 46
4.3.2
Dosage, Administration, and Compliance.............................. 47
4.3.2.1
Ocrelizumab .......................................................................... 47
4.4
Non-Investigational Medicinal Products................................. 48
4.4.1
Premedication........................................................................ 48
4.4.2
Immunizations ....................................................................... 48
4.4.2.1
Tetanus Toxoid Vaccine ........................................................ 48
4.4.2.2
23-Valent Pneumococcal Polysaccharide 
Vaccine.................................................................................. 49
4.4.2.3
Keyhole Limpet Hemocyanin................................................. 49
4.4.2.4
Conjugate Pneumococcal Vaccine........................................ 49
4.4.2.5
Seasonal Influenza Vaccine .................................................. 49
4.4.3
Investigational Medicinal Product Accountability ................... 50
4.4.3.1
Assessment of Compliance ................................................... 50
4.4.4
Destruction of the Investigational Medicinal 
Product .................................................................................. 51
4.5
Post-Trial Access to Ocrelizumab.......................................... 51
4.6
Concomitant Therapy ............................................................ 52


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4.6.1
Definition of Concomitant Treatment ..................................... 52
4.6.2
Treatment for Symptoms of Multiple Sclerosis ...................... 52
4.6.3
Treatment of Relapses .......................................................... 52
4.6.3.1
Prohibited Therapy ................................................................ 52
4.6.4
Immunizations ....................................................................... 53
4.7
Study Assessments ............................................................... 53
4.7.1
Informed Consent Forms and Screening Log........................ 53
4.7.2
Procedures for Enrollment of Eligible Patients....................... 54
4.7.3
Overview of Clinical Visits during the 
Immunization Study Period and the Optional 
Ocrelizumab Extension Period .............................................. 55
4.7.4
Safety Follow-Up ................................................................... 55
4.7.5
Delayed Dosing Visit ............................................................. 56
4.7.6
Unscheduled Visits ................................................................ 56
4.7.7
Withdrawal Visits ................................................................... 56
4.7.8
Safety .................................................................................... 57
4.7.8.1
Medical History and Demographic Data ................................ 57
4.7.8.2
Vital Signs.............................................................................. 57
4.7.8.3
Electrocardiogram ................................................................. 57
4.7.8.4
Physical Examination ............................................................ 57
4.7.8.5
Brain Magnetic Resonance Imaging...................................... 58
4.7.8.6
Neurological Examination...................................................... 58
4.7.8.7
Telephone Interviews ............................................................ 59
4.7.9
Laboratory Assessments ....................................................... 59
4.7.9.1
Standard Laboratory Assessments........................................ 59
4.7.9.2
Immunization Response Laboratory 
Assessments ......................................................................... 60
4.7.9.3
Hepatitis Screening and Liver Function 
Monitoring.............................................................................. 61
4.7.9.4
Pharmacokinetic Assessments.............................................. 61
4.7.10
Optional Ocrelizumab Extension Period ................................ 62
4.8
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 62
4.8.1
Patient Discontinuation.......................................................... 62


OcrelizumabF. Hoffmann-La Roche Ltd
8/Protocol BN29739, Version 8
4.8.2
Criteria for Premature Withdrawal ......................................... 62
4.8.3
Study and Site Discontinuation.............................................. 64
5.
ASSESSMENT OF SAFETY....................................................................... 64
5.1
Safety Plan ............................................................................ 64
5.1.1
Identified Risks and Adverse Drug Reactions 
Associated with Ocrelizumab Use ......................................... 64
5.1.1.1
Infusion-Related Reactions.................................................... 64
5.1.1.2
Infections ............................................................................... 65
5.1.1.3
Decrease in Immunoglobulins ............................................... 66
5.1.1.4
Serious Infections Related to Decrease in 
Immunoglobulins (Particularly in Patients 
Previously Exposed to Immunosuppressive or 
Immunomodulary Drugs or with Preexisting 
Hypogammaglobulinemia)..................................................... 66
5.1.1.5
Delayed Return of Peripheral B cells..................................... 67
5.1.1.6
Impaired Response to Vaccination........................................ 67
5.1.2
Potential Risks Associated with Ocrelizumab Use................. 67
5.1.2.1
Progressive Multifocal Leukoencephalopathy........................ 67
5.1.2.2
Hypersensitivity Reactions..................................................... 68
5.1.2.3
Malignancies, Including Breast Cancer ................................. 68
5.1.2.4
Neutropenia........................................................................... 69
5.1.3
Risks Associated with Corticosteroids ................................... 69
5.1.4
Risks Associated with Antihistamines.................................... 69
5.1.5
Management of Specific Adverse Events .............................. 69
5.1.5.1
Guidance for Diagnosis of Progressive Multifocal 
Leukoencephalopathy ........................................................... 69
5.2
Safety Parameters and Definitions ........................................ 75
5.2.1
Adverse Events ..................................................................... 75
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 76
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 77
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 77
5.3.1
Adverse Event Reporting Period ........................................... 78


OcrelizumabF. Hoffmann-La Roche Ltd
9/Protocol BN29739, Version 8
5.3.2
Eliciting Adverse Event Information....................................... 78
5.3.3
Assessment of Severity of Adverse Events ........................... 78
5.3.4
Assessment of Causality of Adverse Events ......................... 79
5.3.5
Procedures for Recording Adverse Events............................ 80
5.3.5.1
Infusion-Related Reactions.................................................... 80
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 80
5.3.5.3
Adverse Events that Are Secondary to Other 
Events.................................................................................... 80
5.3.5.4
Persistent or Recurrent Adverse Events................................ 81
5.3.5.5
Abnormal Laboratory Values ................................................. 81
5.3.5.6
Abnormal Vital Sign Values ................................................... 82
5.3.5.7
Abnormal Liver Function Tests.............................................. 82
5.3.5.8
Deaths ................................................................................... 83
5.3.5.9
Preexisting Medical Conditions.............................................. 83
5.3.5.10
Hospitalization or Prolonged Hospitalization.......................... 83
5.3.5.11
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 84
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 84
5.4.1
Emergency Medical Contacts................................................ 85
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 85
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 85
5.4.2.2
Events That Occur After Study Drug Initiation ....................... 85
5.4.3
Reporting Requirements for Pregnancies.............................. 86
5.4.3.1
Pregnancies in Female Patients............................................ 86
5.4.3.2
Abortions ............................................................................... 86
5.4.3.3
Congenital Anomalies/Birth Defects ...................................... 87
5.5
Follow-Up of Patients after Adverse Events .......................... 87
5.5.1
Investigator Follow-Up........................................................... 87
5.5.2
Sponsor Follow-Up ................................................................ 87
5.6
Post-Study Adverse Events................................................... 87
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 88


OcrelizumabF. Hoffmann-La Roche Ltd
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6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 88
6.1
Determination of Sample Size ............................................... 88
6.2
Summaries of Conduct of Study............................................ 88
6.3
Summaries of Treatment Group Comparability ..................... 89
6.4
Immunology Endpoints .......................................................... 89
6.4.1
Analysis of Immunology Endpoints........................................ 89
6.5
Safety Analyses..................................................................... 89
6.5.1
Adverse Events ..................................................................... 89
6.5.2
Laboratory Tests.................................................................... 90
6.6
Pharmacokinetic Analyses..................................................... 90
6.7
Interim Analysis ..................................................................... 90
7.
DATA COLLECTION AND MANAGEMENT ............................................... 90
7.1
Data Quality Assurance......................................................... 90
7.2
Electronic Case Report Forms............................................... 90
7.3
Source Data Documentation.................................................. 91
7.4
Use of Computerized Systems .............................................. 91
7.5
Retention of Records............................................................. 92
8.
ETHICAL CONSIDERATIONS.................................................................... 92
8.1
Compliance with Laws and Regulations ................................ 92
8.2
Informed Consent.................................................................. 92
8.3
Institutional Review Board or Ethics Committee.................... 93
8.4
Confidentiality........................................................................ 94
8.5
Financial Disclosure .............................................................. 94
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 94
9.1
Study Documentation ............................................................ 94
9.2
Protocol Deviations................................................................ 94
9.3
Site Inspections ..................................................................... 95
9.4
Administrative Structure......................................................... 95
9.5
Publication of Data and Protection of Trade 
Secrets .................................................................................. 95
9.6
Protocol Amendments ........................................................... 96


OcrelizumabF. Hoffmann-La Roche Ltd 
11/Protocol BN29739, Version 8 
10. REFERENCES ........................................................................................... 97 
 
 
LIST OF TABLES 
Table 1 
Clinical Features to Distinguish between Multiple Sclerosis 
Relapse and Progressive Multifocal Leukoencephalopathy ........ 73 
Table 2 
Magnetic Resonance Imaging Lesion Characteristics Typical 
of Multiple Sclerosis and Progressive Multifocal 
Leukoencephalopathy ................................................................. 74 
Table 3 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 79 
 
 
LIST OF FIGURES 
Figure 1 
Schema of Study Periods ........................................................... 33 
Figure 2 
Study Schema ............................................................................. 34 
Figure 3 
Diagnostic Algorithm Framework for PML (Berger et al. 
2013) ........................................................................................... 72 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments:  Tables AC ................................... 100 
Appendix 2 
Telephone Interviews ................................................................ 114 


OcrelizumabF. Hoffmann-La Roche Ltd
12/Protocol BN29739, Version 8
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE IIIb, MULTICENTER, RANDOMIZED, 
PARALLEL-GROUP, OPEN-LABEL STUDY TO 
EVALUATE THE EFFECTS OF OCRELIZUMAB ON 
IMMUNE RESPONSES IN PATIENTS WITH 
RELAPSING FORMS OF MULTIPLE SCLEROSIS
PROTOCOL NUMBER:
BN29739
VERSION NUMBER:
8
IND NUMBER:
100,593
NCT NUMBER:
NCT02545868
TEST PRODUCT:
Ocrelizumab (RO4964913)
MEDICAL MONITOR:
 M.D.
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 as 
instructed by your local monitor.


OcrelizumabF. Hoffmann-La Roche Ltd
13/Protocol BN29739, Version 8
PROTOCOL SYNOPSIS
TITLE:
A PHASE IIIb, MULTICENTER, RANDOMIZED,
PARALLEL-GROUP, OPEN-LABEL STUDY TO EVALUATE THE 
EFFECTS OF OCRELIZUMAB ON IMMUNE RESPONSES IN 
PATIENTS WITH RELAPSING FORMS OF MULTIPLE SCLEROSIS
PROTOCOL NUMBER:
BN29739
VERSION NUMBER:
8
IND NUMBER:
100,593
NCT NUMBER:
NCT02545868
TEST PRODUCT:
Ocrelizumab (RO4964913)
PHASE:
IIIb
INDICATION:
Relapsing forms of multiple sclerosis
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
The primary efficacy objective for this study is as follows:

To characterize the humoral immune response (IgG) to tetanus toxoid (TT) adsorbed 
vaccine in patients with relapsing forms of multiple sclerosis (RMS) who are treated with 
ocrelizumab (OCR; Group A), compared with that of patients with RMS who are not treated 
with OCR (Group B).
The secondary efficacy objectives for this study are as follows:
1.
To characterize the humoral immune response (IgG) to the 23-valent pneumococcal 
polysaccharide vaccine (23-PPV) in Group A patients (Groups A1 and A2) compared with 
Group B patients.
2.
To characterize the humoral immune response (IgG) in OCR-treated patients to 23-PPV 
boosted by a subsequent 13-valent pneumococcal conjugate (13-PCV) vaccine booster 
(Group A1) compared with unboosted 23-PPV (Group A2).
3.
To characterize the humoral immune response (IgG and IgM) to keyhole limpet 
hemocyanin (KLH) in Group A patients compared with Group B patients.
4.
To characterize the humoral immune response (hemagglutination inhibition [HI]) titers) to 
influenza vaccine in OCR-treated patients (Group A2) patients compared with patients not 
treated with OCR (Group B).
5.
To evaluate the long-term effects of OCR on magnetic resonance imaging (MRI) 
parameters of disease activity during the Optional Ocrelizumab Extension (OOE) Period of 
the study. 
Group A will be split into Group A1 (patients will receive the booster 13-PCV vaccine), and 
Group A2 (patients will receive the influenza vaccine).
Safety Objectives
The safety objectives for this study are to collect additional data on the safety of OCR.
Study Design
Description of Study
This Phase IIIb, multicenter, randomized, open-label study is designed to evaluate immune 
response to vaccines after administration of a dose of OCR (i.e., a dual infusion of OCR 300 mg 


OcrelizumabF. Hoffmann-La Roche Ltd
14/Protocol BN29739, Version 8
on Day 1/Week 1 [Dose 1 Infusion 1] and Day 15/Week 2 [Dose 1 Infusion 2]) in patients 
with RMS.
Following screening, approximately 100 adult patients will be randomized into Groups A and B 
(2:1; active:control) to compare responses to immunization.  Patients in Group B are to receive 
immunization with TT-containing adsorbed vaccine, 23-PPV, influenza vaccine, and repeated 
administration with KLH.  Group B patients will not receive OCR but will remain on no 
MS-specific disease-modifying therapy (DMT) or continue with interferon beta (IFN-) treatment 
until optional OCR treatment at the end of the Immunization Study Period. 
Patients in Group A are to first receive OCR (Day 1/Week 1 [Dose 1 Infusion 1] and 
Day 15/Week 2 [Dose 1 Infusion 2]), and 12 weeks post-OCR treatment, are to receive a similar 
immunization course to Group B.  Group A will be further subdivided into two groups to evaluate 
the effectiveness of a booster 13-PCV vaccination or of influenza vaccination.
For the primary objective and for secondary objectives 1 and 3, Group A (active) will be 
compared with Group B (control).
To determine the outcomes of secondary objectives 2 and 4, patients in Group A will be split 
into two groups with 50% of patients in each group (Groups A1 and A2).  Patients will be 
assigned to either Group A1 or A2:

Group A1 will receive booster 13-PCV (approximately 33 patients)

Group A2 will receive the influenza vaccine (approximately 33 patients but a minimum of 
30 patients).
A minimum of 30 patients will be assigned to Group A2 during the first influenza season.  If a 
minimum of 30 patients (a maximum of 33) are assigned to Group A2 and receive the first 
year's influenza vaccine, all remaining patients in Group A will be assigned to Group A1 and 
receive the 13-PCV booster.  If less than 30 patients have been assigned to Group A2 during 
the first influenza season, further patients assigned to Group A2 will have influenza vaccine 
visits during the subsequent influenza season (i.e., when the next year’s vaccine becomes 
available).
The primary and secondary humoral immunity and immunophenotyping outcomes are to be 
measured by flow cytometry and quantitative Ig measurements.
Approximately 3035 centers will participate in the study in the United States/North America.  
This study consists of up to five study periods:

Screening Period

Immunization Study Period
Group A:  Immunization Study Period and OCR treatment starts at Day 1/Week 1.  
Patients will receive 300 mg of open-label OCR on Day/Week 1 (Dose 1 Infusion 1) and 
Day 15/Week 2 (Dose 1 Infusion 2).  Patients in Group A will be split and be assigned to 
either Group A1 (booster 13-PCV) or Group A2 (influenza vaccine).    At Day 85/Week 12 
patients will start to receive immunizations and undergo post-immunization assessments.  
For all patients in Group A, the Immunization Study Period will end on Day 169/Week 24. 
Group B:  Patients will not receive OCR.  At Day 1/Week 1, patients will start to receive 
immunizations and undergo post-immunization assessments.  For Group B, the 
Immunization Study Period will end at Day 84/Week 12.  

Optional OCR Extension Period: 
–
Groups A1 and A2:  Patients who complete the 24week immunization study period 
will have the option for retreatment with a single infusion of 600 mg OCR (Dose 2) at 
Day 169/Week 24 and subsequent single infusions (600 mg OCR) at intervals of 
24 weeks provided that he or she meets the OOE retreatment criteria and chooses to 
receive retreatment.
–
Group B:  Patients who complete the 12week immunization study period will have the 
option to receive OCR in the OOE; the first dose will be administered as two single 
infusions of 300 mg, on Day 84/Week 12 (Dose 1 Infusion 1) and Day 98/Week 14 
(Dose 1 Infusion 2), and subsequent doses will be administered as single 600 mg 
infusions (Dose 2, Dose 3, etc.) at intervals of 24 weeks provided that he or she meets 
the OOE retreatment criteria and chooses to receive retreatment.  Group B patients 


OcrelizumabF. Hoffmann-La Roche Ltd
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who do not qualify for and/or do not choose treatment with OCR at Week 12 will 
complete the study at Week 12 and will not enter safety follow-up.
Please note that the OOE will continue with all patients who are able to receive OCR as 
per local guidelines, or unless the Sponsor decides to terminate the OCR program for 
multiple sclerosis (MS); however, the OOE will not exceed 4 years after the last patient 
last visit in the Immunization Study Period.  At the end of the OOE, patients may 
choose to continue on commercially available OCR.

Safety Follow-Up (SFU) Period:  Patients who discontinue treatment early for any reason 
and patients who complete the study treatment period will be followed up for 48 weeks 
after the last infusion of OCR.  When patients begin an alternative treatment for MS or 
start treatment with commercial OCR, they will be discontinued from the SFU and from 
the study.
Number of Patients
This study will enroll approximately 100 patients.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Ability to provide written informed consent and to be able to follow the protocoldefined 
schedule of assessments

Diagnosis of RMS in accordance with the revised McDonald criteria 

Age 1855 years, inclusive

Received at least one previous immunization against TT or tetanus and diphtheria (DT/Td)
or tetanus, diphtheria, and acellular pertussis (DTaP/Tdap).

Expanded Disability Status Scale at screening from 05.5 points, inclusive

Contraception requirements:
–
For sexually active female patients of reproductive potential, use of reliable means 
of contraception as described below as a minimum (adherence to local requirements, if 
more stringent, is required):* 
–
One primary method of contraception throughout the trial, including the active 
treatment phase AND for 6 months after the last dose of OCR. 
*Acceptable methods of contraception include one primary (e.g., systemic hormonal 
contraception or tubal ligation, vasectomy of the male partner) OR a double-barrier 
method (e.g., latex condom, intrauterine device, vaginal ring or pessary plus 
spermicide [e.g., foam, vaginal suppository, gel, cream]).
–
For female patients without reproductive potential:
–
Women may be enrolled if post-menopausal (i.e., spontaneous amenorrhea for 
12 months confirmed by a follicle stimulating hormone level 40 mIU/mL) unless 
the patient is receiving a hormonal therapy for her menopause; or surgically sterile 
(i.e., hysterectomy, complete bilateral oophorectomy).
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Contraindications for or intolerance to oral or intravenous (IV) corticosteroids, including 
methylprednisolone administered IV, according to the country label, including:
–
Psychosis not yet controlled by a treatment
–
Hypersensitivity to any of the constituents


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
Known presence of other neurologic disorders, including but not limited to, the following:
–
History of ischemic cerebrovascular disorders (e.g., stroke, transient ischemic attack) or 
ischemia of the spinal cord
–
History or known presence of CNS or spinal cord tumor (e.g., meningioma, glioma)
–
History or known presence of potential metabolic causes of myelopathy (e.g., untreated 
vitamin B12 deficiency)
–
History or known presence of infectious causes of myelopathy (e.g., syphilis, Lyme 
disease, human Tlymphotropic virus-1 [HTLV-1], herpes zoster myelopathy)
–
History of genetically inherited progressive CNS degenerative disorder (e.g., hereditary 
paraparesis; mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke 
syndrome)
–
Neuromyelitis optica
–
History or known presence of systemic autoimmune disorders that potentially cause 
progressive neurologic disease (e.g., lupus, anti-phospholipid antibody syndrome, 
Sjögren’s syndrome, Behçet’s disease)
–
History or known presence of sarcoidosis
–
History of severe, clinically significant brain or spinal cord trauma (e.g., cerebral 
contusion, spinal cord compression)
–
History of progressive multifocal leukoencephalopathy
Patients who meet the following criteria related to their general health will be excluded:

Pregnancy or lactation

Lack of peripheral venous access

History of severe allergic or anaphylactic reactions to humanized or murine monoclonal 
antibodies

Known hypersensitivity to any component of the TT-containing adsorbed vaccine, including 
thiomersal (thimerosal in United States)

History of systematic allergic, neurologic, or other reactions following a previous dose of 
any TT-containing vaccine

Known hypersensitivity to any component of any pneumococcal polysaccharide or 
conjugate vaccine

Known hypersensitivity to any component of the influenza vaccine 

Allergy to shellfish

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 a patient from 
participating in the study

Congestive heart failure (New York Heart Association III or IV functional severity)

Known active bacterial, viral, fungal, mycobacterial infection or other infection (including 
tuberculosis [TB] or atypical mycobacterial disease [but excluding fungal infection of nail 
beds]) or any major episode of infection requiring hospitalization or treatment with IV 
antibiotics within 4 weeks prior to baseline visit or oral antibiotics within 2 weeks prior to 
baseline visit

History or known presence of recurrent or chronic infection (e.g., HIV, syphilis, TB)

History of recurrent aspiration pneumonia that required antibiotic therapy

History of cancer, including solid tumors and hematological malignancies (except basal cell, 
in situ squamous cell carcinomas of the skin, and in situ carcinoma of the cervix of the 
uterus that have been excised and resolved, with documented clean margins on pathology)

Any concomitant disease that may require chronic treatment with systemic corticosteroids 
or immunosuppressants during the course of the study


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
History of alcohol or drug abuse within 24 weeks prior to randomization

History of or currently active primary or secondary immunodeficiency 

Treatment with any investigational agent within 24 weeks of screening (Visit 1) or 
5 half-lives of the investigational drug, whichever is longer, or treatment with any 
experimental procedure for MS (e.g., treatment for chronic cerebrospinal venous 
insufficiency)

Receipt of any pneumococcal vaccine within 5 years prior to screening

Previous exposure to KLH

Previous immunization with any tetanus-containing vaccine within 2 years prior to screening

If scheduled as per protocol to receive the 2015/2016 vaccine and has already received the 
2015/2016 vaccine or if scheduled as per protocol to receive the 2016/2017 vaccine and 
has already received the 2016/2017 vaccine.

Receipt of a live vaccine within 6 weeks prior to randomization*
*Vaccinations before baseline:  in rare cases where a live vaccine must be administered by 
the patient’s physician, the screening period may need to be prolonged but cannot exceed 
8 weeks.

Previous treatment with B-cell targeted therapies (e.g., rituximab, OCR, atacicept, 
belimumab, or ofatumumab)

Any previous treatment with alemtuzumab, anti-CD4, cladribine, cyclophosphamide, 
mitoxantrone, azathioprine, mycophenolate mofetil, cyclosporine, methotrexate, total body 
irradiation, or bone marrow transplantation

Any previous treatment with lymphocyte-trafficking blockers (e.g., natalizumab, fingolimod)

Treatment with IV Ig, plasmapheresis, teriflunomide or dimethyl fumarate, or glatiramer 
acetate within 12 weeks prior to randomization*

Systemic corticosteroid therapy within 4 weeks prior to screening**
* Patients screened for this study should not be withdrawn from therapies for the sole 
purpose of meeting eligibility criteria 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 not 
receive RMS diseasemodifying therapies.  Group B patients can continue with IFN-
treatment.  If the patient has received teriflunomide he or she may need to go through the 
accelerated elimination protocol (Genzyme 2013).
**The screening period may be extended (but cannot exceed 8 weeks) for patients who 
have used systemic corticosteroids for RMS before screening.  In addition, for a patient to 
be eligible, systemic corticosteroids should not have been administered between screening 
and baseline.

Exclusions related to laboratory findings*
–
Positive serum -human chorionic gonadotropin measured at screening
–
Positive screening tests for hepatitis B (hepatitis B surface antigen positive, or positive 
hepatitis B core antibody confirmed by a positive viral DNA polymerase chain reaction), 
or hepatitis C antibody 
–
Positive rapid plasma reagin, if confirmed by microhemagglutination assay or 
fluorescent treponemal antibody absorption test
–
CD4 count 300/L
–
Serum creatinine1.4 mg/dL (124 mol/L) for women or1.6 mg/dL (141 mol/L) 
for men
–
AST/SGOT or ALT/SGPT 2.0upper limit of normal 
–
Platelet count 100,000/L (100109/L)
–
Hemoglobin8.5 g/dL (5.15 mmol/L)


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–
ANC1.5103/L
–
Levels of serum IgG 18% below the LLN (for central laboratory:  IgG4.6 g/L)
–
Levels of serum IgM 8% below the LLN (for central laboratory:  IgM0.37 g/L)
* Retesting before baseline:  in rare cases in which the screening laboratory samples are 
rejected by the central laboratory (example:  hemolyzed sample) or the result is not 
assessable (example: indeterminate) or abnormal, the tests need to be repeated within 
4 weeks.  Any abnormal screening laboratory value that is clinically relevant should be 
retested in order to rule out any progressive or uncontrolled underlying condition.  The last 
value before randomization must meet study criteria.  In such circumstances, the screening 
period may need to be prolonged but cannot exceed 8 weeks.

Based on local Ethics Committees or National Competent Authority requirements, additional 
diagnostic testing may be required for selected patients or selected centers to exclude TB 
(e.g., chest X-ray, tuberculin skin or blood test), Lyme disease, HTLV-1associated 
myelopathy, AIDS, hereditary disorders, connective tissue disorders, or sarcoidosis. Other 
specific diagnostic tests may be requested when deemed necessary by the investigator.
Eligibility for the Optional Ocrelizumab Extension Period
Only patients who have completed the Immunization Study Period are potentially eligible for the 
Optional OCR Extension Period.  Prior to re-treatment with OCR, patients will be evaluated for 
the following conditions and laboratory abnormalities. 
Re-treatment Criteria
Prior to re-treatment, the following conditions must be met:

Absence of severe allergic or anaphylactic reaction to a previous OCR infusion

Absence of any significant or uncontrolled medical condition or treatmentemergent, 
clinically significant laboratory abnormality

Absence of active infection (including active TB infection, either new onset or reactivation)*

ANC 1.5 103/L

CD4 cell count 250/L

IgG 3.3 g/L

Negative pregnancy test**
If any of the conditions are not met prior to re-treatment, further administration of OCR should 
be suspended until resolved or held indefinitely.
* Patients with active TB infection, either new onset or reactivation, must suspend 
ocrelizumab treatment for as long as needed to ensure full resolution of the TB infection.  
These patients should receive medical care in adherence with local/national requirements 
until complete resolution of the TB infection and should be monitored subsequently as per 
local medical plans.  Upon resolution of the TB infection and based on individual benefit-risk 
assessments, these patients will have the opportunity to re-start ocrelizumab treatment if it 
is considered beneficial for them.  Otherwise, the treating Investigator can decide to 
permanently stop ocrelizumab.
** 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 assessments for the OOE; 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.  In 
the OOE period of the study, re-start of ocrelizumab treatment following pregnancy and 
breastfeeding will be decided as a result of a thorough benefit/risk discussion between the 
patient and investigator.


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Length of Study
The treatment period (including OOE) will not exceed 4 years after the last patient last visit 
(LPLV) in the Immunization Study Period.  The last patient last visit in the Safety Follow-Up 
Period (i.e., 48 weeks after the last dose of OCR) is anticipated to be within 5 years after the 
LPLV in the Immunization Study Period.  However, the end of study is defined as the last 
patient last visit in the Safety Follow-Up Period.
End of Study
The end of study is defined as the last patient last visit in the Safety Follow-Up Period.
Outcome Measures
Primary Immunization Outcome Measure
The primary outcome measure is the proportion of patients in Groups A (i.e., combined 
Groups A1 and A2) and B with a positive response (IgG) to TT vaccine measured 8 weeks after 
TT vaccine administration. 

For patients with pre-immunization tetanus antibody titers 0.1 IU/mL, a positive response 
to the booster immunization is defined as an antibody titer 0.2 IU/mL measured 8 weeks 
after immunization.  For patients with pre-immunization tetanus antibody titers 0.1 IU/mL, 
positive response to the booster immunization is defined as a 4-fold increase in antibody 
titers compared with pre-vaccination levels measured 8 weeks after immunization.  
Pre-immunization levels are those obtained immediately prior to administration of a vaccine.
Secondary Outcome Measures
The secondary outcome measures are as follows: 

TT response:
–
The proportion of patients in Groups A (A1 and A2) and B with a positive response 
(IgG) to TT vaccine measured 4 weeks after TT vaccine administration.
–
The proportion of patients in Groups A (A1 and A2) and B with a 2-fold increase in 
tetanus antibody titers, or with tetanus antibody titers 0.2 IU/mL, measured 4 weeks 
after the immunization of patients with pre-immunization tetanus antibody 
titers 0.1 IU/mL or with pre-immunization tetanus antibody titers 0.1 IU/mL, 
respectively.
–
Mean levels of anti-tetanus antibody in patients in Groups A (A1 and A2) and B 
measured immediately prior to and 4 weeks after a booster TT vaccine. 

Pneumococcal vaccine response:
–
The proportion of patients in Groups A (A1 and A2) and B with positive antibody 
responses against an individual pneumococcal serotype measured 4 weeks after the 
23-PPV (23 serotypes).  (A positive response against a serotype is defined as 
developing a 2-fold increase in antibody level or a 1 g/mL rise in level compared with 
pre-immunization levels.  Pre-immunization levels are those obtained immediately prior 
to receipt of 23-PPV.)  Post-immunization levels will be measured 4 and 8 weeks after 
23-PPV administration for Groups A1, A2, and B.
–
The proportion of patients in Groups A (A1 and A2) and B with a positive response 
against at least 2 out of 23 pneumococcal antibody serotypes measured 4 weeks after 
administration of 23-PPV vaccine.
–
The proportion of patients in Groups A (A1 and A2) and B with positive responses 
against at least 50% of the serotypes (12 of 23) measured 4 weeks after 
administration of 23-PPV vaccine. 
–
Mean levels of anti-pneumococcal serotype-specific antibody in patients in Groups A 
(A1 and A2) and B measured immediately prior to and 4 and 8 weeks (which is 4 weeks 
after Group A1 patients received the 13-PCV booster) after administration of 23-PPV 
vaccine. 


OcrelizumabF. Hoffmann-La Roche Ltd
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
KLH response:
–
Mean levels of anti-KLH antibody (IgG and IgM) in patients in Groups A (A1 and A2) 
and B measured immediately prior to the first administration of KLH and 4 weeks after 
the last administration of KLH.
–
Mean levels of anti KLH antibodies (IgG and IgM) in patients in Groups A (A1 and A2) 
and B measured over time at 4, 8, and 12 weeks after first KLH administration.

Strain-specific influenza vaccine response in Groups A2 and B:
–
Proportion of patients who achieve seroprotection defined as specific HI titers 40 at 
4 weeks post-immunization
–
Proportion of patients who achieve a 2-fold increase in specific HI titers at 4 weeks 
post-immunization
–
Proportion of patients who achieve a 4-fold increase in specific HI titers at 4 weeks 
post-immunization
–
Proportion of patients with seroconversion (i.e., a pre-vaccination antibody titer 10 
and a post-vaccination HI titer 40); 
–
Strainspecific geometric mean titers (GMTs) at baseline and at 4 weeks 
post-vaccination
–
Strainspecific GMT ratio (post-vaccination:pre-vaccination)

MRI assessments to evaluate the long-term effects of OCR on MRI parameters of disease 
activity during the OOE Period.
Immunophenotyping Outcome Measures
The humoral and cellular immunity outcome measures in this study are as follows:

Flow cytometry, which will include (but is not limited to) the following cells:
–
Total B cells (CD19 positive)
–
B-cell subsets, e.g., memory B cells, naïve B cells, plasma cells
–
Total T cells (CD3 positive)
–
T helper cells (CD3 positive, CD4 positive)
–
Cytotoxic T lymphocytes (TCTL; CD3 positive, CD8 positive)
–
Natural killer cells (CD3 negative, CD16/56 positive)

Quantitative Ig:  Ig levels (including total Ig, IgG, IgG subtypes, IgM, and IgA) 
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Vital signs*, hematologic laboratory tests, anti-drug antibody formation, physical and 
neurological examinations, and the incidence and severity of adverse events associated 
with OCR and study immunizations.
*To monitor infusion-related reactions (IRRs), vital signs will be obtained immediately 
pre-infusion, every 15 (5) minutes for the first hour during the infusion, every 
30 (5) minutes for the remainder of the infusion, and at the end of the infusion on days of 
OCR administration.
Investigational Medicinal Products
Test Product (Investigational Drug)
During the Immunization Study Period:

Patients in Group A will be administered OCR by IV infusion at a dose of 300 mg on 
Day 1/Week 1 (Dose 1 Infusion 1) and Day 15/Week 2 (Dose 1 Infusion 2).

Patients in Group B will not receive any OCR.


OcrelizumabF. Hoffmann-La Roche Ltd
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During the OOE, for patients who meet the criteria for optional OCR treatment:

Patients from Groups A1 and A2 will be administered OCR by IV infusion at a dose of 
600 mg on Day 169/Week 24 (Dose 2) and subsequent 600 mg single infusions with an 
interval of 24 weeks (minimum interval of 22 weeks).

Patients from Group B will be administered OCR by IV infusion at a dose of 300 mg on 
Day 84/Weeks 12 (Dose 1 Infusion 1) and Day 98/Week 14 (Dose 1 Infusion 2) and at a 
dose of 600 mg on Day 252/Week 36 (Dose 2) and subsequent 600 mg single infusions 
with an interval of 24 weeks (minimum interval of 22 weeks).
Mandatory premedication is required prior to any infusion with OCR.
Non-Investigational Medicinal Products
Premedication:  Premedication is mandatory with methylprednisolone 100 mg IV 30 minutes 
prior to each infusion of OCR, and with an antihistaminic drug (e.g., diphenhydramine) 
approximately 3060 minutes prior to each infusion of OCR. In the rare case when the use of 
methylprednisolone is contraindicated for the patient, an equivalent dose of an alternative 
steroid should be used as premedication prior to the infusion.
Pre-infusion treatment with an oral analgesic/antipyretic (e.g., acetaminophen) 3060 minutes 
prior to each infusion of OCR is also recommended
Tetanus toxoid:  TT vaccine is indicated for the prevention of tetanus. The TT vaccine will be 
administered as part of the combined adsorbed vaccine with diphtheria (Td/DT) and/or acellular 
pertussis (DTaP/Tdap).  In this study, TT adsorbed vaccine is being used to assess whether 
OCR affects antibody production to an antigen to which individuals have pre-existing immunity.

Group A patients will receive a TT-containing absorbed vaccine (0.5 mL) as an 
intramuscular (IM) injection in the deltoid muscle at Day 85/Week 12.

Group B patients will receive a TT-containing absorbed vaccine ([0.5 mL) as an IM injection 
in the deltoid muscle on Day 1/Week 1.
23-PPV:  The 23-PPV is indicated for immunization against pneumococcal disease caused by 
those pneumococcal serotypes included in the vaccine. It has been chosen for this study to 
assess antibody production for a clinically relevant antigen that is unknown to most individuals. 
The 23-PPV will be administered in the deltoid muscle as a single IM injection.

Group A patients will receive the 23-PPV vaccine (0.5 mL) as an IM injection in the deltoid 
muscle at Day 112/Week 16.

Group B patients will receive the 23-PPV (0.5 mL) as an IM injection in the deltoid muscle at 
Day 28/Week 4.
KLH:  KLH is a high molecular weight respiratory metalloprotein found in the hemolymph of 
many mollusks and crustaceans.  However, KLH does not have regulatory approval and is not 
marketed.  Therefore, it may be considered an investigational medicinal product (IMP) in some 
regions.  KLH has been used in global clinical trials as a challenge agent to evaluate patient’s 
immune responses to neo-antigen. In this study, KLH will be used to test primary humoral 
response following B-cell depletion with OCR.

Group A patients will receive subcutaneously (SC) administered KLH (1 mg) at 
Day 85/Week 12, Day 112/Week 16, and Day 140/Week 20.

Group B patients will receive SC administered KLH (1 mg) at Day 1/Week 1, 
Day 28/Week 4, and Day 56/Week 8.
13-PCV:  This study will assess antibody production when administered as 13-PCV booster 
vaccine after 23-PPV vaccine. The 13-PCV is indicated as active immunization for the 
prevention of pneumonia and invasive disease caused by 13 Streptococcus 
pneumoniae serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F). It has been 
chosen for this study to assess antibody production when administered as 13-PCV booster 
vaccine after 23-PPV vaccine (the response to serotype 6A will not be tested in the assay used 
in this study). Booster 13-PCV will be administered in the deltoid muscle as a single IM 
injection.


OcrelizumabF. Hoffmann-La Roche Ltd
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
Group A1 patients will receive the 13-PCV at Week 20/Day 140. Refer to the label for 
dosing and administration guidance.
Seasonal Influenza vaccine:  The influenza vaccine is indicated for immunization against 
influenza caused by the influenza strains included in the vaccine. The inactivated (or 
recombinant) vaccine has been chosen for this study to assess antibody production for a 
commonly used clinically relevant antigen. .

Group A2 patients can receive the influenza vaccine at any time between Day 85/Week 12 
and Day 140/Week 20.

Group B patients will receive the influenza vaccine as an IM injection in the deltoid muscle 
at any time between Day 1/Week 1 and Day 84/Week 12. If a patient needs to receive the 
influenza vaccine after Week 12, the optional OCR infusion must be delayed.
Statistical Methods
Primary Analysis
The proportion of patients with positive responses to TT vaccine measured 8 weeks after 
administration of the TT vaccine for Group A and Group B will be assessed.
For patients with pre-immunization tetanus antibody titers 0.1 IU/mL, a positive response to 
the booster immunization is defined as an antibody titer 0.2 IU/mL measured 8 weeks after the 
immunization.  For patients with pre-immunization tetanus antibody titers 0.1 IU/mL, positive 
response to the booster immunization is defined as a 4-fold increase in antibody titer measured 
8 weeks after the immunization.  Pre-vaccination levels are those obtained immediately prior to 
receipt of a vaccine.
Determination of Sample Size  
Approximately 100 patients will be enrolled using a 2:1 randomization ratio into active (Group A) 
and control (Group B) groups. For the positive response to TT-containing absorbed vaccine 
measured 8 weeks after the administration of vaccine, if both the control and active (OCR) 
groups have 70% response rates, the expected half width of the resulting 95% CI of the 
difference of two response rates is 0.201.


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LIST OF ABBREVIATIONS AND DEFINITIONs OF TERMS
Abbreviation
Definition
ADA
anti-drug antibody
CDI
confirmed disability improvement
CDP
confirmed disability progression
CSF
cerebrospinal fluid
CTCAE
Common Terminology Criteria for Adverse Events
DMT
disease-modifying therapy
DT
diphtheria and tetanus toxoids
Dtap
diphtheria-tetanus-acellular pertussis
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
EDSS
Expanded Disability Status Scale
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
FSS
Functional System Score
Gd
Gadolinium
GMT
geometric mean titers
HAM
HTLV-1associated myelopathy
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HepCAb
hepatitis C antibody
HI/HAI
hemagglutination inhibition
HIPAA
Health Insurance Portability and Accountability Act
HTLV-1
human Tlymphotropic virus-1
IB
investigator’s brochure
ICH
International Conference on Harmonisation
IFN
Interferon
IM
Intramuscular
IMP
investigational medicinal product
IND
Investigational New Drug (application)
IRB
Institutional Review Board
IRR
infusion-related reaction
IV
Intravenous


OcrelizumabF. Hoffmann-La Roche Ltd
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Abbreviation
Definition
IxRS
interactive response system
KLH
keyhole limpet hemocyanin
JCV
John Cunningham virus
LLN
lower limit of normal
MAID
multi-analyte immunodetection (assay)
MRI
magnetic resonance imaging
MS
multiple sclerosis
MTX
Methotrexate
NCI
National Cancer Institute
NK
natural killer
OCR
ocrelizumab
OLE
open-label extension
OOE
optional ocrelizumab extension
PCR
polymerase chain reaction
13-PCV
13-valent pneumococcal conjugate vaccine
PCV
pneumococcal conjugate vaccine
PK
Pharmacokinetic
PML
progressive multifocal leukoencephalopathy
PPMS
primary progressive multiple sclerosis
23-PPV
23-valent pneumococcal polysaccharide vaccine
PPV
pneumococcal polysaccharide vaccine
RA
rheumatoid arthritis
RMS
relapsing forms of multiple sclerosis
RPR
rapid plasma regain
RRMS
relapsing remitting multiple sclerosis
RTX
Rituximab
SC
Subcutaneous
SFU
safety follow-up
TB
tuberculosis
TCTL
cytotoxic lymphocyte T
Td
tetanus-diphtheria 
Tdap
tetanus-diphtheria-acellular pertussis
TT
tetanus toxoid
ULN
upper limit of normal


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1.
BACKGROUND
Ocrelizumab (OCR) is a recombinant humanized monoclonal antibody (mAb) that 
selectively targets CD20-expressing B cells (Klein et al. 2013).
CD20 is a cell surface antigen found on pre-B cells, mature B cells, and memory B cells 
but is not expressed on lymphoid stem cells and plasma cells (Stashenko et al. 1980; 
Loken et al. 1987; Tedder and Engel 1994). While OCR selectively depletes 
CD20-expressing B cells (Kappos et al. 2011), the capacity of B-cell reconstitution and 
preexisting humoral immunity are preserved (Martin and Chan 2006; DeLillo et al. 2008).
In addition, innate immunity and total T-cell numbers are not affected (clinical study 
report [CSR] Study WA21493/ACT4422G).
B cells are thought to play an important role in the pathogenesis of multiple sclerosis
(MS) by doing the following:

Presenting auto-antigens and co-stimulatory signals to activate T cells 
(Constant 1999; Crawford et al. 2006)

Secreting pro-inflammatory cytokines at greater relative proportions than protective 
cytokines (Duddy et al. 2007; Bar-Or et al. 2010)

Producing auto-antibodies that may cause tissue damage and activate 
macrophages and natural killer (NK) cells (Storch et al. 1998; Genain et al. 1999)

Creating meningeal lymphoid folliclelike structures, which are linked to microglia 
activation, local inflammation, and neuronal loss in the nearby cortex
(Serafini et al. 2004; Magliozzi et al. 2010)
The precise mechanisms through which OCR exerts its therapeutic clinical effects in MS 
are not fully elucidated but involve immunomodulation through the reduction in the 
number and function of B cells. These changes are thought to be responsible for the 
consequent improvement of the disease course of MS (Avivi et al. 2013).
Vaccinations against infections are an important part of the management of patients with 
MS. Exacerbations have been well documented as a consequence of infection, and 
infectious diseases have been recognized as a complication of the therapies currently 
employed in the treatment of MS. For example, influenza can cause serious 
complications and has been shown to be associated with a higher occurrence of 
exacerbations in patients with MS (De Keyser et al. 1998; Confavreux et al. 2001).  
Given the effects of OCR on B cells, an impact on immunization responses might be 
expected (Williamson and Berger 2015).  Therefore, it is important to evaluate if patients 
treated with OCR can mount protective immune responses against clinically relevant 
vaccines.
Immunization responses in patients on other anti-CD20 Bcell depleting therapies, such 
as rituximab (RTX) have been studied in rheumatoid arthritis (RA; Bingham et al. 2010). 
RTX treatment has been shown to differentially affect serum antibody levels, especially 


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IgM (Edwards et al. 2004; van Vollenhaven et al. 2010). Conversely, levels of 
IgG specific for infectious antigens, such as tetanus and pneumococcus, have 
remained stable over multiple treatment courses (Edwards et al. 2004; 
van Vollenhaven et al. 2010).
The objective of this study is to characterize the effectiveness of vaccination in patients 
with relapsing MS (RMS) undergoing treatment with OCR in a randomized, 
parallel-group, open-label trial.
1.1
BACKGROUND ON MULTIPLE SCLEROSIS 
1.1.1
Multiple Sclerosis
MS is a chronic, inflammatory, and demyelinating disease of the human CNS, which 
affects approximately 2.3 million people worldwide, with a the highest prevalence in 
North America and Europe, at 140 and 108 per 100,000, respectively (Multiple Sclerosis 
International Federation 2013).  Typically, young adults are affected; 70%80% of 
patients have an age of onset (i.e., initial clinical presentation to a physician) of between 
20 and 40 years (Anderson et al. 1992; Noonan et al. 2002).  MS is a heterogeneous 
disorder both pathophysiologically and phenotypically.  This variability can be seen, on 
the basis of clinical course, via magnetic resonance imaging (MRI) scan assessments,
and pathological analysis of biopsy and autopsy material (Luccinetti et al. 2000).  
The disease manifests itself as a variety of neurological deficits attributable to 
dysfunction of CNS components, such as the spinal cord, brainstem, optic nerve, 
cerebellum, and cerebrum.  Deficits can include weakness, loss of coordination, visual 
loss, cognitive impairment, and loss of bowel and/or bladder control, among others.  
These system-based symptoms are generally superimposed on more chronic, pervasive 
symptoms, including mood disorder, neuropathic pain, fatigue, and sexual dysfunction.
1.1.2
Ocrelizumab
OCR binds to human CD20 with high affinity, selectively depleting B cells through 
several mechanisms, including antibody-dependent cellmediated phagocytosis, 
antibodydependent cellular cytotoxicity, complement-dependent cytotoxicity, and 
induction of apoptosis.
OCR is also known as Ro 4964913, PRO70769, and rhuMAb 2H7 (refer to the 
Ocrelizumab Investigator’s Brochure for further information).
1.1.3
Sponsor Experience with Anti-CD20 Compounds in Multiple 
Sclerosis
The ongoing clinical development program to investigate the safety and efficacy of OCR 
in patients with both relapsing forms (i.e., RMS and relapsing-remitting MS [RRMS]) and 
primary progressive MS (PPMS) includes an ongoing open-label extension (OLE) of the 
Phase II Study WA21493/ACT4422G for RRMS patients and three ongoing Phase III 
pivotal trials: 2 in RMS (WA21092 and WA21093) and 1 in PPMS (WA25046).


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1.1.3.1
Ocrelizumab in Relapsing Forms of Multiple Sclerosis (RMS)
Study WA21493 (which started in January 2008) is a Phase II, randomized, multicenter, 
placebo-controlled, double-blind, dose-finding study to evaluate the efficacy and safety 
of OCR in patients with RRMS. The controlled treatment period of Study WA21493 was 
completed at Week 24, and the open-label period of the study is ongoing.  Data from the 
96-week treatment period and the 48-week treatment-free period (Week 144 data) are 
presented in the Ocrelizumab Investigator's Brochure.
Data presented below are from the completed double-blind, double-dummy treatment 
period of the two pivotal Phase III studies in RMS (Studies WA21092 and WA21093) up 
to the clinical cutoff dates of 2 April 2015 and 12 May 2015, respectively. The efficacy 
results as well as the pooled analysis from these pivotal studies show that OCR 
suppresses relapses and disease progression (clinical and subclinical disease activity) 
compared with interferon (IFN) -1a 44 g SC in patients with RMS over the course of 
2 years (96 weeks).
Efficacy outcomes were consistent between trials and across the primary and key 
clinical and imaging secondary endpoints.
In comparison with IFN -1a 44 g SC, OCR 600 mg demonstrated:

Relative reductions of 46% and 47% for the primary endpoint of protocol-defined 
annualized relapse rate in Studies WA21092 and in WA21093, respectively (both 
p0.0001)

A 40% risk reduction for 12-week confirmed disability progression (CDP) in the 
pooled Study WA21092/WA21093 analysis (p 0.0006). Each individual trial also 
demonstrated a significant reduction of 12-week CDP (43% reduction [p 0.0139] in 
Study WA21092 and 37% [p 0.0169] in Study WA21093).

Relative reductions of 94% and 95% in the number of T1 gadolinium 
(Gd)-enhancing lesions in Studies WA21092 and WA21093, respectively (both 
p 0.0001)

Relative reductions of 77% and 83% in the total number of new and/or enlarging 
T2 lesions in Studies WA21092 and WA21093, respectively (both p 0.0001)

A 33% relative increase in proportion of patients with 12-week confirmed disability 
improvement (CDI) in the pooled Study WA21092/WA21093 analysis (p 0.0194).  
Study WA20192 demonstrated a 61% relative increase in the proportion of patients 
with 12-week CDI (p 0.0106), whereas in Study WA21093, there was no 
statistically significant difference between treatment groups (14% relative increase, 
p 0.4019).

A 40% risk reduction for 24-week CDP in the pooled Study WA21092/WA21093 
analysis (p 0.0025). Each individual trial also demonstrated a significant reduction 
of 24-week CDP (43% reduction [p 0.0278] in Study WA21092 and 37% 
[p0.0370] in Study WA21093).


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
Relative reductions of 57% and 64% (both p0.0001) in the total number of new 
T1 hypointense lesions (chronic black holes) in Studies WA21092 and WA21093, 
respectively
OCR also showed numerically superior outcomes in additional secondary efficacy 
endpoints in the following hierarchical order (for results where the formal testing 
procedure had previously concluded, p-values are indicated as "non-confirmatory"):

Greater mean improvement in the Multiple Sclerosis Functional Composite Scale 
from baseline to Week 96 in Study WA21092 (p 0.3261) and Study WA21093 
(p0.0040)

Relative reduction in rate of brain volume loss from Week 24 to Week 96 of 22.8% 
in Study WA21092 (non-confirmatory, p 0.0042) and 14.9% in Study WA21093 
(p0.0900)

Higher mean change in SF-36 Physical Component Summary score from baseline 
to Week 96 in Study WA21092 (non-confirmatory, p 0.2193) and Study WA21093 
(non-confirmatory, p 0.0404)

74% and 81% relative increases in the proportion of patients with no evidence of 
disease activity in Studies WA21092 and WA21093, respectively (non-confirmatory, 
p 0.0001 for both studies in patients with Expanded Disability Status Scale 
[EDSS]2)
Robust data from the two pivotal Phase III studies WA21092 and WA21093 presented 
above provide compelling evidence of the efficacy of OCR in patients with RMS.
1.1.3.2
Safety in Multiple Sclerosis
Safety data presented below are from the completed controlled treatment periods of the 
two pivotal Phase III studies in RMS (WA21092 and WA21093) and the Phase III study 
in PPMS (WA25046). For more information on data from controlled treatment periods 
and OLE periods from ongoing studies, refer to the Ocrelizumab Investigator’s Brochure. 
In the 96-week controlled treatment period of the Phase III RMS studies (WA21092 and 
WA21093), a total of 1651 patients received study drug and were included in the safety 
analyses of the pooled data (IFN -1a: 826 patients; OCR: 825 patients).
The safety profile in the IFN -1a treatment group was consistent with the labeled safety 
information available for IFN -1a. Compared with results from the Phase II study in 
RRMS (WA21493), there were no new or unexpected safety findings associated with 
OCR during the 96-week controlled treatment period.
The number of patients who experienced any adverse event (83.3% in both groups) and 
the total number of adverse events (IFN -1a: 4141 adverse events; OCR:  4194 
adverse events) were well balanced between the two treatment groups; the majority of 
adverse events were Grade 1 or Grade 2. The proportion of patients who experienced a 
serious adverse event (IFN -1a: 8.7% vs. OCR: 6.9%) was similar between treatment 


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groups. Overall, the rates of adverse events, including serious, remained stable with 
additional exposure to OCR.
A total of 725 patients in the Phase III PPMS controlled treatment period received 
study drug and were included in the safety analysis (placebo: 239 patients; 
OCR: 486 patients). The proportion of patients who experienced at least one adverse 
event was 90% in the placebo treatment group compared with 95.1% in the OCR
treatment group; the majority of adverse events were Grade 1 or 2. The proportion of
patients who experienced a serious adverse event (placebo: 22.2% vs. OCR:  20.4%) 
was similar in both groups. The intensity of most serious adverse events was reported 
as Grade 3.
Further details are provided in the periodically updated Ocrelizumab Investigator’s 
Brochure.
To date, there are no known major safety concerns but known risks for patients being 
treated with OCR; these are discussed in Section 5.1.  Also refer to the latest 
Ocrelizumab Investigator’s Brochure.
1.1.4
Vaccine Response with Ocrelizumab
OCR significantly and rapidly reduces the number of peripheral CD20B cells. In the 
Phase II study WA21493, all patients had completely depleted CD19cells by Day 15 
(99% mean and median change from baseline) and by Week 24, no patient had 
demonstrated any return of peripheral CD19cell counts to baseline values or to the 
lower limit of normal (LLN) of 80 cells/L, (i.e., the protocol-defined measure of 
recovery). B cells repleted for 50% of the patients in all treatment groups by 
Week 144, except for in the OCR 1000 mg group (where 56.4% of the patients were still 
depleted at Week 144). The relevance of patients not having repleted B-cell levels 
(i.e., returned to LLN or baseline) to their response to vaccination is not known.
Results from the Immunization Study Period of this study BN29739 indicate that patients 
being treated with OCR may have an attenuated humoral response when immunized 
with an inactivated vaccine.  The detailed BN29739 study results can be found in the 
current version of the Ocrelizumab Investigator's Brochure.
An integrated analysis of MS patients treated with OCR treatment revealed that after 
treatment with OCR over 2 years, the proportion of patients with positive antibody titers 
against Streptococcus pneumoniae, mumps, rubella, and varicella was generally similar 
to the proportions at baseline. 
1.2
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
This study (BN29739) is being performed to characterize humoral immunity to a variety 
of antigens by evaluating immunization responses in patients with RMS who are treated 
with OCR. 


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This study plans to use the following vaccines to evaluate different immune response 
pathways after administration of a course of OCR in patients with RMS:

The TT-containing vaccination was chosen to assess the T-cell dependent 
anamnestic humoral response.

The 23-valent PPV (23-PPV) vaccination was chosen to assess a mostly T-cell 
independent or pure ‘B-cell’ humoral response.

KLH was chosen to explore immune response to neo-antigen.

The influenza vaccination was chosen as it is considered important from a clinical 
perspective. 

The booster 13-valent conjugate pneumococcal vaccine (13-PCV) was chosen to 
assess the clinical efficacy of the 23-PPV vaccine followed by the booster 13-PCV 
compared to 23-PPV vaccine alone.
Characterization of the humoral immune response in RMS patients who have received 
OCR will provide guidance regarding the efficacy and safety of vaccine administration in 
these patients. Please refer to Section 3.1 for further details on study design.
Substantial measures have been taken to enroll only appropriate patients and to 
decrease the risk to patients who participate in this study.  Refer to eligibility criteria in 
Section 4.1 and the safety plan in Section 5.1, respectively.
2.
OBJECTIVES
2.1
PRIMARY OBJECTIVE
The primary objective for this study is as follows:

To characterize the humoral immune response (IgG) to TT vaccine in patients with 
RMS who are treated with OCR (Group A), compared with that of patients with RMS
who are not treated with OCR (Group B).
2.2
SECONDARY OBJECTIVES
The secondary objectives of this study are:
1.
To characterize the humoral immune response (IgG) to the 23-PPV in Group A
(Groups A1 and A2) patients compared with Group B patients.
2.
To characterize the humoral immune response (IgG) in OCR-treated patients to 
23-PPV boosted by a subsequent 13-PCV booster (Group A1) compared with 
unboosted 23-PPV (Group A2).
3.
To characterize the humoral immune response (IgG and IgM) to KLH in Group A 
patients compared with Group B patients.
4.
To characterize the humoral immune response (HI titers) to influenza vaccine in 
OCR-treated patients (Group A2) patients compared with patients not treated with 
OCR (Group B).


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5.
To evaluate the long-term effects of OCR on MRI parameters of disease activity 
during the Optional Ocrelizumab Extension (OOE) Period of the study. 
Group A will be split into Group A1 (patients will receive the booster 13-PCV), and 
Group A2 (patients will receive the influenza vaccine; see Section 3.1).
2.3
SAFETY OBJECTIVES
The safety objectives for this study are to collect additional data on the safety of OCR.
3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
This Phase IIIb, multicenter, randomized, open-label study is designed to evaluate 
immune response to vaccines after administration of a dose of OCR (i.e., a dual infusion
of OCR 300 mg on Day 1/Week 1 [Dose 1 Infusion 1] and Day 15/Week 2 [Dose 1 
Infusion 2]) in patients with RMS.
Following screening, approximately 100 adult patients will be randomized into Groups A 
and B (2:1; active:control) to compare responses to immunization. Patients in Group B 
are to receive immunization with TT-containing adsorbed vaccine, 23-PPV, influenza 
vaccine, and repeated administration with KLH. Group B patients will not receive OCR 
but will remain on no MS-specific disease-modifying therapy (DMT) or continue with 
IFN-treatment until optional OCR treatment at the end of the Immunization Study 
Period. 
Patients in Group A are to first receive OCR (Day 1/Week 1 [Dose 1 Infusion 1] and 
Day 15/Week 2 [Dose 1 Infusion 2]), and 12 weeks post-OCR treatment, are to receive a 
similar immunization course to Group B. Group A will be further subdivided into 
two groups to evaluate the effectiveness of a booster 13-PCV vaccination or of influenza 
vaccination.
For the primary objective and for secondary objectives 1 and 3 (see Sections 2.1 and 
2.2, respectively), Group A (active) will be compared with Group B (control).
To determine the outcomes of secondary objectives 2 and 4, patients in Group A will be 
split into two groups with 50% of patients in each group (Groups A1 and A2).  Patients 
will be assigned to either Group A1 or A2:

Group A1 will receive booster 13-PCV (approximately 33 patients)

Group A2 will receive the influenza vaccine (approximately 33 patients but a 
minimum of 30 patients).
A minimum of 30 patients will be assigned to Group A2 during the first influenza season.  
If a minimum of 30 patients (a maximum of 33) are assigned to Group A2 and receive 
the first year's influenza vaccine, all remaining patients in Group A will be assigned to 


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Group A1 and receive the 13-PCV booster. If less than 30 patients have been assigned 
to Group A2 during the first influenza season, further patients assigned to Group A2 will 
have influenza vaccine visits during the subsequent influenza season (i.e., when the 
next year’s vaccine becomes available).
The primary and secondary humoral immunity and immunophenotyping outcomes are to 
be measured by flow cytometry and quantitative Ig measurements.
Approximately 3035 centers will participate in the study in the United States/
North America.  This study consists of up to five study periods:

Screening Period

Immunization Study Period
Group A: Immunization Study Period and OCR treatment starts at Day 1/Week 1.  
Patients will receive 300 mg of open-label OCR on Day/Week 1 (Dose 1 Infusion 1)
and Day 15/Week 2 (Dose 1 Infusion 2). Patients in Group A will be split and be 
assigned to either Group A1 (booster 13-PCV) or Group A2 (influenza vaccine).    
At Day 85/Week 12 patients will start to receive immunizations and undergo 
post-immunization assessments. For all patients in Group A, the Immunization 
Study Period will end on Day 169/Week 24.
Group B:  Patients will not receive OCR. At Day 1/Week 1, patients will start to 
receive immunizations and undergo post-immunization assessments. For Group B, 
the Immunization Study Period will end at Day 84/Week 12.
The timing of immunizations and post-baseline assessments are detailed in 
Appendix 1.

Optional OCR Extension (OOE) Period: 
–
Groups A1 and A2:  Patients who complete the 24week immunization study 
period will have the option for retreatment with a single infusion of 600 mg OCR 
(Dose 2) at Day 169/Week 24 and subsequent single infusions (600 mg OCR) 
at intervals of 24 weeks provided that he or she meets the OOE retreatment 
criteria and chooses to receive retreatment.
–
Group B:  Patients who complete the 12week immunization study period will 
have the option to receive OCR in the OOE; the first dose will be administered 
as two single infusions of 300 mg, on Day 84/Week 12 (Dose 1 Infusion 1) and 
Day 98/Week 14 (Dose 1 Infusion 2), and subsequent doses will be 
administered as single 600 mg infusions (Dose 2, Dose 3, etc.) at intervals of 
24 weeks provided that he or she meets the OOE retreatment criteria and
chooses to receive retreatment.  Group B patients who do not qualify for and/or 
do not choose treatment with OCR at Week 12 will complete the study at 
Week 12 and will not enter safety follow-up.


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Please note that the OOE will continue with all patients who are able to receive 
OCR as per local guidelines, or unless the Sponsor decides to terminate the 
OCR program for MS; however, the OOE will not exceed 4 years after the last 
patient last visit in the Immunization Study Period. At the end of the OOE, 
patients may choose to continue on commercially available OCR.

Safety Follow-Up (SFU) Period:  Patients who discontinue treatment early for any 
reason and patients who complete the study treatment period will be followed up 
for 48 weeks after the last infusion of OCR. When patients begin an alternative 
treatment for MS (see Section 4.6.3.1 on prohibited therapies), or start treatment 
with commercial OCR, they will be discontinued from the SFU and from the study.
A schedule of assessments is provided in Appendix 1.  Study Schemas are provided in 
Figure 1 and Figure 2.
Figure 1
Schema of Study Periods
OCRocrelizumab; OOEOptional Ocrelizumab Extension Period; SFUsafety follow-up.


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Figure 2
Study Schema


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Figure 2
Study Schema (cont.)
KLHkeyhole limpet heamocyanin; OCR ocrelizumab; PCVpneumococcal conjugate vaccine; PPVpolysaccharide pneumococcal vaccine; 
TTtetanus toxoid-containing vaccine; Wkweek
Influenza vaccine: Group B: The influenza vaccine can be given any time between Week 1 and 12. If a patient needs to receive the vaccine 
after Week 12, the OCR infusion can be delayed. For patients in Group A2 and Group B who, as per the Schedule of Assessment, are due to 
receive the influenza vaccine during their country-specific influenza vaccine blackout period, administration of the vaccine should be given prior to 
the start of this blackout period.
*Group A split: Patients assigned to Group A2 will receive the influenza vaccine. Patients assigned to Group A1 will receive the 13-PCV booster.


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3.2
END OF STUDY
The end of study is defined as the last patient last visit in the Safety Follow-Up Period.
3.3
RATIONALE FOR STUDY DESIGN
The primary objective of this study is to characterize the effects of OCR on immune 
responses in patients with RMS as measured by vaccine titers. The randomized,
open-label nature of this study is not expected to significantly affect vaccine titers in 
either Group A or B (active or control, respectively). 
3.3.1
Rationale for Specific Antigens
This trial will investigate the effect of B-cell depletion by OCR on primary humoral 
response, recall response, and persistent acquired immunity to specific antigens.

A TT-containing adsorbed vaccine will be administered to assess whether one dose 
of OCR affects the integrity of a T-celldependent anamnestic humoral response.

A 23-valent PPV has been selected to assess a mostly T-cell independent or ‘pure 
B-cell’ humoral response for a clinically relevant antigen.    

KLH will be used to test primary humoral neoantigen response as it is a novel 
immunogen for most individuals.

An influenza vaccine has been selected to test the ability to mount a humoral
immune response to a clinically relevant vaccine.
3.3.2
Rationale for Timing of Vaccinations
Experience with OCR in MS in the Phase II study (Study WA21493/ACT4422G) has 
determined that the majority of patients are still peripherally CD19positive B-cell 
depleted between 12 and 24 weeks post-treatment.  Therefore, Day 85/Week 12 is an 
appropriate time to begin vaccinations in patients to evaluate the effect of peripheral 
CD19positive B-cell depletion by OCR on immune response to vaccination.  
3.3.2.1
Tetanus Toxoid Adsorbed Vaccine
TT vaccine will be administered as a combined adsorbed vaccine with diphtheria
(tetanus-diphtheria [Td] or diphtheria and tetanus toxoid [DT]) or with diphtheria and
acellular pertussis (diptheria-tetanus-acellular pertussis [DTaP] or 
tetanus-diphtheria-acellular pertussis [Tdap]). 
Group A (active) patients will receive a TT-containing vaccine 12 weeks after the first 
OCR administration. Serum anti-tetanus titers will be measured 4 and 8 weeks after 
vaccine administration and compared with levels immediately prior to vaccine 
administration.
Group B (control) patients will not receive OCR during the Immunization Study Period.
They will receive a TT-containing vaccine at Day 1/Week 1.  Serum anti-tetanus titers
will be measured 4 and 8 weeks after vaccine administration (Day 28/Week 4 and


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Day 56/Week 8) and will be compared with levels immediately prior to vaccine 
administration.
3.3.2.2
23-Valent Pneumococcal Polysaccharide Vaccine
The 23-PPV will be administered to Group A (active) patients 16 weeks after the first 
OCR administration. Serum titers against all 23 serotypes (1, 2, 3, 4, 5, 6b, 7F, 8,9N, 
9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F and 33F) will be 
measured 4 and 8 weeks after vaccine administration and will be compared with levels 
immediately prior to vaccine administration.
Group B patients will receive the 23-PPV vaccine at Day 28/Week 4. Serum titers will be 
measured 4 and 8 weeks after vaccine administration and will be compared with levels 
immediately prior to vaccine administration.
3.3.2.3
Keyhole Limpet Hemocyanin
Group A (active) patients will receive KLH at 12, 16, and 20 weeks after OCR
administration. Serum titers will be measured 4, 8, and 12 weeks after the initial KLH 
administration (Day 112/Week 16, Day 140/Week 20, and Day 169/Week 24) and will be 
compared with levels immediately prior to the first KLH administration.
Group B patients will receive KLH at Day 1/Week 1, Day 28/Week 4, and 
Day 56/Week 8. Serum titers will be measured 4 weeks after KLH administration 
(Day 28/Week 4, Day 56/Week 8, and Day 84/Week 12) and will be compared with 
levels immediately prior to the first KLH administration.
3.3.2.4
Influenza Vaccine 
Group A (active) patients are to be split and patients assigned to Group A2 will receive 
the influenza vaccine after OCR administration (refer to Section 3.1 for details on the 
assignment on patients to Group A1 or A2). Patients can receive the influenza vaccine 
at any time between Weeks 12 and 20. Serum titers will be measured 4 weeks after the
initial vaccine administration and will be compared with levels immediately prior to 
vaccine administration. 
Group B patients can receive the influenza vaccine between Week 1 and 12. 
If necessary, Group B patients can receive the influenza vaccine after Week 12, in which 
case the OCR infusion visit must be delayed. Serum titers will be measured 4 weeks 
after vaccine administration and will be compared with levels immediately prior to 
vaccine administration.
Group A1 patients can receive the influenza vaccine at any time at the discretion of the 
investigator.
3.3.2.5
Conjugate Pneumococcal Vaccine Booster (13-PCV)
Group A (active) patients will be split at randomization and approximately 33 patients will 
be in Group A1 and receive a booster 13-PCV at Day 140/Week 20 (refer to Section 3.1


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for details on the assignment on patients to Group A1 or A2). Serum antibody titers will 
be measured 4 weeks after the booster 13-PCV administration (Day 169/Week 24).
3.3.3
Rationale for Ocrelizumab Dose Selection
The dose of 600 mg of OCR administered intravenously (IV; given as dual infusions of 
300 mg on Days 1 (Dose 1 Infusion 1) and 15 (Dose 1 Infusion 2) for the first dose and 
subsequently as a single infusion of 600 mg every 24 weeks) is under investigation in 
the Phase III RMS clinical program. This has been selected as a clinically appropriate
dose based on the results from Study WA21493/ACT4422g.
3.3.4
Rationale for Group B
In Group B, patients will be eligible for the study provided that they are on no 
MS-specific DMT or continuing with IFN-treatment.
Group B patients will enter the study on their current IFN-MS treatment or remain on 
no MS-specific DMT until Week 12 at which point they can receive OCR
(300 mg2 infusions at Day 84/Week 12 and Day 98/Week 14). The study has been
designed with the shortest Immunization Study Period feasible for patients in Group B 
before they can receive OCR.
3.3.5
Rationale for the Safety Follow-Up Period
Data collected during this period will allow evaluation of safety after OCR treatment is 
stopped.
3.4
OUTCOME MEASURES 
3.4.1
Primary Immunization Outcome Measure
The primary outcome measure is the proportion of patients in Groups A (i.e., combined
Groups A1 and A2) and B with a positive response (IgG) to TT vaccine measured 
8 weeks after TT vaccine administration. 
For patients with pre-immunization tetanus antibody titers 0.1 IU/mL, a positive 
response to the booster immunization is defined as an antibody titer 0.2 IU/mL 
measured 8 weeks after immunization. For patients with pre-immunization tetanus 
antibody titers 0.1 IU/mL, positive response to the booster immunization is defined as 
a 4-fold increase in antibody titers compared with pre-vaccination levels measured 
8 weeks after immunization.  Pre-immunization levels are those obtained immediately 
prior to administration of a vaccine.


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3.4.2
Secondary Outcome Measures
The secondary outcome measures are as follows: 

TT response:
–
The proportion of patients in Groups A (A1 and A2) and B with a positive 
response (IgG) to TT vaccine measured 4 weeks after TT vaccine 
administration.
–
The proportion of patients in Groups A (A1 and A2) and B with a 2-fold increase 
in tetanus antibody titers, or with tetanus antibody titers0.2 IU/mL, measured 
4 weeks after the immunization of patients with pre-immunization tetanus 
antibody titers0.1 IU/mL or with pre-immunization tetanus antibody 
titers0.1 IU/mL, respectively.
–
Mean levels of anti-tetanus antibody in patients in Groups A (A1 and A2) and B 
measured immediately prior to and 4 weeks after a booster TT vaccine. 

Pneumococcal vaccine response:
–
The proportion of patients in Groups A (A1 and A2) and B with positive antibody
responses against an individual pneumococcal serotype measured 4 weeks 
after the 23-PPV (23 serotypes). (A positive response against a serotype is 
defined as developing a 2-fold increase in antibody level or a 1 g/mL rise in 
level compared with pre-immunization levels. Pre-immunization levels are 
those obtained immediately prior to receipt of 23-PPV.) Post-immunization 
levels will be measured 4 and 8 weeks after 23-PPV administration for Groups
A1, A2, and B.
–
The proportion of patients in Groups A (A1 and A2) and B with a positive 
response against at least 2 out of 23 pneumococcal antibody serotypes 
measured 4 weeks after administration of 23-PPV vaccine.
–
The proportion of patients in Groups A (A1 and A2) and B with positive 
responses against at least 50% of the serotypes (12 of 23) measured 4 weeks 
after administration of 23-PPV vaccine. 
–
Mean levels of anti-pneumococcal serotype-specific antibody in patients in 
Groups A (A1 and A2) and B measured immediately prior to and 4 and 8 weeks 
(which is 4 weeks after Group A1 patients received the 13-PCV booster) after 
administration of 23-PPV vaccine. 

KLH response:
–
Mean levels of anti-KLH antibody (IgG and IgM) in patients in Groups A 
(A1 and A2) and B measured immediately prior to the first administration of KLH 
and 4 weeks after the last administration of KLH.
–
Mean levels of anti KLH antibodies (IgG and IgM) in patients in Groups A 
(A1 and A2) and B measured over time at 4, 8, and 12 weeks after first KLH 
administration.


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
Strain-specific influenza vaccine response in Groups A2 and B:
–
Proportion of patients who achieve seroprotection defined as specific
HI titers40 at 4 weeks post-immunization
–
Proportion of patients who achieve a 2-fold increase in specific HI titers at 
4 weeks post-immunization
–
Proportion of patients who achieve a 4-fold increase in specific HI titers at 
4 weeks post-immunization
–
Proportion of patients with seroconversion (i.e., a pre-vaccination antibody 
titer10 and a post-vaccination HI titer40); 
–
Strainspecific geometric mean titers (GMTs) at baseline and at 4 weeks 
post-vaccination
–
Strainspecific GMT ratio (post-vaccination:pre-vaccination)

MRI assessments to evaluate the long-term effects of OCR on MRI parameters of 
disease activity during the OOE Period.
3.4.3
Immunophenotyping Outcome Measures
The humoral and cellular immunity outcome measures in this study are as follows:

Flow cytometry, which will include (but is not limited to) the following cells:
–
Total B cells (CD19 positive)
–
B-cell subsets, e.g., memory B cells, naïve B cells, plasma cells
–
Total T cells (CD3 positive)
–
T helper cells (CD3 positive, CD4 positive)
–
Cytotoxic T lymphocytes (TCTL; CD3 positive, CD8 positive)
–
NK cells (CD3 negative, CD16/56 positive)

Quantitative Ig: Ig levels (including total Ig, IgG, IgG subtypes, IgM, and IgA) 
3.4.4
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Vital signs*, hematologic laboratory tests, anti-drug antibody (ADA) formation,
physical and neurological examinations, and the incidence and severity of adverse 
events associated with OCR and study immunizations.
*To monitor infusion-related reactions (IRRs), vital signs will be obtained immediately 
pre-infusion, every 15 (5) minutes for the first hour during the infusion, every 
30 (5) minutes for the remainder of the infusion, and at the end of the infusion on days 
of OCR administration. 


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4.
MATERIALS AND METHODS
4.1
PATIENTS
Adult patients with RMS who fulfill the eligibility criteria specified in Sections 4.1.1 and 
4.1.2 are eligible for enrollment into the study. For the eligibility criteria for the OOE
period, see Section 4.1.3 and Section 4.1.4.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Ability to provide written informed consent and to be able to follow the 
protocoldefined schedule of assessments

Diagnosis of RMS in accordance with the revised McDonald criteria (Polman et al. 
2011)

Age 1855 years, inclusive

Received at least one previous immunization against TT or tetanus and diphtheria 
(DT/Td) or tetanus, diphtheria, and acellular pertussis (DTaP/Tdap).

Expanded Disability Status Scale (EDSS) at screening from 05.5 points, inclusive

Contraception requirements:
–
For sexually active female patients of reproductive potential, use of reliable 
means of contraception as described below as a minimum (adherence to local 
requirements, if more stringent, is required):*
–
One primary method of contraception throughout the trial, including the 
active treatment phase AND for 6 months after the last dose of OCR. 
*Acceptable methods of contraception include one primary (e.g., systemic 
hormonal contraception or tubal ligation, vasectomy of the male partner) OR a 
double-barrier method (e.g., latex condom, intrauterine device, vaginal ring or 
pessary plus spermicide [e.g., foam, vaginal suppository, gel, cream]).
–
For female patients without reproductive potential: 
–
Women may be enrolled if post-menopausal (i.e., spontaneous 
amenorrhea for 12 months confirmed by a follicle stimulating hormone 
[FSH] level 40 mIU/mL) unless the patient is receiving a hormonal therapy 
for her menopause; or surgically sterile (i.e., hysterectomy, complete 
bilateral oophorectomy).


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4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Contraindications for or intolerance to oral or IV corticosteroids, including 
methylprednisolone administered IV, according to the country label, including:
–
Psychosis not yet controlled by a treatment
–
Hypersensitivity to any of the constituents

Known presence of other neurologic disorders, including but not limited to, the 
following:
–
History of ischemic cerebrovascular disorders (e.g., stroke, transient ischemic 
attack) or ischemia of the spinal cord
–
History or known presence of CNS or spinal cord tumor (e.g., meningioma, 
glioma)
–
History or known presence of potential metabolic causes of myelopathy 
(e.g., untreated vitamin B12 deficiency)
–
History or known presence of infectious causes of myelopathy (e.g., syphilis, 
Lyme disease, human Tlymphotropic virus-1 [HTLV-1], herpes zoster 
myelopathy)
–
History of genetically inherited progressive CNS degenerative disorder 
(e.g., hereditary paraparesis; mitochondrial myopathy, encephalopathy, lactic 
acidosis, and stroke syndrome)
–
Neuromyelitis optica
–
History or known presence of systemic autoimmune disorders that potentially 
cause progressive neurologic disease (e.g., lupus, anti-phospholipid antibody 
syndrome, Sjögren’s syndrome, Behçet’s disease)
–
History or known presence of sarcoidosis
–
History of severe, clinically significant brain or spinal cord trauma (e.g., cerebral
contusion, spinal cord compression)
–
History of PML

Patients who meet the following criteria related to their general health will be 
excluded:
–
Pregnancy or lactation
–
Lack of peripheral venous access
–
History of severe allergic or anaphylactic reactions to humanized or murine 
monoclonal antibodies
–
Known hypersensitivity to any component of the TT-containing adsorbed 
vaccine, including thiomersal (thimerosal in United States)
–
History of systematic allergic, neurologic, or other reactions following a previous 
dose of any TT-containing vaccine


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–
Known hypersensitivity to any component of any pneumococcal polysaccharide 
or conjugate vaccine
–
Known hypersensitivity to any component of the influenza vaccine 
–
Allergy to shellfish
–
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 a patient from participating in the study
–
Congestive heart failure (New York Heart Association III or IV functional 
severity)
–
Known active bacterial, viral, fungal, mycobacterial infection or other infection 
(including tuberculosis [TB] or atypical mycobacterial disease [but excluding
fungal infection of nail beds]) or any major episode of infection requiring 
hospitalization or treatment with IV antibiotics within 4 weeks prior to baseline 
visit or oral antibiotics within 2 weeks prior to baseline visit
–
History or known presence of recurrent or chronic infection (e.g., HIV, 
syphilis, TB)
–
History of recurrent aspiration pneumonia that required antibiotic therapy
–
History of cancer, including solid tumors and hematological malignancies 
(except basal cell, in situ squamous cell carcinomas of the skin, and in situ 
carcinoma of the cervix of the uterus that have been excised and resolved, with 
documented clean margins on pathology)
–
Any concomitant disease that may require chronic treatment with systemic 
corticosteroids or immunosuppressants during the course of the study
–
History of alcohol or drug abuse within 24 weeks prior to randomization
–
History of or currently active primary or secondary immunodeficiency 

Treatment with any investigational agent within 24 weeks of screening (Visit 1) or 
5 half-lives of the investigational drug, whichever is longer, or treatment with any 
experimental procedure for MS (e.g., treatment for chronic cerebrospinal venous 
insufficiency)

Receipt of any pneumococcal vaccine within 5 years prior to screening

Previous exposure to KLH

Previous immunization with any tetanus-containing vaccine within 2 years prior to 
screening

If scheduled as per protocol to receive the 2015/2016 vaccine and has already 
received the 2015/2016 vaccine or if scheduled as per protocol to receive the 
2016/2017 vaccine and has already received the 2016/2017 vaccine.


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
Receipt of a live vaccine within 6 weeks prior to randomization*
*Vaccinations before baseline: in rare cases where a live vaccine must be 
administered by the patient’s physician, the screening period may need to be 
prolonged but cannot exceed 8 weeks.

Previous treatment with B-cell targeted therapies (e.g., RTX, OCR, atacicept, 
belimumab, or ofatumumab)

Any previous treatment with alemtuzumab, anti-CD4, cladribine, cyclophosphamide, 
mitoxantrone, azathioprine, mycophenolate mofetil, cyclosporine, MTX, total body 
irradiation, or bone marrow transplantation

Any previous treatment with lymphocyte-trafficking blockers (e.g., natalizumab, 
fingolimod)

Treatment with  IV Ig, plasmapheresis, teriflunomide or dimethyl fumarate, or 
glatiramer acetate within 12 weeks prior to randomization*

Systemic corticosteroid therapy within 4 weeks prior to screening**
* Patients screened for this study should not be withdrawn from therapies for the 
sole purpose of meeting eligibility criteria 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 not receive RMS diseasemodifying therapies.  Group B patients 
can continue with IFN-treatment. If the patient has received teriflunomide he or 
she may need to go through the accelerated elimination protocol (Genzyme 2013).
**The screening period may be extended (but cannot exceed 8 weeks) for patients 
who have used systemic corticosteroids for RMS before screening. In addition, for a 
patient to be eligible, systemic corticosteroids should not have been administered 
between screening and baseline.

Exclusions related to laboratory findings:*
–
Positive serum -human chorionic gonadotropin (hCG) measured at screening
–
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 polymerase chain reaction [PCR]), or hepatitis C antibody 
(HepCAb) 
–
Positive rapid plasma reagin (RPR), if confirmed by microhemagglutination 
assay or fluorescent treponemal antibody absorption test
–
CD4 count300/L
–
Serum creatinine1.4 mg/dL (124 mol/L) for women or1.6 mg/dL 
(141 mol/L) for men
–
AST/SGOT or ALT/SGPT2.0upper limit of normal (ULN)
–
Platelet count100,000/L (100109/L)
–
Hemoglobin8.5 g/dL (5.15 mmol/L)


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–
ANC1.5103/L
–
Levels of serum IgG 18% below the LLN (for central laboratory:  IgG4.6 g/L)
–
Levels of serum IgM 8% below the LLN (for central laboratory: IgM0.37 g/L)
* Retesting before baseline: in rare cases in which the screening laboratory 
samples are rejected by the central laboratory (example: hemolyzed sample) or the 
result is not assessable (example: indeterminate) or abnormal, the tests need to be 
repeated within 4 weeks. Any abnormal screening laboratory value that is clinically 
relevant should be retested in order to rule out any progressive or uncontrolled 
underlying condition. The last value before randomization must meet study criteria. 
In such circumstances, the screening period may need to be prolonged but cannot 
exceed 8 weeks.
Based on local Ethics Committees or National Competent Authority requirements, 
additional diagnostic testing may be required for selected patients or selected 
centers to exclude TB (e.g., chest X-ray, tuberculin skin or blood test), Lyme 
disease, HTLV-1associated myelopathy (HAM), AIDS, hereditary disorders, 
connective tissue disorders, or sarcoidosis. Other specific diagnostic tests may be
requested when deemed necessary by the investigator.
4.1.3
Eligibility for the Optional Ocrelizumab Extension Period
Only patients who have completed the Immunization Study Period are potentially eligible 
for the Optional OCR Extension Period.
Prior to re-treatment with OCR, patients will be evaluated for the following conditions and 
laboratory abnormalities. 
4.1.4
Re-treatment Criteria
Prior to re-treatment, the following conditions must be met:

Absence of severe allergic or anaphylactic reaction to a previous OCR infusion

Absence of any significant or uncontrolled medical condition or treatment-emergent, 
clinically significant laboratory abnormality

Absence of active infection (including active TB infection, either new onset or 
reactivation)*

ANC1.5103/L

CD4 cell count250/L

IgG3.3 g/L

Negative pregnancy test **
If any of the conditions are not met prior to re-treatment, further administration of OCR 
should be suspended until resolved or held indefinitely.
* Patients with active TB infection, either new onset or reactivation, must suspend 
ocrelizumab treatment for as long as needed to ensure full resolution of the TB 


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infection.  These patients should receive medical care in adherence with 
local/national requirements until complete resolution of the TB infection and should 
be monitored subsequently as per local medical plans.  Upon resolution of the TB 
infection and based on individual benefit-risk assessments, these patients will have 
the opportunity to re-start ocrelizumab treatment if it is considered beneficial for 
them.  Otherwise, the treating Investigator can decide to permanently stop 
ocrelizumab.
** 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 assessments for the OOE; 
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.  In the OOE period of the 
study, re-start of ocrelizumab treatment following pregnancy and breastfeeding will 
be decided as a result of a thorough benefit/risk discussion between the patient and 
investigator.
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
Subjects will be randomized in a 2:1 ratio to Group A (OCR) or Group B.
Randomization will be performed by an independent vendor via an interactive response 
system (IxRS).
4.3
STUDY TREATMENT 
4.3.1
Formulation, Packaging, and Handling
Study drug packaging will be overseen by the Roche clinical trial supplies department 
and bear a label with the identification required by local law, the protocol number, drug 
identification, and dosage.
The packaging and labeling of the study drug will be in accordance with Roche 
standards and local regulations.
Upon arrival of investigational products at the site, site personnel should check them for 
damage and verify proper identity, quantity, integrity of seals and temperature 
conditions, and report any deviations or product complaints to the monitor upon 
discovery.
Ocrelizumab Formulation
OCR is a clear or slightly opalescent, colorless to pale brown solution supplied as a 
liquid formulation containing 30 mg/mL OCR in 20 mM sodium acetate at pH 5.3, with 
4% (106 mM) trehalose dihydrate and 0.02% polysorbate 20.  The drug product is 
provided as a single-use liquid formulation in a 15 cc Type I USP glass vial, fitted with a 


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20 mm fluoro-resin laminated stopper and an aluminum seal with a flip-off plastic cap 
and contains a nominal 300 mg OCR.  No preservative is used as each vial is designed 
for single use.
Ocrelizumab Packaging
The hospital units/pharmacy will receive study medication kits for each patient.
Each study medication kit will contain one single-use liquid vial OCR. 
For Dose 1, consisting of two 300 mg infusions 14 days apart, one study medication kit
will be used per visit.
For subsequent doses, a 600 mg OCR infusion in the OOE, two study medication kits 
will be used per visit. 
Ocrelizumab Preparation
OCR drug product must be diluted before administration. Solutions of OCR for IV
administration are prepared by dilution of the drug product into an infusion bag 
containing 0.9% sodium chloride, to a final drug concentration of 12 mg/mL.
Detailed instructions are provided in the Dose Preparation Guidelines.
Storage of Ocrelizumab Vials for Infusion
OCR vials are stable at 2C8°C (refrigerated storage).  They should not be used 
beyond the expiration date.  Expiration dating may be extended during the trial; the 
Sponsor will provide documentation.  OCR vials should not be frozen or shaken and 
should be protected from direct sunlight.  The study drug labels will be produced in 
accordance with the local requirements.
The prepared infusion solution of OCR is physically and chemically stable for 24 hours at 
2C8C and subsequently for 8 hours at room temperature.  The prepared infusion 
solution should be used immediately. If not used immediately, it can be stored for up to 
24 hours at 2C8C. Infusion solution must be completely administered to the patient 
within 32 hours of preparation (not to exceed 24 hours at 2C8C and 8 hours at room 
temperature). 
In the event an IV infusion cannot be completed the same day, the remaining solution 
should be discarded.
4.3.2
Dosage, Administration, and Compliance
4.3.2.1
Ocrelizumab
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 to 0.22 m). OCR may contain 
fine translucent and/or reflective particles associated with enhanced opalescence. Do 
not use the solution if it is discolored or if the solution contains discrete foreign 
particulate matter.


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Mandatory premedication is required prior to any infusion with OCR (see Section 4.4.1).
During the Immunization Study Period:

Patients in Group A will be administered OCR by IV infusion at a dose of 300 mg on 
Day 1/Week 1 (Dose 1 Infusion 1) and Day 15/Week 2 (Dose 1 Infusion 2).

Patients in Group B will not receive any OCR.
During the OOE, for patients who meet the criteria for optional OCR treatment (refer to 
Section 4.1.3 and Section 4.1.4):

Patients from Groups A1 and A2 will be administered OCR by IV infusion at a dose 
of 600 mg on Day 169/Week 24 (Dose 2) and subsequent 600 mg single infusions 
with an interval of 24 weeks (minimum interval of 22 weeks).

Patients from Group B will be administered OCR by IV infusion at a dose of 300 mg 
on Day 84/Week 12 (Dose 1 Infusion 1) and Day 98/Week 14 (Dose 1 Infusion 2)
and at a dose of 600 mg on Day 252/Week 36 (Dose 2) and subsequent 600 mg 
single infusions with an interval of 24 weeks (minimum interval of 22 weeks).
4.4
NON-INVESTIGATIONAL MEDICINAL PRODUCTS
4.4.1
Premedication
Premedication is mandatory with methylprednisolone 100 mg IV 30 minutes prior to each 
infusion of OCR, and with an antihistaminic drug (e.g., diphenhydramine) approximately 
3060 minutes prior to each infusion of OCR.  In the rare case when the use of 
methylprednisolone is contraindicated for the patient, an equivalent dose of an 
alternative steroid should be used as premedication prior to the infusion.
Pre-infusion treatment with an oral analgesic/antipyretic (e.g., acetaminophen)
3060 minutes prior to each infusion of OCR is also recommended.
4.4.2
Immunizations 
4.4.2.1
Tetanus Toxoid Vaccine
TT vaccine is indicated for the prevention of tetanus. The TT vaccine will be 
administered as part of the combined adsorbed vaccine with diphtheria (Td/DT) and/or 
acellular pertussis (DTaP/Tdap). In this study, TT adsorbed vaccine is being used to 
assess whether OCR affects antibody production to an antigen to which individuals have 
pre-existing immunity.
Group A patients will receive a TT-containing adsorbed vaccine (0.5 mL) as an 
intramuscular (IM) injection in the deltoid muscle at Day 85/Week 12.
Group B patients will receive a TT-containing adsorbed vaccine ([0.5 mL) as an IM 
injection in the deltoid muscle on Day 1/Week 1.


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4.4.2.2
23-Valent Pneumococcal Polysaccharide Vaccine
The 23-PPV is indicated for immunization against pneumococcal disease caused by 
those pneumococcal serotypes included in the vaccine.  It has been chosen for this 
study to assess antibody production for a clinically relevant antigen that is unknown to 
most individuals. The 23-PPV will be administered in the deltoid muscle as a single 
IM injection.
Group A patients will receive the 23-PPV vaccine (0.5 mL) as an IM injection in the 
deltoid muscle at Day 112/Week 16.
Group B patients will receive the 23-PPV (0.5 mL) as an IM injection in the deltoid 
muscle at Day 28/Week 4.
4.4.2.3
Keyhole Limpet Hemocyanin
KLH is a high molecular weight respiratory metalloprotein found in the hemolymph of 
many mollusks and crustaceans.  However, KLH does not have regulatory approval and 
is not marketed. Therefore, it may be considered an investigational medicinal product 
(IMP) in some regions. KLH has been used in global clinical trials as a challenge agent 
to evaluate patient’s immune responses to neo-antigen (Mestecky et al. 2005; 
Miller et al. 2005; Spazierer et al. 2009).  In this study, KLH will be used to test primary 
humoral response following B-cell depletion with OCR.
Group A patients will receive subcutaneously (SC) administered KLH (1 mg) at 
Day 85/Week 12, Day 112/Week 16, and Day 140/Week 20.
Group B patients will receive SC administered KLH (1 mg) at Day 1/Week 1, 
Day 28/Week 4, and Day 56/Week 8.
4.4.2.4
Conjugate Pneumococcal Vaccine
This study will assess antibody production when administered as 13-PCV booster 
vaccine after 23-PPV vaccine.  The 13-PCV is indicated as active immunization for the 
prevention of pneumonia and invasive disease caused by 13 Streptococcus pneumoniae
serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F). It has been chosen 
for this study to assess antibody production when administered as 13-PCV booster 
vaccine after 23-PPV vaccine (the response to serotype 6A will not be tested in the 
assay used in this study).  Booster 13-PCV will be administered in the deltoid muscle as 
a single IM injection.
Group A1 patients will receive the 13-PCV at Week 20/Day 140.  Refer to the label for 
dosing and administration guidance.
4.4.2.5
Seasonal Influenza Vaccine 
The influenza vaccine is indicated for immunization against influenza caused by the 
influenza strains included in the vaccine.  The inactivated (or recombinant) vaccine has


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been chosen for this study to assess antibody production for a commonly used clinically 
relevant antigen. 
Group A2 patients can receive the influenza vaccine at any time between 
Day 85/Week 12 and Day 140/Week 20.
Group B patients will receive the influenza vaccine as an IM injection in the deltoid 
muscle at any time between Day 1/Week 1 and Day 84/Week 12.  If a patient needs to 
receive the influenza vaccine after Week 12, the optional OCR infusion must be delayed.
Group A1 patients can receive the influenza vaccine at any time at the discretion of the 
investigator.
Refer to the label for dosing and administration guidance.
4.4.3
Investigational Medicinal Product Accountability
The investigator is responsible for the control of drugs under investigation. Adequate 
records for the receipt and disposition of the study drug must be maintained. 
Accountability will be assessed by maintaining adequate drug dispensing and return 
records.
Accurate records must be kept for each study drug provided by the Sponsor. These 
records must contain the following:

Documentation of drug shipments received from the Sponsor (date received and 
quantity)

Disposition of unused study drug not dispensed to patient.
A Drug Dispensing Log must be kept current and should contain the following 
information:

The identification of the patient to whom the study drug was administered

The date[s] and quantity of the study drug administered to the patient
All records and drug supplies must be available for inspection/accountability by the 
monitor at every monitoring visit.
4.4.3.1
Assessment of Compliance
Patient compliance will be assessed by maintaining adequate study drug dispensing 
records. The investigator is responsible for ensuring that dosing is administered in 
compliance with the protocol. Delegation of this task must be clearly documented and 
approved by the investigator.
The study pharmacist should keep all OCR vials to measure compliance.


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4.4.4
Destruction of the Investigational Medicinal Product
Local or institutional regulations may require immediate destruction of used IMP for 
safety reasons. In these cases, it may be acceptable for investigational site staff to 
destroy dispensed IMP before a monitoring inspection provided that source document 
verification is performed on the remaining inventory and reconciled against the 
documentation of quantity shipped, dispensed, returned and destroyed. Written 
authorization must be obtained from the Sponsor at study start up before destruction. 
Written documentation of destruction must contain the following:

Identity (batch numbers or medication numbers) of IMP destroyed

Quantity of IMP destroyed

Date of destruction

Method of destruction

Name and signature of responsible person who destroyed the IMP
Wherever possible, preferably drug should be destroyed locally on site according to their 
local policies and procedures once drug accountability has been completed by the 
monitor.
4.5
POST-TRIAL ACCESS TO OCRELIZUMAB
The Sponsor will offer continued access to OCR 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 OCR 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 OCR 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 OCR after completing the study if any of the 
following conditions are met:

OCR is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of OCR or data suggest that OCR is 
not effective for MS

The Sponsor has reasonable safety concerns regarding OCR as treatment for MS

Provision of the OCR is not permitted under the laws and regulations of the 
patient's country


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The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.6
CONCOMITANT THERAPY
4.6.1
Definition of Concomitant Treatment
A concomitant medication is any drug or substance taken during the study, including the 
screening period. Over-the-counter medications and preventative vaccines received 
during the study are considered concomitant medications.
Concomitant medications will be reported at each visit in the relevant electronic Case 
Report Forms (eCRFs) starting from the baseline visit (including medication and 
procedures taken between screening and baseline). 
4.6.2
Treatment for Symptoms of Multiple Sclerosis
The investigator should attempt to maintain therapies or treatments for symptoms 
related to MS (e.g., walking ability, spasticity, incontinence, pain, fatigue) reasonably 
constant throughout the study. Note: Patients in Group B can continue on IFN-
treatment that should be maintained at a stable dose as much as possible. During the 
OOE, initiation of therapy with dalfampridine (Fampyra/Ampyra) is allowed, if indicated 
by the treating physician.
4.6.3
Treatment of Relapses
Patients who experience a relapse during Immunization Study Period or the OOE 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 period 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 4.8).
4.6.3.1
Prohibited Therapy
Therapies for MS noted in the exclusion criteria under “Exclusions Related to 
Medications” (Section 4.1.2) are not permitted during the Immunization Study Period 
with the exception of systemic corticosteroids for the treatment of a relapse.
After patients have finished the treatment with OCR, they may receive alternative
treatment for their MS as judged clinically appropriate by the investigator. However, as
sufficient data are not available to inform regarding risks associated with switching to 
other products, the following recommendations are given: 

Caution is advised while patients remain B-cell depleted. 


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
Because of the unknown safety risk of administering disease-modifying treatments 
for MS after discontinuation of OCR, 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). 
When patients begin an alternative treatment for MS, they will be discontinued from 
the study.
4.6.4
Immunizations
Physicians are advised to review the immunization status of patients who are considered 
for treatment with OCR and follow local/national guidance for adult vaccination against 
infectious disease. Known dates of immunizations will be recorded on specific eCRF 
pages, i.e., ‘Vaccination History’. Immunizations (excluding tetanus-containing vaccines, 
23-PPV, influenza, and 13-PCV) should be completed at least 6 weeks prior to first 
administration of OCR.
Patients who require de novo hepatitis B vaccination (three separate doses of vaccine) 
should also have completed the course at least 6 weeks prior to the first infusion of 
study drug.
The safety of immunization with live or live-attenuated vaccines following OCR
therapy has not been studied. Immunization with any live or live-attenuated vaccine 
(i.e., measles, mumps, rubella, oral polio vaccine, bacille Calmette-Guérin, typhoid, 
yellow fever, vaccinia, cold adapted live influenza strain vaccine, or any other vaccines 
not yet licensed but belonging to this category) is not recommended within 6 weeks of 
first dosing (see Section 4.1.2), during OCR treatment, and for as long as the patient is 
B-cell depleted.
Patients who are eligible for a yearly influenza vaccine or who require immunizations or 
boosters for other diseases can receive immunization with killed/toxoid vaccines 
consistent with normal clinical practice.
For details regarding vaccinations during OCR treatment, please refer to the current 
version of the Ocrelizumab Investigator's Brochure.
4.7
STUDY ASSESSMENTS 
Please see Appendix 1 for the schedule of assessments performed during the study.
4.7.1
Informed Consent Forms and Screening Log
All patients must sign and date the most current Institutional Review Board
(IRB)/Institutional Ethics Committee’s approved written informed consent before any 
study-specific assessments or procedures are performed.


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Patients who consent to participate in this study will enter the 4-week screening period to 
be evaluated for eligibility.  For details please refer to the Appendix 1.  Patients must 
fulfill all entry criteria for participation in the study.
The screening period can be extended to a total period of 8 weeks in cases when a 
laboratory blood test needs to be repeated for confirmation during the screening interval,
if a live vaccine must be administered by the patient’s physician, or for other relevant 
clinical, administrative, or operational reasons.
Please note that based on local Ethics Committees or National Competent Authority 
requirements, additional diagnostic testing may be required for selected patients or 
elected centers to exclude TB, Lyme disease, HAM, AIDS, hereditary disorders, 
connective tissue disorders, or sarcoidosis. 
An Eligibility Screening Form that documents the investigator’s assessment of each 
screened patient with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the investigator.
Each patient screened must be registered in the IxRS by the investigator or the 
investigator’s research staff at screening. A screen failure record must be maintained by
the investigator, and reasons for screen failure must be captured in the IxRS. 
The medical record should state that the patient is participating in this clinical study.
4.7.2
Procedures for Enrollment of Eligible Patients
Once a patient has fulfilled all eligibility criteria, he or she will be randomized via IxRS to 
one of two treatment groups:  

Group A: OCR 600 mg (given as 300 mg 2, 14 days apart) 

Group B: control group
Patient eligibility information will be provided to the IxRS by the investigator or the
investigator’s research staff at randomization. The patient will be randomized and
assigned a unique treatment box number (medication number) and randomization
number. As confirmation, the site will be provided with a verification of each patient’s
randomization.
The patient randomization numbers will be generated by Roche or its designee. 
The patient randomization numbers are to be allocated sequentially in the order in which
the patients are enrolled according to the specification document agreed with the 
external randomization company/center.
Treatment with the first study drug infusion should occur within 24 hours of
randomization for patients in Group A. In exceptional cases where all baseline 
assessments cannot be completed within 24 hours, the first study drug infusion can be 


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administered within 48 hours of randomization provided that the investigator assures that 
all inclusion and exclusion criteria are still met on the day of dosing. In particular, there 
should be no evidence of an ongoing infection at the time of dosing.
No patient may begin treatment prior to randomization and assignment of a 
medication number.
4.7.3
Overview of Clinical Visits during the Immunization Study 
Period and the Optional Ocrelizumab Extension Period
After the screening visit, patients who fulfill the entry criteria will be scheduled for 
baseline assessments. Randomization will occur only after the patient meets all 
inclusion and exclusion criteria on Day 1. Visits will take place as described in 
Appendix 1.
Visits should be scheduled with reference to the date of the baseline visit (Day 1).
A minimum interval of 20 weeks should be kept between the second infusion of OCR
in Dose 1 (i.e., infusion Week 2) and the single infusion of Dose 2 (Week 24).  
For subsequent single infusions, a minimum of 22 weeks should be maintained between 
each infusion.
At infusion visits, patients treated with OCR should remain in observation for at least 
1 hour after the completion of the infusion. If for logistical reasons the OCR 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 re-scheduled for a delayed dosing visit (see Section 4.7.4). Additional
unscheduled visits for the assessment of potential relapses, new neurological 
symptoms, or safety events may occur at any time.
4.7.4
Safety Follow-Up 
Patients who discontinue treatment early for any reason and patients who complete the 
study treatment period will be followed up for 48 weeks after the last infusion of OCR. 
When patients begin an alternative treatment for MS (see Section 4.6.3.1 on prohibited 
therapies), or start treatment with commercial OCR, they will be discontinued from the
SFU and from the study.  SFU visits will be performed at 12-week intervals.
A dedicated (scheduled or unscheduled) safety follow-up visit directly prior to the start of 
an alternative MS treatment is required in order to assess the patient’s clinical status and 
safety parameters. Additionally, an MRI scan should be performed within 4 weeks prior 
to the start of an alternative MS treatment (unless MRI has already been performed 
within prior 8 weeks; for details on assessments, Appendix 1).


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4.7.5
Delayed Dosing Visit
Delayed dosing visits may be scheduled only if the infusion cannot be administered at 
the timepoints defined in Schedule of Assessments (Appendix 1). Thus, a patient who 
had all assessments of a dosing visit performed, but could not receive his/her infusion, 
should be re-scheduled for the infusion. For patients in Group A, delayed-dosing visits
should not be scheduled for the first infusion of the first treatment (Dose 1 Infusion 1 on 
Day 1), as treatment with the first study drug infusion should occur within 24 hours of 
randomization (in exceptional cases within 48 hours of randomization provided that the 
investigator assures that all inclusion and exclusion criteria are still met on the day of 
dosing; see Section 4.7.3).
In unforeseen situations, if the infusion of the first treatment dose (Day 1) is delayed for 
patients in Group A, then the visit for the second infusion should be scheduled 14 days 
after the delayed first infusion (2 days). At the delayed-dosing visit, additional tests or 
assessments, such as routine safety laboratory tests, may be performed when the 
investigator judges that these are warranted.
4.7.6
Unscheduled Visits
Patients who develop new or worsening neurological symptoms should be seen at the
investigational site as soon as possible regardless of the treatment group to which they
were randomized, regardless of the dates of their pre-planned, scheduled study visits, 
and regardless of the study period. Assessments performed at unscheduled 
(non-dosing) visits will depend on the clinical needs of the patient.
Please refer also to Section 5.1.5.1 for guidance on the diagnosis of PML.
4.7.7
Withdrawal Visits
At the moment a patient meets one or more of the withdrawal criteria (Section 4.8.2), the
patient will be regarded as withdrawn from treatment. Patients who withdraw from OCR
treatment will need to complete all assessments as shown in Appendix 1 and will enter 
the SFU. Patients in Group B who do not receive an infusion of OCR in the OOE will not 
enter SFU.
After entering the SFU, if patients begin an alternative treatment for MS (see 
Section 4.6.3.1 on prohibited therapies), or start treatment with commercial OCR, they 
will be discontinued from the SFU and from the study.
All patients will undergo a complete final evaluation according to the ‘Withdrawal from 
Treatment Visit’ in the Schedule of Assessments (Appendix 1). Thereafter, all patients 
will be treated according to individual center practice.
For patients who have withdrawn from the Immunization Study Period or the OOE or 
who are not eligible for treatment with OCR, the investigator should decide on further
treatment of the underlying disease.


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However, as sufficient data are not available to inform risks associated with switching to 
other products, certain treatments for MS, such as lymphocyte-depleting agents or 
lymphocyte-trafficking blockers (alemtuzumab, natalizumab, fingolimod, dimethyl 
fumarate, cladribine, daclizumab, cyclophosphamide, azathioprine, 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) 
(see also Section 4.6.3.1 for recommendations on alternative treatments for MS). 
Please note: at the withdrawal from the Immunization Period or the OOE Period for
patients in Groups A and B, an MRI scan will be required only if not performed in the 
prior 4 weeks.
4.7.8
Safety
Adverse events, vital signs, weight, physical and neurological examinations, clinical 
laboratory tests (including pregnancy tests), 12-lead ECGs, and data on concomitant 
medications and diseases will be collected throughout the study.
4.7.8.1
Medical History and Demographic Data
Relevant medications taken for the treatment of MS and medications taken for the 
symptoms of MS prior to the baseline visit will be recorded at screening.  
Additionally, any relevant medications and medical/surgical procedures administered 
for any non-MS condition prior to the baseline visit will be recorded at screening.
4.7.8.2
Vital Signs
On the infusion days, the vital signs should be taken within 45 minutes prior to the 
methylprednisolone infusion in all patients. In addition, the vital signs should be 
obtained prior to the study drug infusion, then every 15 minutes (5 minutes) for the first 
hour; then every 30 minutes (10 minutes) until 1 hour after the end of the infusion. 
On immunization days, vital signs should be taken prior to immunization. 
On non-infusion/non-immunization days, the vital signs may be taken at any time during 
the visit. Additional vital signs readings may be taken at the discretion of the investigator 
in the event of an IRR or if clinically indicated and should be recorded on the 
unscheduled vital signs eCRF.
4.7.8.3
Electrocardiogram
A 12-lead ECG should be taken at the visits indicated in Appendix 1. Comments 
generated automatically by the ECG machine should not be recorded in the eCRF 
unless confirmed by a physician. An ECG is also required if the patient prematurely 
withdraws from the study.
4.7.8.4
Physical Examination
The physical examination will be performed as per Appendix 1. Diagnosis of new 
abnormalities or clinically significant worsening of pre-existing abnormalities should be 
recorded as adverse events if appropriate.


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4.7.8.5
Brain Magnetic Resonance Imaging
Brain MRI scans will be obtained in all patients prior to baseline and annually as 
indicated in Appendix 1. It is recommended that patients be assessed as eligible for the 
trial (i.e., meet other study entrance criteria, where possible) prior to performance of the 
MRI scan.
The annual MRIs should be carried out as close as possible within a year of the baseline 
MRI performed at study entry.  It can be performed at an unscheduled visit or be carried 
out at a scheduled visit.  It is recommended that the MRI is performed at the visit 
scheduled 2 weeks prior the next OCR infusion (Visit q22), where retreatment criteria 
are assessed.  To reduce the burden of additional visits for Group B patients, the 
scheduling of the annual MRI can be adapted to the pre-infusion visit schedule starting 
from the first annual MRI after the baseline MRI.
In patients receiving corticosteroids for an MS relapse, there should be an interval of 
3 weeks between the last dose of corticosteroids and the scan.
An MRI scan should be performed within 4 weeks prior to the start of an alternative 
MS treatment (unless an MRI has already been performed within prior 8 weeks;
see Section 4.6.3.1).
At the withdrawal from treatment visit, an MRI scan will be required only if not performed 
in the prior 4 weeks.
4.7.8.6
Neurological Examination
A neurological examination will be performed at every planned visit and at unscheduled
visits in which a physical examination is performed.
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, cerebellar symptoms/signs (e.g., gait abnormalities, limb 
incoordination). A brain MRI scan and cerebrospinal fluid (CSF) analysis may be 
warranted to assist in the diagnosis of PML. See Section 5.1.5.1 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 Section 5.1.5.1). The Sponsor’s
Medical Monitor should be contacted by email. In addition, the Sponsor’s Medical 
Monitor should be immediately contacted by phone.


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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 5.1.5.1).
4.7.8.7
Telephone Interviews
The purpose of this semi-structured interview is to identify and collect information on 
any changes in the patient’s health status that warrant an unscheduled visit.
The telephone interview will be conducted by site personnel familiar with the patient(s) 
every 4 weeks (3 days) between the study visits throughout all periods and the SFU 
until 48 weeks after the last infusion of OCR.
The site will record in the eCRF the date of interview or if the site was unable to contact 
the patient. The documentation of the interview will be maintained in the patient’s study 
file and all relevant safety information recorded in the eCRF.  See Appendix 2 for the 
semi-structured telephone interview.
4.7.9
Laboratory Assessments
All laboratory samples collected during the study, with the exception of urine pregnancy 
tests, which will be analyzed locally, will be shipped to a Central Laboratory.
The procedures for the collection, handling, and shipping of laboratory samples are
specified in the Laboratory Manual. The samples for this study should be classified, 
packed and shipped as UN3373 Biological Substance, Category B.
Full details of the central laboratory sample handling, shipment and reporting of results
will be described in the Laboratory Manual.
4.7.9.1
Standard Laboratory Assessments
Further details will be provided in Laboratory Manual.
Hematology: hemoglobin, hematocrit, RBC, WBC (absolute and differential), ANC, and 
quantitative platelet count.
Blood chemistry: AST/SGOT, ALT/SGPT, glutamyl transferase, alkaline 
phosphatase, amylase, lipase, total protein, albumin, cholesterol, total bilirubin, urea, 
uric acid, creatinine, random glucose, potassium, sodium, calcium, phosphorus, LDH, 
creatine phosphokinase, and triglycerides.
Thyroid function test: thyroid stimulating hormone will be tested at screening. Thyroid 
autoantibodies will be assayed at screening.
Flow cytometry will include (but is not limited to) the following cells:

Total B cells (CD19 positive)




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KLH Antibody Assay
A KLH antibody assay will be used to measure anti-KLH antibody levels (IgG and IgM) in 
human serum samples. The KLH antibody assay is an ELISA format using KLH as the 
plate coating and anti-human IgG-horseradish peroxidase for detection. Results are 
reported in titer units.
Influenza Vaccine
The hemagglutination inhibition (HAI) assay will be used to measure anti-influenza 
antibody levels in human serum samples. Results are reported in HAI units.
4.7.9.3
Hepatitis Screening and Liver Function Monitoring
Patients with recurrent or chronic hepatitis B or history/presence of hepatitis C infection 
must be excluded from enrollment into the study (see Section 4.1.2). In addition,
hepatitis B and C serology will be performed at screening. Patients who have a positive 
result to either HBsAg, or total HBcAb associated with positive viral DNA titers as 
measured by PCR, or a positive result for HepCAb should be excluded from the trial. 
Patients with evidence of past resolved hepatitis B infection (i.e., positive total HBcAb
associated with a negative viral DNA) can be enrolled, and will have the hepatitis B viral 
DNA checked regularly as per Appendix 1. 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 OCR and will enter the SFU. Liver 
function (i.e., ALT/SGPT, AST/SGOT, glutamyl transferase, alkaline phosphatase, 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 or C 
should be withdrawn from the study and should enter the SFU. 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. Please refer also to 
Section 5.3.5.7 for further guidelines on liver function monitoring.
4.7.9.4
Pharmacokinetic Assessments
Blood samples will be collected to evaluate the trough concentrations.
For all infusion visits, a blood sample should be taken 530 minutes before the 
methylprednisolone infusion and as indicated in the Schedule of Assessments 
(Appendix 1). At other times (non-infusion visits), samples may be taken at any time 
during the visit.
For sampling procedures, storage conditions, and shipment instructions, see the Sample
Handling and Logistics Manual, which will be provided to each site.


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4.7.10
Optional Ocrelizumab Extension Period
The OOE starts on Dose 2 (600 mg, single infusion) for patients in Group A and as 
2300 mg single infusions for patients in Group B.
In order to verify re-treatment criteria for infusions in the OOE, patients should attend a 
scheduled visit 2 weeks prior to an infusion visit (the first visit will be added prior to 
Dose 3 for patients in Group A and prior to Dose 2 [600 mg single infusion] for patients 
in Group B).
Additional unscheduled visits for safety events may occur at any time. Assessments 
performed at unscheduled (non-dosing) visits will depend on the clinical needs of the 
patient.
Refer to Appendix 1 for study procedures at OOE and unscheduled visits.
4.8
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.8.1
Patient Discontinuation
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 at any time

Any medical condition that the investigator or Sponsor determines may jeopardize
the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient
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 form.  However, patients will not be followed for any reason after 
consent has been withdrawn.  Patients who withdraw from the study will not be replaced.
4.8.2
Criteria for Premature Withdrawal
Patients have the right to withdraw from the study at any time for any reason. Patients
must be withdrawn from treatment (regardless of whether they are in the Immunization 
Study Period or the OOE) under the following circumstances:

Life threatening (Common Terminology Criteria for Adverse Events [CTCAE]
Grade 4) infusion-related event that occurred during a previous OCR infusion

Patients who demonstrate active hepatitis B or C infection, either new onset or
reactivation in the case of hepatitis B

Patients with PML

Patients who decide to discontinue the treatment

The investigator decides that discontinuation of treatment is in the best clinical
interest of the patient


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Patients who discontinue treatment early for any reason and patients who complete the 
study treatment period will be followed up for 48 weeks after the last infusion of OCR. 
When patients begin an alternative treatment for MS (see Section 4.6.3.1 on prohibited 
therapies), or start treatment with commercial OCR, they will be discontinued from the 
SFU and from the study.
If the patient discontinues from the study, he/she should be asked if he/she can still be 
contacted for further information. The outcome of that discussion should be documented 
in both the medical records and in the eCRF. If lost to follow-up, the investigator should 
contact the 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 by the investigator without their consent.
The investigator may withdraw patients from the study in the event of intercurrent illness,
adverse events, treatment failure, after a prescribed procedure, lack of compliance with
the study and/or study procedures (e.g., dosing instructions, study visits), cure, or for 
any reason where it is felt by the investigator that it is in the best interest of the patient to 
be terminated from the study. Any administrative or other reasons for withdrawal must 
be documented and explained to the patient. If the reason for removal of a patient from 
the study is an adverse event, the principal specific event will be recorded on the eCRF. 
If possible, the patient should be followed until the adverse event has resolved.
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.
Please note:  It is important to distinguish between withdrawal from treatment and 
withdrawal from study.  Patients who discontinue treatment early for any reason and 
patients who complete the study treatment period will be followed up for 48 weeks after 
the last infusion of OCR. When patients begin an alternative treatment for MS (see 
Section 4.6.3.1 on prohibited therapies), or start treatment with commercial OCR, they 
will be discontinued from the SFU and from the study.
Upon withdrawal from the study, any untested routine samples will be destroyed.
However, information already obtained from samples up until the time of withdrawal will 
be used.


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4.8.3
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of 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.  
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 Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice

No study activity (i.e., all patients have completed and all obligations have been 
fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Ocrelizumab was approved in the U.S. on 28 March 2017 under the trade name 
Ocrevusfor the treatment of patients with RMS and PPMS, and in Canada on 
14 August 2017 for the treatment of patients with RRMS.  The safety plan for this study 
is designed to ensure patient safety and will include specific eligibility criteria and 
monitoring assessments as detailed below.  For the most recent information regarding 
identified and potential risks associated with ocrelizumab, please refer to the current 
version of the Ocrelizumab Investigator’s Brochure.
5.1.1
Identified Risks and Adverse Drug Reactions Associated with 
Ocrelizumab Use
5.1.1.1
Infusion-Related Reactions
For this study, an IRR is defined as an event that occurs during or within 24 hours after 
the end of the infusion and which can be reasonably assumed as being related to 
study medication.
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 in order to reduce frequency and severity of IRRs), symptoms of IRRs may 
occur during any ocrelizumab infusion but have been more frequently reported during 
the first infusion. Physicians should alert patients that IRRs can occur within 24 hours of 


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an infusion. Across the RMS and PPMS trials, symptoms associated with IRRs 
included, but were not limited to: pruritus, rash, urticaria, erythema, throat irritation, 
oropharyngeal pain, dyspnea, pharyngeal or laryngeal edema, flushing, hypotension, 
pyrexia, fatigue, headache, dizziness, nausea, tachycardia and anaphylaxis.  
Some of these events have been severe enough to warrant interruption or 
discontinuation of the infusion.  Symptoms are often reversible if the infusion is 
interrupted and/or patients receive additional treatment with an antihistaminic, 
acetaminophen, epinephrine, or an IV corticosteroid.   
Patients should be observed for at least 1 hour after the completion of the infusion for 
any symptom of IRR and should be informed about the possibility of delayed post-
infusion symptoms and instructed to contact their study physician if they develop such 
symptoms. 
Hypotension, as a symptom of IRR, may occur during ocrelizumab infusion. Therefore, 
withholding of antihypertensive treatments should be considered for 12 hours prior to 
and throughout each ocrelizumab infusion.
In this study, patients will be pre-medicated with IV methylprednisolone (100 mg) and an 
antihistamine, an antipyretic drug is also recommended to prevent IRRs. 
5.1.1.2
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%).
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 beta-
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 RA 
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 for 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 MS 
patients treated with ocrelizumab, but it had been reported for 1 RA patient treated with 
ocrelizumab. HBV screening should be performed in all patients before initiation of 


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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.
See Section 4.7.9.3 for hepatitis screening and monitoring of liver function.
Delay OCR administration in patients with an active infection until the infection is 
resolved. Physicians should exercise caution when considering the use of OCR in 
patients with underlying conditions that may predispose patients to serious infection.  
Patients who develop signs/symptoms of infection while participating in this trial should 
be seen immediately, samples should be taken for appropriate microbiological analysis, 
and appropriate treatment should be initiated promptly.
For PML, see potential risk below.
Patients should be screened for TB according to national guidelines.  As with other 
infections, patients with active TB should not be enrolled; patients with latent TB should 
be treated prior to enrollment.
Patients should be warned that the risk of infection may be increased by exposure to the 
medications to be used in this study and should be asked to contact the clinic staff if they 
start to develop signs of infection.  
5.1.1.3
Decrease in Immunoglobulins
Treatment with ocrelizumab resulted in a decrease in total Igs over the controlled period 
of the studies, mainly driven by reduction in IgM.  The proportion of 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 (see Section 5.1.1.4 and the Ocrelizumab 
Investigator’s Brochure for further details).
5.1.1.4
Serious Infections Related to Decrease in Immunoglobulins 
(Particularly in Patients Previously Exposed to 
Immunosuppressive or Immunomodulary Drugs or with 
Preexisting Hypogammaglobulinemia)
Based on additional patient exposure, an apparent association between sustained 
decrease in Igs and serious infections with ocrelizumab was observed and was most 
apparent with IgG. There was no difference in the pattern (type, latency, duration, 
outcome) of the serious infections reported in this subset of 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.


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5.1.1.5
Delayed Return of Peripheral B cells
Treatment with ocrelizumab leads to rapid depletion of CD19+ B cells in blood by 
14 days post-treatment (first timepoint of assessment) and is an expected 
pharmacologic effect. This was sustained throughout the treatment period. The longest 
follow-up time after the last ocrelizumab infusion is from 51 patients in Study WA21493 
and indicates that the median time to B-cell repletion (returned to baseline or LLN, 
whichever occurred first) of B cells was 72 weeks (range:  27175 weeks).
5.1.1.6
Impaired Response to Vaccination
After treatment with ocrelizumab over 2 years in pivotal clinical trials, the proportion of 
patients with positive antibody titers against S. pneumoniae, mumps, rubella, and 
varicella were generally similar to the proportions at baseline.
In the Immunization Study Period of this Study BN29739, the humoral responses to 
tetanus toxoid (TT), 23-valent pneumococcal polysaccharide (23-PPV), keyhole limpet 
hemocyanin (KLH) neoantigen, and seasonal influenza vaccines were decreased in 
RMS patients treated with OCR (compared with those patients not treated with OCR) at 
all timepoints measured.  Nevertheless, RMS patients who received OCR and were 
peripherally B-cell depleted were able to mount humoral responses, albeit decreased, to 
clinically relevant vaccines (TT, 23-PPV, influenza) and the neoantigen KLH.  The 
results of the study confirm the current recommendation that patients should complete 
local vaccination requirements 6 weeks prior to initiation of OCR to obtain full 
effectiveness of the vaccines.  In addition, for seasonal influenza vaccines, it is still 
recommended to vaccinate patients receiving OCR, as a humoral response to the 
vaccine, even if attenuated, can be expected.
Due to the potential depletion of B cells in neonates and infants of mothers who have 
been exposed to OCR during pregnancy, it is recommended that vaccination of 
neonates and infants with live or live-attenuated vaccines should be delayed until B-cell 
levels have recovered.  Therefore, measuring CD19-positive B-cell levels in neonates 
and infants prior to vaccination is recommended.
Physicians 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.
The safety of immunization with live or live-attenuated viral vaccines following 
ocrelizumab therapy has not been studied and vaccination with live-attenuated or live 
vaccines is not recommended while B cells are depleted.  Please see Section 4.6.4 for 
guidance on immunization.
5.1.2
Potential Risks Associated with Ocrelizumab Use
5.1.2.1
Progressive Multifocal Leukoencephalopathy
PML is a potentially fatal neurological condition linked to reactivation of a polyomavirus 
(John Cunningham virus [JCV]) and active viral replication in the brain. Polyomavirus 
infection is acquired in childhood and up to 80% of adults demonstrate serological 


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evidence of past infection. Reactivation of JCV replication with transient viremia or 
viruria unassociated with clinical symptoms may occur spontaneously in healthy 
persons. Less frequently, CNS symptoms associated with active viral replication in brain 
tissue are observed. The clinical syndrome is significantly more frequent among 
immune-suppressed patients.  There is no known treatment or cure for PML. Treatment 
considerations are discussed in the medical literature (Berger 2014).
PML is an important potential risk for ocrelizumab. It has been reported in patients 
receiving ocrelizumab but only in patients where other contributory factors were present, 
such as prior immunosuppressive treatment (e.g., natalizumab or fingolimod).  
Physicians should be vigilant for early signs and symptoms of PML, which can include 
any new onset or worsening of neurological signs or symptoms, as these can be similar 
to an MS relapse.  If PML is suspected, dosing with ocrelizumab must be withheld.  
Evaluation of PML, including MRI, confirmatory CSF testing for JC viral DNA, and repeat 
neurological assessments, should be considered.  If PML is confirmed, ocrelizumab 
must be discontinued permanently.  Please refer to the current Ocrelizumab 
Investigator’s Brochure for further details.
Healthcare professionals should be alerted to the 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. Please refer to Section 5.1.5.1 for guidance on 
the diagnosis of PML.
If PML is suspected, a neurological consultation should be obtained and treatment 
suspended until PML has been ruled out.
If PML is confirmed in a patient who has received OCR, no further infusions should be 
administered and the patient will be withdrawn from treatment (see Section 4.8) and 
enter the SFU period of the study. 
PML should be reported as a serious adverse event (with all available information) with 
immediate notification of the Medical Monitor.
5.1.2.2
Hypersensitivity Reactions
Hypersensitivity may be difficult to distinguish from IRRs in terms of symptoms.  
A hypersensitivity reaction may present during any infusion, although not typically during 
the first infusion.  For subsequent infusions, more severe symptoms than previously 
experienced, or new severe symptoms, should prompt consideration of a potential 
hypersensitivity reaction.  If a hypersensitivity reaction is suspected during an infusion, 
the infusion must be stopped immediately and permanently.  Patients with known 
IgE-mediated hypersensitivity to ocrelizumab must not be treated.
5.1.2.3
Malignancies, Including Breast Cancer
An increased risk of malignancy with OCR may exist. In controlled trials in MS, 
malignancies, including breast cancer, occurred more frequently in OCR-treated 


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patients. Breast cancer occurred in 6 of 781 females treated with OCR and none of 
668 females treated with INF-beta-1a (Rebif®) or placebo. 
Patients should follow standard breast cancer screening guidelines.
5.1.2.4
Neutropenia
In the controlled treatment period, decreased neutrophils were observed in 12% and 
15% of MS patients treated with ocrelizumab, in PPMS and RMS, respectively.  Most 
events 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. Based on 
additional patient exposure, an association between neutropenia and serious infections 
with ocrelizumab treatment was not observed.
In case the ANC decreases below the exclusionary level of 1.5 x 103/L, further 
administration of OCR should be suspended until resolution of this laboratory 
abnormality or held indefinitely (as per the Re-treatment criteria, Section 4.1.4). 
5.1.3
Risks Associated with Corticosteroids
The adverse reactions of corticosteroids may result from unwanted glucocorticoid
actions or from inhibition of the hypothalamic-adrenal axis.  Please refer to the local 
prescribing information.
5.1.4
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.  Please refer to local Prescribing Information.
5.1.5
Management of Specific Adverse Events
5.1.5.1
Guidance for Diagnosis of Progressive Multifocal 
Leukoencephalopathy
The following safety monitoring algorithm (Figure 3) will be implemented in this study.
Comprehensive neurological assessments will be performed at each planned and 
unscheduled visit that a physical examination is performed, and all patients will be 
required to undergo a neurological exam for calculation of an EDSS at baseline and if 
PML is suspected.  This requires that Functional System Score (FSS) also be 
determined. The examination to calculate the FSS includes cognitive, visual and motor 
assessments, the neurological systems most often affected by PML, as well as 
assessments of other neurological systems.
In the eCRF, the investigator will record the presence or absence of neurological deficits 
localized to the cerebral cortex (e.g., cortical symptoms/signs, behavioral and 
neuropsychological alteration, retrochiasmal visual defects, hemiparesis), cerebellar 
symptoms/signs (e.g., gait abnormalities, limb incoordination), at each visit. Presence of 
such neurological findings will be recorded as adverse events. If a diagnosis for the 


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deficits is identified, the symptoms should be replaced by the diagnosis in the adverse 
event eCRF.
Patients will undergo a telephone interview between the study visits by site personnel 
familiar with the patient(s). The purpose of this interview is to identify and collect 
information on any changes in the patient’s health status, including new or worsening 
neurological symptoms, that warrant an unscheduled visit (Appendix 1). Partners or 
caregivers of study patients, if applicable, will be informed on symptoms and signs that 
may be suggestive of PML and should be instructed to contact the site, should any such 
signs or symptoms appear.
In the event that new or worsening neurological symptoms are considered during the 
telephone interview, a neurological evaluation will be conducted. Should a non-MS 
etiology, such as PML, be considered, further assessments should be done. 
The evaluation of PML may include a brain MRI scan and CSF analysis per the 
proposed treatment algorithm (see Figure 3).
The following clinical guidance is provided:
Treatment of relapse and other neurological symptoms:

As in all MS studies, new or recurrent neurological symptoms that occur in study 
patients should prompt careful clinical evaluation.

Anti-CD20 antibodies have been associated with PML. A risk of PML cannot be 
ruled out.  PML should be considered in patients who develop worsening 
neurological signs or symptoms.

There are no pathognomonic signs or symptoms that distinguish MS from PML, but 
there are certain clinical features that may help differentiate between the 
two conditions (see Table 1 and Table 2).

In addition to PML and MS, other CNS conditions (e.g., stroke, migraine) should be 
considered when evaluating a patient with new neurological changes.

Relapses should be managed according to the study protocol.

Corticosteroid treatment should only be considered for cases in which PML is 
unlikely on clinical grounds and when the severity of the relapse warrants such 
treatment. Lack of response to corticosteroids should trigger further investigation.
Action steps if PML is suspected:

If the clinical presentation is suggestive of PML, further investigations should include 
brain MRI evaluation as soon as possible. If MRI evaluation reveals lesions 
suspicious for PML (see Figure 3) a lumbar puncture with evaluation of the CSF for 
the detection of JCV DNA using a validated sensitive assay should be undertaken. 
A diagnosis of PML can potentially be made by evaluating clinical and MRI findings 
plus the identification of JCV in the CSF.


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Please note: In the event that PML is suspected, additional blood, urine, and CSF 
samples should be obtained for JCV analysis. CSF samples will be analyzed upon 
receipt and the results will be provided directly to the investigational site and to the 
Sponsor. The additional blood and urine samples will be stored up to 1 year after 
LPLV in the study. For details, please refer to the most up-to-date laboratory
manual providing storage conditions and shipment instructions.
MRI assessment:

Although there are no pathognomonic findings that differentiate PML from MS, a 
brain MRI scan that includes fluid-attenuated inversion recovery (FLAIR) and T2-
and T1-weighted sequences, with and without Gd, should be performed to assess 
patients with neurological changes suggestive of PML (see Figure 3)

Comparison with a baseline scan may assist with interpretation of the findings on 
the newly acquired MRI (see Table 1 and 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.


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Figure 3
Diagnostic Algorithm Framework for PML (Berger et al. 2013)
CSFcerebrospinal fluid; FLAIRfluid-attenuated inversion recovery; JCVJohn Cunningham 
virus; MRImagnetic resonance imaging; PCRpolymerase chain reaction; PML progressive 
multifocal leukoencephalopathy; PRESposterior reversible encephalopathy syndrome; 
VZVvaricella zoster virus.


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Table 1
Clinical Features to Distinguish between Multiple Sclerosis 
Relapse and Progressive Multifocal Leukoencephalopathy
MS Relapse
PML
Onset
Acute
Subacute
Evolution
Over hours to days
Normally stabilizes
Resolves spontaneously         
or with treatment
Over weeks
Progressive
Clinical presentation
Diplopia
Paresthesia
Paraparesis
Optic neuritis
Myelopathy
Cortical signs and symptoms
Behavioral and 
neuropsychological alterations 
Retrochiasmal visual deficits
Hemiparesis
Cerebellar symptoms/signs 
(e.g., gait abnormalities, limb 
incoordination)
MSmultiple sclerosis; PMLprogressive multifocal leukoencephalopathy.


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Table 2
Magnetic Resonance Imaging Lesion Characteristics Typical of 
Multiple Sclerosis and Progressive Multifocal 
Leukoencephalopathy
Feature
MS Relapse
PML
Location of new lesions
Mostly focal; affect entire brain 
and spinal cord, in white and 
possibly gray matter
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; 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


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Table 2
Magnetic Resonance Imaging Lesion Characteristics Typical of 
Multiple Sclerosis and Progressive Multifocal 
Leukoencephalopathy (cont.)
Feature
MS Relapse
PML
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; MSmultiple sclerosis; PMLprogressive
multifocal leukoencephalopathy.
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 5.1.5.1).
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.9


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
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)
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 the National 
Cancer Institute [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).
The exception to this definition of a serious adverse event is in the rare event that a 
patient is hospitalized following an MS relapse, as long as the reason for hospitalization 
is to receive standard treatment with IV methylprednisolone. The rationale for this 


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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.
When the MS relapse results in hospitalization for any reason other than for routine 
treatment of the relapse (such as for a treatment course beyond the standard treatment 
described in Section 4.6.3) 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 
include the following:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s law (see Section 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 Section 5.4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).  


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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.
New or worsening neurological symptoms not considered MS-related should be 
recorded on an adverse event page and the monitor should be informed.
After informed consent has been obtained but prior to initiation of study 
treatments, 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 treatments, all adverse events will be reported until Week 48 
of the SFU Period.  After this period, the investigator should report any serious adverse 
events that are believed to be related to prior study drug treatment (see 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 (v4.0) will be used for 
assessing adverse event severity.  Table 3 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 3
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 (v4.0), 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 or 
not an adverse event is considered to be related to the study drug, indicating "yes" or 
"no" accordingly.  The following guidance should be taken into consideration:

Temporal relationship of event onset to the initiation of study drug

Course of the event, considering especially 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 
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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 ocrelizumab infusion should be captured as a diagnosis 
(e.g., “infusion-related reaction” or “anaphylactic reaction”) on the Adverse Event eCRF. 
If possible, avoid ambiguous terms such as “systemic reaction.”  Associated signs and 
symptoms and their associated details should be recorded on the dedicated IRR eCRF 
page.  Investigators should consider a local IRR for any symptoms affecting the skin, 
and localized to only one place. Any other IRR should be considered as systemic.
5.3.5.2
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.3
Adverse Events that Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.


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


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be recorded as the adverse event.  For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3 ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3 ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2).


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5.3.5.8
Deaths
All deaths that occur during the protocolspecified adverse event reporting period 
(see Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  
This includes death attributed to progression of 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.  
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
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol


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
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event
An event that leads to hospitalization under the following circumstance is not considered 
to be a serious adverse event, but should be reported as an adverse event instead:

Hospitalization for an adverse event that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available
5.3.5.11
Adverse Events Associated with an Overdose or Error in Drug 
Administration
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).
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 (see Section 5.4.2 for further details)

Adverse events of special interest (see Section 5.4.2 for further details)

Pregnancies (see Section 5.4.3 for further details)
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


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
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
Medical Monitor Contact Information 
Medical Monitor:
 M.D.
Mobile Telephone No.:
To ensure the 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 
Monitor, 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 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 Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
investigators.
5.4.2.2
Events That Occur After Study Drug Initiation
After initiation of study drug, serious adverse events, and adverse events of special 
interest will be reported until Week 48 of the SFU Period.  
Investigators should record all case details that can be gathered immediately (i.e., within 
24 hours after learning of the event) on the Adverse Event eCRF and submit the report 
via the electronic data capture (EDC) system.  A report will be generated and sent to 
Roche Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form 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.  


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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.  The investigator should report the pregnancy on the Clinical Trial Pregnancy 
Reporting Form and submit the form 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 
withhold study drug for the duration of the pregnancy and breastfeeding and counsel the 
patient, discussing the risks of the pregnancy and the possible effects on the fetus.  
Monitoring of the patient should continue until conclusion of the pregnancy.  Any serious 
adverse events associated with the pregnancy (e.g., an event in the fetus, an event in 
the mother during or after the pregnancy, or a congenital anomaly/birth defect in the 
child) should be reported on the Adverse Event eCRF.  In addition, the investigator will 
submit a Clinical Trial Pregnancy Reporting Form when updated information on the 
course and outcome of the pregnancy becomes available.  
The pregnancy outcome and the health status of the child will be followed until the child 
is 1 year of age. Data collection is voluntary only; it does not include any interventions 
or invasive procedures. A Pregnancy Outcome and Infant Health Information on First 
Year of Life questionnaire will be submitted to Health Authorities and IRB/IECs for their 
approval, along with the infant data release consent form.  For more information on the 
Infant Health Questionnaire, please refer to the latest version of the Infant Health 
Questionnaire Guidance document.
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.


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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).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.  
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.
5.6
POST-STUDY ADVERSE EVENTS
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 Serious Adverse Event/Adverse Event of Special Interest Reporting Form 
using the fax number or email address provided to investigators.


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5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents:

Ocrelizumab Investigator's Brochure

Keyhole Limpet Hemocyanin (KLH) Summary of Product Characteristics
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.  The Sponsor 
will not be expediting reporting of any adverse events related to the vaccines (i.e., TT, 
pneumococcal polysaccharide, conjugate pneumococcal booster and influenza)
administered in this study to health authorities as all vaccines used within this study are 
non-Sponsor non-IMPs.
Certain adverse events are anticipated to occur in the study population at some 
frequency independent of study drug exposure and will be excluded from expedited 
reporting (please refer to the current Ocrelizumab Investigator’s Brochure).  
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
6.1
DETERMINATION OF SAMPLE SIZE
Approximately 100 patients will be enrolled using a 2:1 randomization ratio into active 
(Group A) and control (Group B) groups. For the positive response to TT-containing 
adsorbed vaccine measured 8 weeks after the administration of vaccine, if both the 
control and active (OCR) groups have 70% response rates, the expected half width of 
the resulting 95% CI of the difference of two response rates is 0.201.
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of subjects who are randomized, treated and have completed the study will 
be tabulated by treatment group. Reasons for premature study withdrawal will be 
summarized and listed by treatment group. Key eligibility criteria violations and other 
major protocol deviations will be summarized by treatment group. 


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6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Treatment groups will be compared with respect to demographics (e.g., age, sex, and 
race/ethnicity) and baseline characteristics measured on Day 1 (e.g., body weight, 
background corticosteroid usage, years since prior vaccinations and pre-vaccination 
levels). Results will be summarized by treatment group using means, standard 
deviations, medians, and ranges for continuous variables and proportions for categorical 
variables. 
6.4
IMMUNOLOGY ENDPOINTS
6.4.1
Analysis of Immunology Endpoints
Primary Endpoint 
The proportion of patients with positive responses to TT vaccine measured 8 weeks after 
administration of the TT vaccine for Group A and Group B will be assessed.
For patients with pre-immunization tetanus antibody titers0.1 IU/mL, a positive 
response to the booster immunization is defined as an antibody titer0.2 IU/mL 
measured 8 weeks after the immunization. For patients with pre-immunization 
tetanus antibody titers0.1 IU/mL, positive response to the booster immunization is 
defined as a 4-fold increase in antibody titer measured 8 weeks after the immunization. 
Pre-vaccination levels are those obtained immediately prior to receipt of a vaccine.
Secondary Endpoints
All secondary endpoints are as defined in Section 3.4.2. Descriptive statistical analyses 
will be used to compare the proportion of patients with responses in the assessments 
and groups as specified in that section. The mean level of antibody parameters will be 
presented using geometric means.
Exploratory analyses will be performed to assess the possible relationship among 
measurements, and clinical response and will be specified in the statistical analysis plan.
6.5
SAFETY ANALYSES
All subjects who received any amount of OCR or any vaccine will be included in the 
safety analyses and will be analyzed according to the treatment received. 
6.5.1
Adverse Events
Verbatim descriptions of treatment-emergent adverse events will be mapped to 
thesaurus terms. Adverse events will be tabulated by body system and treatment group. 
Adverse events will also be summarized by maximum intensity for each treatment group 
(Groups A and B). Separate summaries will be provided for serious adverse events, 
treatmentrelated adverse events, and adverse events leading to study withdrawal. 


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6.5.2
Laboratory Tests
Descriptive summaries of laboratory values and changes from Day 1 and throughout the 
study will be generated. The proportion of patients who experience treatment-emergent 
laboratory abnormalities will be compared between groups. 
6.6
PHARMACOKINETIC ANALYSES 
The PK analysis will be conducted with all ocrelizumab concentration versus time data 
from the Immunization Study Period, plus all PK data from the OOE and SFU period 
available at the time of the PK analysis.  All 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 
which may interfere with PK evaluation.  The PK data of this study may be pooled with 
more extensive data from other studies.  The PK analysis will be reported separately 
from the main CSR.
Trough concentrations of ocrelizumab at all time-points of ADA sampling will be reported 
as part of the immunogenicity/ADA listings in the CSR.
6.7
INTERIM ANALYSIS
An interim analysis will not be conducted.
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 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.
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.


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All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/Ethics Committee (EC) review.  The study site must 
also allow inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change.


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7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, 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, patient 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.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. Food and Drug 
Administration (FDA) regulations and applicable local, state, and federal laws.  
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form will be provided to each site.  
If applicable, it will be provided in a certified translation of the local language.  
The Sponsor or its designee must review and approve any proposed deviations from the 
Sponsor's sample Informed Consent Forms or any alternate consent forms proposed by 
the site (collectively, the "Consent Forms") before IRB/ EC submission.  The final 
IRB/ECapproved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 


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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 of 1996 (HIPAA).  If the site 
utilizes a separate Authorization Form for patient authorization for use and disclosure of 
personal health information under the HIPAA regulations, the review, approval, 
and other processes outlined above apply except that IRB review and approval may not 
be required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 


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for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the 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.
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local health authorities, Sponsor
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., last patient last visit 
in SFU Period).
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 


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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
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.
9.4
ADMINISTRATIVE STRUCTURE
This study will be sponsored by Roche.  Approximately 100 patients are expected be 
enrolled in this study; approximately 3035 centers will participate in the study in the 
United States and Canada.  Patients will be enrolled and randomized using an IxRS.  
A central laboratory will be used for all laboratory assessments with the exception of 
urine pregnancy tests.  Any remaining PK or ADA samples may be used for exploratory 
experiments for PK and ADA assay development purposes and additional safety 
assessments (e.g., JCV testing in case of a confirmed PML diagnosis) as appropriate.  
These remaining samples will be stored for up to 5 years following database closure. 
9.5
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, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Study Information at the following Web site:
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective 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 


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proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
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).


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10.
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Avivi I, Stroopinsky D, Katz T. Anti-CD20 monoclonal antibodies: beyond B-cells. Blood 
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Bar-Or A, Favaz J, Fan B, et al. Abnormal B-cell cytokine responses a trigger of T-
cellmediated disease in MS? Ann Neurol 2010;67(4):452-61.
Berger JR. Progressive multifocal leukoencephalopathy. Handb Clin Neurol 
2014;123:35776.
Berger JR, Aksamit AJ, Clifford DB, et al. PML diagnostic criteria: consensus statement 
from the AAN Neuroinfectious Disease Section. Neurology 2013;80:14308.
Bingham CO 3rd, Looney RJ, Deodhar A, et al. Immunization responses in rheumatoid  
arthritis patients treated with rituximab: results from a controlled clinical trial. 
Arthritis Rheum 2010;62:6474.  
Confavreux C, Suissa S, Saddier P, et al.; Vaccines in Multiple Sclerosis Study Group. 
Vaccinations and the risk of relapse in multiple sclerosis. Vaccines in Multiple 
Sclerosis Study Group. N Engl J Med 2001;344(5):31926. 
Constant SL. B lymphocytes as antigen-presenting cells for CD4+ T cell priming in vivo. 
J Immunol 1999;162(10):5695703.
Crawford A, MacLeod M, Schumacher T, et al. Primary T cell expansion and 
differentiation in vivo requires antigen presentation by B cells. J Immunol 
2006;176(6):3498506.
De Keyser J, Zwanikken C, Boon M. Effects of influenza vaccination and influenza 
illness on exacerbations in multiple sclerosis. J Neurol Sci 1998;159(1):513.
DeLillo DJ, Hamaguchi Y, Ueda Y, et al. Maintenance of long-lived plasma cells and 
serological memory despite mature and memory B cell depletion during CD20 
immunotherapy in mice. J Immunol 2008;180(1):36171.
Duddy M, Niino M, Adatia F, et al. Distinct effector cytokine profiles of memory and naïve 
human B cell subsets and implication in multiple sclerosis. J Immunol 
2007;178(10):60929.
Edwards JC, Szczepanski L, Szechinski J, et al. Efficacy of B-cell-targeted therapy with 
rituximab in patients with rheumatoid arthritis. N Engl J Med 2004;350:2572–81.
Genain CP, Cannella B, Hauser SL, et al. Identification of autoantibodies associated with 
myelin damage in multiple sclerosis. Nat Med 1999;5(2):1705.


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Genzyme Corporation, A Sanofi Company. A Guide to the Excelerated Elimination 
Procedure for Aubagio (teriflunomide). [Updated 2013; Accessed 8 June 2014]] 
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http://www.aubagio.com/media/pdf/Guide_to_Accelerated_Elimination_Procedure_
for_AUBAGIO(R)(teriflunomide).pdf
Kappos L, Li D, Calebresi PA, et al. Ocrelizumab in relapsing-remitting multiple 
sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet
2011;378(9805):177987.
Klein C, Lammens A, Schäfer W, et al. Epitope interactions of monoclonal antibodies 
targeting CD20 and their relationship to functional properties. mAbs 
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Loken MR, Shah VO, Dattilio KL, et al. Flow cytometric analysis of human bone marrow. 
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Luccinetti CF, Bruck W, Parisi J, et al. Hetergeneity of multiple sclerosis legions: 
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Magliozzi R, Howell OW, Reeves C, et al. A gradient of neuronal loss and meningeal 
inflammation in multiple sclerosis. Ann Neurol 2010;68(4):47793.
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Annu Rev Immunol 2006;24:46796.
Mestecky J, Moldoveanu Z, Elson CO. Immune response versus mucosal tolerance to 
mucosally administered antigens. Vaccine 2005;23(15):18003. 
Miller JS, Curtsinger J, Berthold M, et al. Diminished neo-antigen response to keyhole 
limpet hemocyanin (KLH) vaccines in patients after treatment with chemotherapy 
or hematopoietic cell transplantation. Clin Immunol 2005;117:14451. 
Multiple Sclerosis International Federation. Atlas of MS 2013 [resource on the internet; 
accessed 21 Feb 2016]. Available from: 
http://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf.
Noonan CW, Kathman SJ, White MC. Prevalence estimates for MS in the United States 
and evidence of an increasing trend for women. Neurology 2002;58:1368.
Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 
2010 Revisions to the McDonald criteria. Annals of Neurology. 
2011;69(2):292302. 
Serafini B, Rosicarelli B, Magliozzi R, et al. Detection of ectopic B-cell follicles with 
germinal centers in the meninges of patients with secondary progressive multiple 
sclerosis. Brain Pathol 2004;14(2):16474.
Spazierer D, Skvara H, Dawid M, et al. T helper 2 biased de novo immune response to 
Keyhole Limpet Hemocyanin in humans. Clin Exp Allergy 2009;39(7):9991008.


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Stashenko P, Nadler L, Hardy R, et al. Characterization of a human B 
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Storch MK, Piddlesden S, Haltia M, et al. Multiple sclerosis: in situ evidence for 
antibody- and complement-mediated demyelination. Ann Neurol 
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Tedder TF and Engel P. CD20: a regulator of cell-cycle progression of B lymphocytes. 
Immunol Today 1994;15(9):4504.
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CNS Drugs 2015;29(3):22944.


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Appendix 1 Schedule of Assessments:  Tables AC
TABLE A: SCHEDULE OF ASSESSMENTS FOR IMMUNIZATION STUDY PERIOD AND OPTIONAL OCRELIZUMAB 
TREATMENT PERIOD FOR GROUP A (A1 AND A2)
Group A (A1 and A2)
Screening1
Immunization Study Period
OOE2,3
WD from 
Treatment Unscheduled4
Delayed 
Dosing5
Study Day (unless 
noted)
(Window)
-28 to -1
1 
(BL)1
15
(2 d)
85
(4 d)
112
(4 d)
140
(4 
d)
1692
(4 
d)
1692
(4 d)
q22w
(4 d)
(-2 w
prior to 
q24 w)
q24 w3
(2 w)
Week
-4 to -1
1
2
12
16
20
24
24
q22 w3 q24 w3
↓OCR infusion
↓
↓
↓
↓
Informed consent6
x
Medical history, 
MS history, prior 
and concomitant
treatments
x
Eligibility review
x
x
x
x
Physical and 
neurological exam
x
x
x
x
x
x
x
x
x
x
x
Vital signs7
x
x
x
x
x
x
x
x
x
x
x
x
12-lead ECG8
x
x
x
x
x
x
x
Height
x
Weight
x
x9
x9
x
EDSS10
x


Appendix 1 Schedule of Assessments: Table A (cont.)
OcrelizumabF. Hoffmann-La Roche Ltd
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Group A (A1 and A2)
Screening1
Immunization Study Period
OOE2,3
WD from 
Treatment Unscheduled4
Delayed 
Dosing5
Study Day (unless 
noted)
(Window)
-28 to -1
1 
(BL)1
15
(2 d)
85
(4 d)
112
(4 d)
140
(4 
d)
1692
(4 
d)
1692
(4 d)
q22w
(4 d)
(-2 w
prior to 
q24 w)
q24 w3
(2 w)
Week
-4 to -1
1
2
12
16
20
24
24
q22 w3 q24 w3
MRI (once annually
[4 w]) 11
x
x
Adverse events/MS 
relapse
Only 
SAEs12
x
x
x
x
x
x
x
x
x
x
x
x
Telephone 
interview
Every 4 weeks13
Concomitant 
treatments
x
x
x
x
x
x
x
x
x
x
x
x
Pregnancy test14
x
x
x
x
x
x
x
x
x
x
x
x
ADA15
x
x
x
x
x
x
x
PK sampling16
x
x
x
x
x
x
x
x
x
FSH17
x
Hepatitis 
screening18
x
HBV DNA 
monitoring19
x
x
x
x
x
x
RPR
x


Appendix 1 Schedule of Assessments: Table A (cont.)
OcrelizumabF. Hoffmann-La Roche Ltd
102/Protocol BN29739, Version 8
Group A (A1 and A2)
Screening1
Immunization Study Period
OOE2,3
WD from 
Treatment Unscheduled4
Delayed 
Dosing5
Study Day (unless 
noted)
(Window)
-28 to -1
1 
(BL)1
15
(2 d)
85
(4 d)
112
(4 d)
140
(4 
d)
1692
(4 
d)
1692
(4 d)
q22w
(4 d)
(-2 w
prior to 
q24 w)
q24 w3
(2 w)
Week
-4 to -1
1
2
12
16
20
24
24
q22 w3 q24 w3
CD4 count20
x
x
x
x
x
x
IgG subtype
x
x
x
x
Total Ig, IgA, IgG, 
IgM
x
x
x
x
x
x
x
Flow cytometry21
x
x
x
X
x
x
x
x
x
x
Routine safety 
labs22
x
x
x
x
x
x
x
x
x
x
x
x
Pretreatment with 
IV 
methylprednisolone
and an 
antihistamine
23
x
x
x
x
x
IV OCR24
x
x
x
x
x
Influenza vaccine25
I/M25 →Influenza →
post-vaccine assessment 
after 4 weeks
KLH
I/M26
I/M26
I/M26
M
M26


Appendix 1 Schedule of Assessments: Table A (cont.)
OcrelizumabF. Hoffmann-La Roche Ltd
103/Protocol BN29739, Version 8
Group A (A1 and A2)
Screening1
Immunization Study Period
OOE2,3
WD from 
Treatment Unscheduled4
Delayed 
Dosing5
Study Day (unless 
noted)
(Window)
-28 to -1
1 
(BL)1
15
(2 d)
85
(4 d)
112
(4 d)
140
(4 
d)
1692
(4 
d)
1692
(4 d)
q22w
(4 d)
(-2 w
prior to 
q24 w)
q24 w3
(2 w)
Week
-4 to -1
1
2
12
16
20
24
24
q22 w3 q24 w3
23-PPV
I/M26
M
M
M26
13-PCV27
I/M26
M
M26
TT-containing 
vaccine28
I/M26
M
M
ADA=anti-drug antibodies; -hCG=-human chorionic gonadotropin; BL=baseline; CD4=cluster of differentiation; 13-PCVConjugate 
pneumococcal vaccine; d day; ECG=electrocardiogram; eCRF=electronic case report form; EDSS=Expanded Disability Status Scale; 
FSH=follicle-stimulating hormone; I= immunization;; IV=intravenous;; KLH= Keyhole Limpet hemocyanin; M= measurement pre-immunization 
and/or post-baseline immunization assessment; OOE=Optional Ocrelizumab Extension Period; PK=pharmacokinetic; 23-PPV= 23-valent 
polysaccharide pneumococcus vaccine; RPR=rapid plasma reagin; SAE=serious adverse event; TT: Tetanus toxoid–containing vaccine; 
SC=subcutaneous; w=week; WDwithdrawal.  
1 The Screening Period can be extended to a total period of 8 weeks in cases when a laboratory blood test needs to be repeated for confirmation 
during the screening interval, if a live vaccine must be administered by the patient’s physician, or for other relevant clinical, administrative, or 
operational reasons.
2 The Immunization Study Period will end at Day 169 (Week 24).  Assessments shown under Immunization Study Period should be performed on 
all patients.  Assessments indicated in the OOE column should only be done if the patient chooses and is eligible to receive OCR.
3 Patients can continue to receive OCR (600 mg single infusion) at an interval of 24 weeks (minimum interval of 22 weeks).
4 Unscheduled Visit:  assessments performed at unscheduled (non-dosing) visits will depend on the clinical needs of the patient.  Other 
tests/assessments may be done as appropriate.
5 A delayed dosing visit will be performed and recorded in the Delayed Dosing Visit eCRF form when dosing cannot be administered at the 
scheduled dosing visit.  Other tests or assessments may be done as appropriate.


Appendix 1 Schedule of Assessments: Table A (cont.)
OcrelizumabF. Hoffmann-La Roche Ltd
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6 Informed Consent will be obtained in written form from all patients at screening in order to meet eligibility for the study.
7 Vital signs will be obtained while the patient is in the semi supine position (after 5 minutes), i.e., pulse rate, systolic, and diastolic blood 
pressure, respiration rate, and temperature.  On OCR infusion visits, the vital signs should be taken within 45 minutes prior to the 
methylprednisolone infusion in all patients.  In addition, vital signs should be obtained prior to the study drug infusion, then every 15 minutes 
(5 minutes) for the first hour; then every 30 minutes (10 minutes) until 1 hour after the end of the infusion.  On immunization days, vital signs 
should be taken prior to immunization.  On non-infusion/non-immunization days, the vital signs may be taken at any time during the visit.
8 ECG (pre- and post-dose):  On infusion visits, ECG should be taken within 45 minutes prior to the methylprednisolone infusion in all patients, 
and within 60 minutes after completion of the OCR infusion.  On non-infusion days, the ECG may be taken at any time during the visit.  
9 Weight should be obtained prior to the OCR infusion.
10 The EDSS should be obtained at baseline (pre-dose). An EDSS should also be performed if PML is suspected
11 MRI should be done at Baseline and annually throughout the OOE period (4-week window) as per Section 4.7.8.5. The annual MRIs in the 
OOE should be carried out as close as possible within a year of the baseline MRI performed at study entry.  It can be performed at an 
unscheduled visit or be carried out at a scheduled visit, e.g., at the visit scheduled 2 weeks prior to the next OCR infusion (Visit q22), where 
retreatment criteria are assessed.  Please note: at the withdrawal from Immunization Period or OOE Period, an MRI scan will be required only if 
not performed in the prior 4 weeks.
12 After  informed consent, but prior to initiation of study medications, only SAEs caused by a protocol-mandated intervention will be collected 
(e.g., SAEs related to  invasive procedures such as biopsies, medication washout, or no treatment run-in).
13 Telephone interview:  The telephone interview will be conducted by site personnel familiar with the patient(s) every 4 weeks (3 days) between 
the study visits throughout all periods and the SFU until 48 weeks after the last infusion of OCR. The telephone interview is done to identify and 
collect information on any changes in the patient’s health status that warrant an unscheduled visit. See Appendix 2 for the semi-structured 
telephone interview.
14 Pregnancy test: Serum -hCG must be performed at screening in women of childbearing potential.  Subsequently, urine -hCG [sensitivity of at 
least 25 mIU/mL] will be done.  On infusion and immunization visits, the urine pregnancy test should be performed prior to methylprednisolone 
infusion in all women of child-bearing potential.  If positive, do not dose and confirm with a serum pregnancy test.
15 ADA:  On infusion visits, samples are collected prior to the methylprednisolone infusion.
16 PK samples:  On infusion visits, a blood sample should be taken before the methylprednisolone infusion and on infusion visits at Weeks 1, 2, 
and 24 an additional sample within 30 minutes after the end of the OCR infusion.  At other times (non-infusion visits), samples may be taken at 
any time during the visit.
17 FSH:  FSH only applicable to women to confirm the post-menopausal status at screening.
18 Hepatitis screening: to be eligible, all patients must have negative a negative HepCAb, a negative HBsAg result and either negative HBcAb or 
a positive HBcAb but negative HBV DNA.
19 Hepatitis B virus DNA monitoring.  For those eligible patients enrolled with positive total HBcAb, HB virus DNA (PCR) must be repeated every 
24 weeks.


Appendix 1 Schedule of Assessments: Table A (cont.)
OcrelizumabF. Hoffmann-La Roche Ltd
105/Protocol BN29739, Version 8
20 CD4 count: will be measured separately at screening, and be included in the flow cytometry (FACS) panel at all following visits including every 
q22-week visit in order to inform eligibility/re-treatment criteria. Other re-treatment labs will be measured as part of IgG and routine safety labs 
(see item 21 and 22).
21 Flow cytometry: including CD19 and other circulating B-cell subsets, T-cells (including CD4 cells), NK cells and other leukocytes.  On the 
infusion days, samples should be collected prior to infusion of methylprednisolone.
22 Routine safety labs.  On infusion visits, all urine and blood samples should be collected prior to the infusion of methylprednisolone.   At other 
times, samples may be taken at any time during the visit.
23 All patients will receive prophylactic treatment with 100 mg of methylprednisolone IV 30 minutes prior to, and an IV or oral antihistamine such 
as diphenhydramine 50 mg 3060 minutes prior to OCR infusions. In patients where methylprednisolone is contraindicated, corresponding 
doses of other IV steroids (e.g., dexamethasone) may be used as premedication.  It is also recommended that patients receive an 
analgesic/antipyretic such as acetaminophen/paracetamol (1 g), 3060 minutes prior to OCR infusions.
24 Study drug administration:  The investigator must review the clinical and laboratory re-treatment criteria prior to re-dosing patients with study 
drug at Day 168 (Week 24) and prior to any subsequent OCR infusion.
25 Influenza vaccine and post-vaccination assessment for Group A2 only. Influenza can be administered between Weeks 1220. Post-vaccine 
assessments must be done after 4 weeks. For patients in Group A2 who are due to receive the influenza vaccine during their country-specific 
influenza vaccine blackout period, administration of the vaccine should be given prior to the start of this blackout period. Group A1 patients can 
receive the influenza vaccine at any time at the discretion of the investigator.
26 MSample to be taken prior to immunization on days when vaccines are administered. On infusion visits, all urine and blood samples should be 
collected prior to the infusion of methylprednisolone.  At other times, samples may be taken at any time during the visit.
27 Group A1 only.
28 TT-containing adsorbed vaccine refers to the combined tetanus and diphtheria (Td/DT) or tetanus, diphtheria, and acellular pertussis 
(DTaP/Tdap) vaccines.


Appendix 1 Schedule of Assessments: Table B 
OcrelizumabF. Hoffmann-La Roche Ltd
106/Protocol BN29739, Version 8
TABLE B:  SCHEDULE OF ASSESSMENTS FOR IMMUNIZATION STUDY PERIOD AND OPTIONAL OCRELIZUMAB
TREATMENT PERIOD
Group B
Screening
1
Immunization Study Period
OOE2,3
WD 
from 
Treat
ment4
Unsched
uled4
Delayed 
Dosing5
Study Day (Unless 
Noted)
Window 
-28 to -1
1
28 
(4 d)
56
(4 d)
841
(4 d)
841
(4 d)
98
(2 d)
238   
(4 d)
252
(2 d)
q22w
(4 d)
(-2 w 
prior to 
q24 w)
q24 w3
(2 w)
Week
-4 to -1

4
8
12
12
14
34
36
q22 w3
q24 w3
↓OCR infusion
↓
↓
↓
↓
Informed consent6
x
Medical history, MS 
history, prior and 
concomitant 
treatments
x
Eligibility review
x
x
x
x
x
Physical and 
neurological 
examination
x
x
x
x
x
x
x
x
x
Vital signs7
x
x
x
x
x
x
x
x
x
x
x
x
12-lead ECG8
x
x
x
x
x
x
x
Height
x


Appendix 1 Schedule of Assessments: Table B (cont.)
OcrelizumabF. Hoffmann-La Roche Ltd
107/Protocol BN29739, Version 8
Group B
Screening
1
Immunization Study Period
OOE2,3
WD 
from 
Treat
ment4
Unsched
uled4
Delayed 
Dosing5
Study Day (Unless 
Noted)
Window 
-28 to -1
1
28 
(4 d)
56
(4 d)
841
(4 d)
841
(4 d)
98
(2 d)
238   
(4 d)
252
(2 d)
q22w
(4 d)
(-2 w 
prior to 
q24 w)
q24 w3
(2 w)
Week
-4 to -1

4
8
12
12
14
34
36
q22 w3
q24 w3
Weight9
x
x
x
x
x
EDSS10
x
MRI (once annually  
[4 w])11
x
x
Adverse events
Only 
SAEs12
x
x
x
x
x
x
x
x
x
x
x
x
x
Telephone interview
Every 4 weeks13
Concomitant 
treatments
x
x
x
x
x
x
x
x
x
x
x
x
x
Pregnancy test14
x
x
x
x
x
x
x
x
x
x
x
x
ADA15
x
x
x
x
x
x
x
PK samples16
x
x
x
x
x
FSH17
x
Hepatitis screening18
x


Appendix 1 Schedule of Assessments: Table B (cont.)
OcrelizumabF. Hoffmann-La Roche Ltd
108/Protocol BN29739, Version 8
Group B
Screening
1
Immunization Study Period
OOE2,3
WD 
from 
Treat
ment4
Unsched
uled4
Delayed 
Dosing5
Study Day (Unless 
Noted)
Window 
-28 to -1
1
28 
(4 d)
56
(4 d)
841
(4 d)
841
(4 d)
98
(2 d)
238   
(4 d)
252
(2 d)
q22w
(4 d)
(-2 w 
prior to 
q24 w)
q24 w3
(2 w)
Week
-4 to -1

4
8
12
12
14
34
36
q22 w3
q24 w3
HBV DNA19
monitoring
x
x
x
x
x
x
x
RPR
x
CD4 count20
x
x
x
x
x
x
x
IgG subtype
x21
x21
x21
x
x
x
Total Ig, IgA, IgG, 
IgM
x
x
x
x
x
x
x
x
x
Flow cytometry22
x
x
x
x
x
x
x
x
x
Routine safety labs23
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Pretreatment with IV 
methylprednisolone
and an 
antihistamine24
x
x
x
x
x
IV OCR25
x
x
x
x
x


Appendix 1 Schedule of Assessments: Table B (cont.)
OcrelizumabF. Hoffmann-La Roche Ltd
109/Protocol BN29739, Version 8
Group B
Screening
1
Immunization Study Period
OOE2,3
WD 
from 
Treat
ment4
Unsched
uled4
Delayed 
Dosing5
Study Day (Unless 
Noted)
Window 
-28 to -1
1
28 
(4 d)
56
(4 d)
841
(4 d)
841
(4 d)
98
(2 d)
238   
(4 d)
252
(2 d)
q22w
(4 d)
(-2 w 
prior to 
q24 w)
q24 w3
(2 w)
Week
-4 to -1

4
8
12
12
14
34
36
q22 w3
q24 w3
Influenza26
M26 →Influenza →4 weeks 
M
KLH
I/M27
I/M27
I/M27
M
M27
23-PPV
I/M27
M
M
M27
TT-containing 
vaccine28
I/M27
M
M
ADA=anti-drug antibodies; -hCG=-human chorionic gonadotropin; BL=baseline; CD4=cluster of differentiation; 13-PCV-23= Conjugate 
pneumococcal vaccine; ECG=electrocardiogram; eCRF=electronic case report form; EDSS=Expanded Disability Status Scale; FSH=follicle-
stimulating hormone; I= immunization; IV=intravenous; KLH= Keyhole Limpet hemocyanin; M= measurement pre-immunization and/or post-
baseline immunization assessment;; OOE=Optional Ocrelizumab Extension Period; PK=pharmacokinetic; 23-PPV= 23-valent polysaccharide 
pneumococcus vaccine; RPR=rapid plasma reagin; SAE=serious adverse event; TT: Tetanus toxoid-containing vaccine SC=subcutaneous; 
w=week.
1 The screening period can be extended to a total period of 8 weeks in cases when a laboratory blood test needs to be repeated for confirmation 
during the screening interval, if a live vaccine must be administered by the patient’s physician, or for other relevant clinical, administrative, or 
operational reasons.
2 The Immunization Study Period will end at Day 84 (Week 12).  Assessments shown under Immunization Study Period should be performed on 
all patients.  Assessments indicated in the OOE column should only be done if the patient chooses and is eligible to receive OCR.
3 Patients can continue to receive OCR (600 mg, single infusion) at an interval of 24 weeks (minimum interval of 22 weeks).


Appendix 1 Schedule of Assessments: Table B (cont.)
OcrelizumabF. Hoffmann-La Roche Ltd
110/Protocol BN29739, Version 8
4 Unscheduled Visit:  assessments performed at unscheduled (non-dosing) visits will depend on the clinical needs of the patient.  Other 
tests/assessments may be done as appropriate.
5 A delayed dosing visit will be performed and recorded in the Delayed Dosing Visit eCRF form when dosing cannot be administered at the 
scheduled dosing visit.  Other tests or assessments may be done as appropriate.
6 Informed Consent will be obtained in written form from all patients at screening in order to meet eligibility for the study.
7 Vital signs will be obtained while the patient is in the semi supine position (after 5 minutes), i.e., pulse rate, systolic, and diastolic blood 
pressure, respiration rate, and temperature.  On OCR infusion visits, the vital signs should be taken within 45 minutes prior to the 
methylprednisolone infusion in all patients.  In addition, vital signs should be obtained prior to the study drug infusion, then every 15 minutes (5 
minutes) for the first hour; then every 30 minutes (10 minutes) until 1 hour after the end of the infusion.  On immunization days, vital signs 
should be taken prior to immunization.  On non-infusion/non-immunization days, the vital signs may be taken at any time during the visit.
8 ECG (pre- and post-dose):  On infusion visits, ECG should be taken within 45 minutes prior to the methylprednisolone infusion in all patients, 
and within 60 minutes after completion of the OCR infusion.  On non-infusion days, the ECG may be taken at any time during the visit.  
9 Weight should be obtained prior to the OCR infusion.
10 The EDSS should be obtained at baseline (pre-dose). An EDSS should also be performed if PML is suspected.
11 MRI should be done at Baseline and annually throughout the OOE Period, (4-week window) as per Section 4.7.8.5. The annual MRIs in the 
OOE should be carried out as close as possible within a year of the baseline MRI performed at study entry. It can be performed at an 
unscheduled visit or be carried out at a scheduled visit, e.g , at the visit scheduled 2 weeks prior the next OCR infusion (Visit q22), where 
retreatment criteria are assessed.  To reduce the burden of additional visits for Group B patients, the scheduling of the annual MRI can be 
adapted to the pre-infusion visit schedule starting from the first annual MRI after the baseline MRI.  Please note: at the withdrawal from treatment 
visits, an MRI scan will be required only if not performed in the prior 4 weeks.
12 After  informed consent, but prior to initiation of study medications, only SAEs caused by a protocol-mandated intervention will be collected 
(e.g., SAEs related to  invasive procedures such as biopsies, medication washout, or no treatment run-in).
13 Telephone interview:  A semi-structured telephone interview will be done on a 4-week (± 3 days) basis between visits from Week 5 to identify 
and collect information on any changes in the patient’s health status that warrant an unscheduled visit. See Appendix 2 for the semi-structured 
telephone interview.
14 Pregnancy test: Serum -hCG must be performed at screening in women of childbearing potential.  Subsequently, urine -hCG [sensitivity of at 
least 25 mIU/mL] will be done.  On infusion and immunization visits, the urine pregnancy test should be performed prior to methylprednisolone 
infusion in all women of child-bearing potential.  If positive, do not dose and confirm with a serum pregnancy test.
15 ADA:  On infusion visits, samples are collected prior to the methylprednisolone infusion.


Appendix 1 Schedule of Assessments: Table B (cont.)
OcrelizumabF. Hoffmann-La Roche Ltd
111/Protocol BN29739, Version 8
16 PK samples:  On infusion visits, a PK blood sample should be taken before the methylprednisolone infusion and on infusion visits at Weeks 12, 
14, and 36 an additional sample within 30 minutes after the end of the OCR infusion.  At other times (non-infusion visits), samples may be taken 
at any time during the visit.
17 FSH:  FSH only applicable to women to confirm the post-menopausal status at screening.
18 Hepatitis screening: to be eligible, all patients must have negative a negative HepCAb, a negative HBsAg result and either negative HBcAb or 
a positive HBcAb but negative HBV DNA.
19 Hepatitis B virus DNA monitoring.  For those eligible patients enrolled with positive total HBcAb, HB virus DNA (PCR) must be repeated every 
24 weeks.
20 CD4 count: will be measured separately at screening, and be part of the flow cytometry ( FACS) panel at all following visits, including every 
q22w visit in order to inform eligibility/re-treatment criteria. Other re-treatment labs will be measured as part of IgG and routine safety labs 
(see item 20).
21 IgG subtypes:  sample to be taken prior to immunization and /or OCR infusion. 
22 Flow cytometry: including CD19 and other circulating B-cell subsets, T-cells (including CD4 cells), NK cells and other leukocytes.  On the 
infusion days, samples should be collected prior to infusion of methylprednisolone.
23 Routine safety labs.  On infusion visits, all urine and blood samples should be collected prior to the infusion of methylprednisolone.   At other 
times, samples may be taken at any time during the visit.
24 All patients will receive prophylactic treatment with 100 mg of methylprednisolone IV 30 minutes prior to, and an IV or oral antihistamine such 
as diphenhydramine 50 mg 3060 minutes prior to OCR infusions. In patients where methylprednisolone is contraindicated, corresponding 
doses of other IV steroids (e.g., dexamethasone) may be used as premedication.  It is also recommended that patients receive an 
analgesic/antipyretic such as acetaminophen/paracetamol (1 g) 3060 minutes prior to OCR infusions.
25 Study drug administration:  The investigator must review the clinical and laboratory re-treatment criteria prior to dosing patients with study drug 
at Day 84 (Week 12) and prior to every subsequent OCR infusion.
26 Influenza vaccine for Group B: Influenza can be administered between Weeks 1 and 12.  For patients who need to receive the influenza vaccine 
after Week 12, the OCR infusion must be delayed.  Post-vaccine assessments must be done after 4 weeks. For patients in Group B who are due 
to receive the influenza vaccine during their countryspecific influenza vaccine blackout period, administration of the vaccine should be given 
prior to the start of this blackout period
27 MSample to be taken prior to immunization on days when vaccines are administered. On infusion visits, all urine and blood samples should be 
collected prior to the infusion of methylprednisolone.   At other times, samples may be taken at any time during the visit.
28 TT-containing adsorbed vaccine refers to the combined tetanus and diphtheria (DT/Td) or tetanus, diphtheria, and acellular pertussis 
(DTaP/Tdap) vaccines.


Appendix 1 Schedule of Assessments: Table C 
OcrelizumabF. Hoffmann-La Roche Ltd
112/Protocol BN29739, Version 8
TABLE C:  SCHEDULE OF ASSESSMENTS FOR SAFETY FOLLOW-UP PERIOD (ALL PATIENTS)
Safety Follow-Up1,8
End of Observation or withdrawal
from Safety Follow-Up1
Assessment
Visits every 12 weeks (±7 days)
Flow cytometry2
x
x
Telephone follow-up3
x
Urine pregnancy test
x
x
Routine safety labs4
x
x
Total Ig, IgA, IgG, IgM
x5
x
ADA6
x5
x
IgG subtype
x5
x
HBV DNA7
x
x
Vital signs
x
x
Physical and neurological 
examination
x5
x
Adverse events
x
x
Concomitant treatments
x
x
DNA=deoxyribonucleic acid; ADA= anti-drug- antibodies.


Appendix 1 Schedule of Assessments: Table C (cont.)
OcrelizumabF. Hoffmann-La Roche Ltd
113/Protocol BN29739, Version 8
1 Safety Follow-Up: Patients who discontinue treatment early for any reason and patients who complete the study treatment period will be 
followed up for 48 weeks after the last infusion of OCR. When patients begin an alternative treatment for MS (see Section 4.6.3.1 on 
prohibited therapies), or start commercial OCR, they will be discontinued from the SFU and from the study.
2 Flow cytometry:  including CD19 and other circulating B-cell subsets, T cells, NK cells, and other leukocytes.
3 A semi-structured telephone interview will be conducted by site personnel familiar with the patient(s) every 4 weeks (3 days) between the 
study visits throughout all periods and the SFU until 48 weeks after the last infusion of OCR. See Appendix 2 for the semi-structured telephone 
interview.
4 Routine safety labs:  hematology and chemistry.
5 Needs to be assessed only every 24 weeks.
6 ADA:  two serum samples are required.  
7 Hepatitis monitoring:  hepatitis to be monitored only in patients with screening results of HBsAg negative, HBcAb positive, and HBV DNA
negative, inclusive (HBcAb test to be done every 24 weeks).
8 A dedicated (scheduled or unscheduled) safety follow-up visit directly prior to the start of an alternative MS treatment is required for patients who 
begin an alternative treatment for MS while in safety follow-up in order to assess the patient’s clinical status and safety parameters.


OcrelizumabF. Hoffmann-La Roche Ltd
114/Protocol BN29739, Version 8
Appendix 2
Telephone Interviews
The purpose of this interview is to identify any new or worsening neurological symptoms 
that warrant an unscheduled visit and to collect data on possible events of infections.
Telephone interviews should be performed by study personnel every 4 weeks between 
clinic visits.
Please ask the following questions and record patient’s answers during the Telephone 
Interview:
Questions: No / Yes
1.
Since your last visit or telephone interview, have you had any new or worsening  
medical problems (such as sudden changes in your thinking, alterations in your 
behavior, visual disturbances, extremity weakness, limb coordination problems, or 
gait abnormalities) that have persisted over more than one day?
2.
Since your last visit or telephone interview, have you had any signs of infection?
3.
Since your last visit or telephone interview, have you had any other new or 
worsening medical problems or conditions (including pregnancy), surgery, or 
hospitalization?
4.
Since your last visit or telephone interview, have you taken any new medicines 
(including medicines to treat cancer or MS or any other new medicines that weaken 
your immune system or steroid medicines other than for the treatment of a recent 
relapse)?
If the patient answered YES to any question, contact the Investigator and review the 
patient’s answers.  The Investigator can determine if an unscheduled visit is required. 
Please record any relevant safety information in the appropriate eCRF form.
Record any pertinent comments made by the patient during the interview:
Patient ID:
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
NAME:______________________________ Date:______________________________
Name of person completing the telephone interview

SAP_000.pdf: 
 
Document Type: 
SAP 
Official Title: 
A PHASE IIIB, MULTICENTER, RANDOMIZED, PARALLEL-
GROUP, OPEN-LABEL STUDY TO EVALUATE THE EFFECTS OF 
OCRELIZUMAB ON IMMUNE RESPONSES IN PATIENTS WITH 
RELAPSING FORMS OF MULTIPLE SCLEROSIS 
NCT Number: 
NCT02545868 
Document Date(s): 
SAP: 7 November 2016 
 
 




Clinical Study Report: ocrelizumab - F. Hoffmann-La Roche Ltd
Protocol BN29739     Report Number 1079337
2122
 
TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................ 6 
2. 
STUDY DESIGN ........................................................................................... 6 
2.1 
Protocol Synopsis.................................................................... 7 
2.2 
Outcome Measures ................................................................. 7 
2.2.1 
Primary Immunization Outcome Measure................................ 7 
2.2.2 
Secondary Outcome Measures ............................................... 7 
2.2.3 
Immunophenotyping Outcome Measures................................ 8 
2.2.4 
Safety Outcome Measures ...................................................... 9 
2.3 
Determination of Sample Size ................................................. 9 
2.4 
Analysis Timing ....................................................................... 9 
3. 
STUDY CONDUCT....................................................................................... 9 
3.1 
Randomization Issues ............................................................. 9 
4. 
STATISTICAL METHODS .......................................................................... 10 
4.1 
Analysis Populations ............................................................. 10 
4.1.1 
Intent-to-Treat Population...................................................... 10 
4.1.2 
Observed Cases Population.................................................. 10 
4.1.3 
Safety Population .................................................................. 10 
4.2 
Analysis of Study Conduct..................................................... 11 
4.3 
Analysis of Treatment Group Comparability .......................... 11 
4.3.1 
Demography.......................................................................... 12 
4.3.2 
Multiple Sclerosis Disease History......................................... 12 
4.3.3 
Previous and Concomitant Diseases Other than 
Multiple Sclerosis................................................................... 12 
4.3.4 
Previous and Concomitant Treatments ................................. 13 
4.3.5 
Passive Immunization History and Vaccination 
History ................................................................................... 13 
4.3.6 
Expanded Disability Status Scale.......................................... 14 
4.3.7 
Pre-Vaccination/Pre-Immunization Immunology 
Assessments ......................................................................... 14 
4.3.8 
Baseline Magnetic Resonance Imaging Data........................ 15 
4.4 
Outcome Analysis.................................................................. 16 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
2/Statistical Analysis Plan BN29739 


Clinical Study Report: ocrelizumab - F. Hoffmann-La Roche Ltd
Protocol BN29739     Report Number 1079337
2123
4.4.1 
Primary Immunology Endpoint............................................... 16 
4.4.2 
Secondary Immunology Endpoints........................................ 17 
4.4.2.1 
Tetanus Toxoid Adsorbed Vaccine Response 
Measured 4 weeks after Vaccine Administration................... 17 
4.4.2.2 
23-Valent Pneumococcal Polysaccharide 
Vaccine and Pneumococcal Conjugate Booster.................... 18 
4.4.2.3 
Keyhole Limpet Hemocyanin................................................. 20 
4.4.2.4 
Influenza Vaccine Response ................................................. 20 
4.4.3 
Other Secondary Endpoints (Magnetic 
Resonance Imaging) ............................................................. 21 
4.4.4 
Exploratory Immunology Endpoints ....................................... 21 
4.4.4.1 
Overall Antibody Response to 23-PPV Vaccine .................... 21 
4.4.4.2 
Overall Antibody Response to 13-PCV Vaccine.................... 22 
4.4.5 
Sensitivity Analyses............................................................... 22 
4.4.6 
Subgroup Analyses ............................................................... 22 
4.5 
Immunophenotyping Analyses............................................... 22 
4.6 
Safety Analyses..................................................................... 23 
4.6.1 
Exposure to Study Medication (Ocrelizumab)........................ 23 
4.6.1.1 
Exposure to Ocrelizumab during the ISP............................... 23 
4.6.1.2 
Exposure to Ocrelizumab during the OOE............................. 24 
4.6.2 
Adverse Events ..................................................................... 25 
4.6.2.1 
Adverse Events during the ISP.............................................. 25 
4.6.2.2 
Adverse Events during the OOE............................................ 27 
4.6.2.3 
Adverse Events, All Study Periods ........................................ 27 
4.6.3 
Selected Adverse Events....................................................... 28 
4.6.3.1 
Progressive Multifocal Leukoencephalopathy........................ 28 
4.6.3.2 
Infections and Serious Infections........................................... 28 
4.6.3.3 
Infusion-Related Reactions.................................................... 28 
4.6.3.4 
Malignancies and Premalignant Lesions ............................... 30 
4.6.4 
Laboratory Data..................................................................... 30 
4.6.4.1 
General Laboratory Evaluation.............................................. 30 
4.6.4.2 
Anti-Drug Antibodies.............................................................. 31 
4.6.5 
Vital Signs and Electrocardiogram......................................... 31 
4.6.6 
Pregnancies........................................................................... 32 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
3/Statistical Analysis Plan BN29739 


Clinical Study Report: ocrelizumab - F. Hoffmann-La Roche Ltd
Protocol BN29739     Report Number 1079337
2124
4.7 
Missing Data.......................................................................... 32 
4.8 
Interim Analyses .................................................................... 32 
 
 
LIST OF APPENDICES 
Appendix 1 
Protocol Synopsis ....................................................................... 33 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
4/Statistical Analysis Plan BN29739 


Clinical Study Report: ocrelizumab - F. Hoffmann-La Roche Ltd
Protocol BN29739     Report Number 1079337
2125
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
13-PCV 
13-valent pneumococcal conjugate vaccine 
23-PPV 
23-valent pneumococcal polysaccharide vaccine 
ADA 
anti-drug antibody 
CCOD 
clinical cutoff date 
eCRF 
electronic Case Report Form 
EDSS 
Expanded Disability Status Scale 
ELISA 
enzyme-linked immunosorbent assay 
Gd 
gadolinium 
GMT 
geometric mean titer 
HI 
hemaglutination inhibition 
IFN-β 
interferon beta 
Ig 
immunoglobulin 
IgA 
immunoglobulin A 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
IRR 
infusion-related reaction 
ISP 
Immunization Study Period 
ITT 
Intent-to-Treat 
IV 
intravenous 
KLH 
keyhole limpet hemocyanin 
LLQ 
lower limit of quantification 
MRI 
magnetic resonance imaging 
MS 
multiple sclerosis 
OC 
Observed Cases 
OOE 
Optional Ocrelizumab Extension 
PK 
pharmacokinetic 
PML 
progressive multifocal leukoencephalopathy 
PT 
Preferred Term 
RMS 
relapsing forms of multiple sclerosis 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SFU 
Safety Follow-Up 
SOC 
System Organ Class 
SPMS 
secondary progressive multiple sclerosis 
TB 
tuberculosis 
TT 
tetanus toxoid 
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1. 
BACKGROUND 
This Phase IIIb, multicenter, randomized, open-label study is designed to evaluate 
immune response to vaccines in patients with relapsing forms of multiple sclerosis (MS) 
after administration of a dose of ocrelizumab. 
The clinical cutoff date (CCOD) will be the earliest date on which all randomized patients 
will have completed the Week 24 visit for Group A, completed the Week 12 visit for 
Group B, or prematurely discontinued during the Immunization Study Period (ISP) if they 
have discontinued before the Week 24 visit for Group A or before the Week 12 visit for 
Group B.   
The scope of this statistical analysis plan includes the following: 
• 
The primary analysis of immunology and safety endpoints evaluated in the ISP 
• 
Analysis of all data available at the CCOD from the following periods: 
The Optional Ocrelizumab Extension (OOE) after completing the ISP 
The Safety Follow-Up (SFU) Period after the ISP for patients who did not enter 
the OOE 
The SFU Period after completing the OOE 
 
2. 
STUDY DESIGN 
This Phase IIIb, multicenter, randomized, open-label study is designed to evaluate 
immune response to vaccines after administration of a dose of ocrelizumab. 
The study consists of the following periods:  Screening, an ISP, an OOE, SFU, and a 
Continued B-cell Monitoring Period. 
Following screening, approximately 100 adult patients will be randomized into Groups A 
and B (2:1 active:control) to compare responses to immunization.  Patients in Group B 
are to receive immunization with tetanus toxoid (TT)-containing adsorbed vaccine, 23-
valent pneumococcal polysaccharide vaccine (23-PPV), influenza vaccine, and repeated 
administration with keyhole limpet hemocyanin (KLH).  Group B patients will not receive 
ocrelizumab, but will remain treatment-naïve or continue with interferon beta (IFN-β) 
treatment until optional ocrelizumab treatment at the end of the ISP. 
Patients in Group A are to first receive a 600 mg dose of ocrelizumab, 300mg on Day 1 
(Infusion 1) and 300mg on Day 15 (Infusion 2), and starting 12 weeks after Day 1 
(Infusion 1 of ocrelizumab) are to receive a similar immunization course to Group B.  
Group A will be further subdivided into two groups (non-randomly, based on seasonality 
considerations) to evaluate the effectiveness of a booster 13-valent pneumococcal 
conjugate vaccination (13-PCV; Group A1) or influenza vaccination (Group A2).  For 
additional details, see the protocol and Schedule of Assessments. 
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2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is in Appendix 1.  Please note that, in the event that the version 
of the protocol synopsis in Appendix 1 differs from the version in the current protocol, 
then the version in the current protocol takes precedence over the version included in 
this Statistical Analysis Plan (SAP).  Appendix 1 will only be updated in the event that 
the protocol synopsis amended in the future and includes changes that impact this SAP. 
2.2 
OUTCOME MEASURES 
2.2.1 
Primary Immunization Outcome Measure 
The primary outcome measure is the proportion of patients in Groups A (i.e., combined 
Groups A1 and A2) and B with a positive response (IgG) to TT vaccine measured 8 
weeks after TT vaccine administration (defined fully in Section 4.4.1). 
2.2.2 
Secondary Outcome Measures 
The secondary outcome measures are as follows: 
• 
TT response 
The proportion of patients in Groups A (A1 and A2 combined) and B with a 
positive response (IgG) to TT vaccine measured 4 weeks after booster TT 
vaccine administration (defined fully in Section 4.4.2.1) 
Mean levels of anti-tetanus antibody in patients in Groups A (A1 and A2 
combined) and B measured immediately prior to and 4 weeks after a booster 
TT vaccine 
• 
23-valent pneumococcal polysaccharide vaccine (23-PPV) response and 13-PCV 
booster response: 
The proportion of patients in Groups A1, A2, A (A1 and A2 combined), and B 
with positive responses against an individual anti-pneumococcal antibody 
serotype measured 4 weeks after the 23-PPV (23 serotypes) (defined fully in 
Section 4.4.2.2) 
The proportion of patients in Groups A1, A2, A (A1 and A2 combined), and B 
with a positive response against at least 2 out of the 23 serotypes measured 4 
weeks after and 8 weeks after administration of the 23-PPV vaccine (defined 
fully in Section 4.4.2.2) 
The proportion of patients in Groups A1, A2, A (A1 and A2 combined), and B 
with positive responses against at least 50% of the serotypes (≥ 12 of 23) 
measured 4 weeks after administration of the 23-PPV vaccine (defined fully in 
Section 4.4.2.2) 
The proportion of patients in Groups A1, A2, A (A1 and A2 combined), and B 
with positive responses against each of the 23 serotypes measured 8 weeks 
after patients received the 23-PPV vaccine (which is 4 weeks after Group A1 
received the booster 13-PCV) (defined fully in Section 4.4.2.2) 
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Mean levels of anti-pneumococcal antibody (23 serotypes) in patients in 
Groups A1, A2, A (A1 and A2 combined), and B measured immediately prior 
to, 4 weeks after and 8 weeks after patients received the 23-PPV (this is 4 
weeks after Group A1 received the 13-PCV immunization) 
• 
KLH 
Mean levels of anti-KLH antibody (IgG) in patients in Groups A (A1 and A2 
combined) and B measured immediately prior to the first administration of KLH 
and 4 weeks after the last administration of KLH 
Mean levels of anti-KLH antibodies (IgG and IgM) in Groups A (A1 and A2 
combined) over time at 4, 8, and 12 weeks after first KLH immunization 
• 
Influenza vaccine response: 
Proportion of patients in Groups A2 and B who achieve seroprotection defined 
as specific hemaglutination inhibition (HI) titers > 40 at 4 weeks post-
immunization 
Proportion of patients in Groups A2 and B who achieve a 2-fold increase in 
specific HI titers at 4 weeks post-immunization 
Proportion of patients in Groups A2 and B who achieve a 4-fold increase in 
specific HI titers at 4 weeks post-immunization 
Proportion of patients in Groups A2 and B with seroconversion (i.e., a 
pre-vaccination antibody titer < 10 and a post-vaccination HI titer > 40) 
Strain−specific geometric mean titers (GMTs) in patients in Groups A2 and B at 
baseline and Week 4 
Strain−specific GMT ratio (post-vaccination:pre-vaccination) in patients in 
Groups A2 and B 
• 
Magnetic resonance imaging (MRI) assessments in patients in Groups A (A1 and 
A2 combined) and B to evaluate the long-term effects of ocrelizumab on MRI 
parameters of disease activity and progression during the OOE 
 
2.2.3 
Immunophenotyping Outcome Measures 
The humoral and cellular immunity outcome measures in this study are as follows: 
• 
Flow cytometry panel (i.e., circulating B cells and T cells), which will include (but is 
not limited to) the following cells: 
Total B cells (CD19+) 
B-cell subsets (e.g., memory B cells, naïve B cells, and plasma cells) 
Total T cells (CD3+) 
T helper cells (CD3+ and CD4+) 
Cytotoxic lymphocyte T (CD3+and CD8+) 
Natural killer cells (CD3− and CD16/56+) 
• 
Quantitative Ig:  Ig levels (including total Ig, IgG, IgG subtypes, IgM, and IgA) 
 
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2.2.4 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Vital signs pre-, during, and post-infusion 
• 
Hematologic laboratory tests 
• 
Anti-drug antibody (ADA) formation 
• 
Urinalyses 
• 
Incidence and severity of adverse events associated with ocrelizumab and study 
immunizations 
 
2.3 
DETERMINATION OF SAMPLE SIZE 
For the positive response to TT-containing adsorbed vaccine measured 8 weeks after 
the administration of vaccine, if both the control and active (ocrelizumab) groups have 
70% response rates, the expected half-width of the resulting 95% CI of the difference of 
2 response rates is 0.201.  To achieve this precision, approximately 100 patients will be 
enrolled using a 2:1 randomization ratio into active ocrelizumab (Group A) and control 
(Group B) groups. 
2.4 
ANALYSIS TIMING 
The primary analysis of immunology and safety endpoints evaluated in the ISP and the 
analysis of available OOE data will be performed at the CCOD, which is defined as the 
date when all randomized patients have completed the Week 24 visit for Group A or the 
Week 12 visit for Group B, or the date on when all randomized patients have 
prematurely discontinued the ISP if they have discontinued before the Week 24 visit for 
Group A or before the Week 12 visit for Group B. 
Regular interim safety analyses may be performed, approximately every 6 months, to 
allow pooled safety analyses of MS patients treated with ocrelizumab.  These analyses 
are not described in this document. 
Interim pharmacokinetic (PK) analyses may also be performed during the study.  These 
PK analyses are not described here but in a separate document. 
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION ISSUES 
Patients were randomized into two groups (Group A or Group B) in a 2:1 randomization 
ratio.  Randomization was performed by an independent vendor via an interactive 
response system. 
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4. 
STATISTICAL METHODS 
Except where stated otherwise, all tabular and graphical summaries of data, which are 
presented by treatment group, will separately show results from the following four groups: 
• 
Group A1 (ocrelizumab + 13-PCV vaccine) 
• 
Group A2 (ocrelizumab + influenza vaccine) 
• 
Group A overall (Groups A1 + A2) 
• 
Group B (control) 
 
All listings will show study data for each treatment group in the order shown above. 
4.1 
ANALYSIS POPULATIONS 
4.1.1 
Intent-to-Treat Population 
All randomized patients will be included in the Intent-to-Treat (ITT) Population.  Patients 
who prematurely withdraw from the study for any reason and for whom an assessment is 
not performed for whatever reason will still be included in the ITT analysis.  Patients who 
receive an incorrect medication or vaccination rather than the one they are assigned to 
will be summarized according to their randomized treatment group. 
In the event that at least 1 randomized patient withdraws from the study before the end 
of the ISP, then tabular summaries of baseline characteristics only will be presented for 
the ITT Population.  If all randomized patients complete the ISP, then no 
summaries/analyses will be presented for ITT Population. 
4.1.2 
Observed Cases Population 
The Observed Cases (OC) Population is defined as all randomized patients who 
complete the ISP.  Patients who receive an incorrect medication or vaccination rather 
than the one that they are assigned to will be summarized according to their randomized 
treatment group. 
All immunization outcome measures will be analyzed using the OC Population. 
4.1.3 
Safety Population 
The Safety Population will include all patients who received any ocrelizumab or any 
vaccine.  Randomized patients who received an incorrect medication or vaccine rather 
than the one they were assigned to will be summarized in the group according to the 
medication or vaccine actually received. 
All safety outcome measures will be analyzed using the Safety Population. 
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4.2 
ANALYSIS OF STUDY CONDUCT 
All data up to the point of the CCOD will be included to evaluate study conduct.  This will 
include complete data from the ISP and any data from the OOE and SFU Periods 
available at the CCOD. 
The following analyses will be performed to evaluate the study conduct: 
• 
Summary of enrollment by country and center (numbers and percentages of 
patients enrolled, presented by treatment group) 
Summaries of randomized patients, of the ITT Population if any summaries are 
produced for this population, and of the OC and Safety Populations (numbers 
and percentages of patients in each population, presented by treatment group) 
• 
Summary of patient disposition for the ISP and OOE and SFU Periods (at each 
visit/during each study period, numbers and percentages of patients completing, 
discontinuing and ongoing, presented by treatment group) 
• 
Summary of reasons for patients discontinuing during the following study periods 
(numbers and percentages of patients discontinuing for each reason within each 
period, presented by treatment group): 
ISP 
SFU Period after the ISP (these patients did not enter the OOE) 
OOE 
SFU Period after completing the OOE 
Study as a whole 
A listing of reasons for all patient discontinuations from the study will also be 
provided. 
• 
Listing of key eligibility criteria violations and other major protocol deviations 
 
4.3 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
For continuous variables, the mean, median, SD, minimum and maximum will be 
presented for each treatment group.  For categorical variables, number and percentage 
of patients in each category will be presented for each treatment group.   
Except where stated, all assessments of treatment group comparability will utilize the 
date of the baseline visit (not the date of the screening visit) as the reference point in 
time. 
Except where stated, summary tables will be presented for both OC and Safety 
Populations.  In the event that at least one randomized patient withdraws from the study 
before the end of the ISP, then tabular summaries of baseline characteristics will also be 
presented for the ITT Population. 
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4.3.1 
Demography 
The following demographic characteristics will be analyzed: 
• 
Age (years):  summary statistics, including mean, median, SD, minimum and 
maximum, percentage, and number in each age (at randomization) category (age 
categories < 18, 18−65, > 65, used in the Development Safety Update Report)  
• 
Sex:  number and percentage of male and female patients 
• 
Race:  number and percentage of patients who are White, Black or African 
American, Asian (Indian Subcontinent, Other than Indian subcontinent), American 
Indian or Alaskan native, Native Hawaiian or other Pacific Islander, and Other 
• 
Ethnicity:  number and percentage of patients who are Hispanic or Latino and not 
Hispanic or Latino 
• 
Weight (kg):  summary statistics, including mean, median, SD, minimum, and 
maximum 
• 
Body mass index (calculated from weight and height):  summary statistics, including 
mean, median, SD, minimum, and maximum  
 
Listings will be provided for demography and for randomization information. 
4.3.2 
Multiple Sclerosis Disease History 
The following MS disease history characteristics will be analyzed: 
• 
Duration since MS-symptom onset (years; i.e., divided by 365.25):  summary 
statistics, including mean, median, SD, minimum, and maximum  
• 
Duration since MS diagnosis (years; i.e., divided by 365.25):  summary statistics 
calculated, including mean, median, SD, minimum, and maximum  
Duration since MS symptom/diagnosis onset will be calculated up to the 
randomization date.  If the month of symptom/diagnosis onset date is missing, 
the month of January will be used.  If the day of symptom/diagnosis onset date 
is missing, the first of the month will be used. 
• 
Type of MS diagnosed:  number and percentage of patients with relapsing MS, 
secondary progressive MS with relapses (SPMS with relapses), secondary 
progressive MS without relapses (SPMS without relapses), progressive relapsing 
MS, and primary progressive MS 
 
A listing of MS disease history will also be provided. 
4.3.3 
Previous and Concomitant Diseases Other than Multiple 
Sclerosis 
The following previous and concomitant diseases other than MS will be analyzed: 
• 
Previous diseases (other than MS) by System Organ Class (SOC) and Preferred 
Term (PT):  number and percentage of patients with previous non-MS diseases, and 
number and percentage of patients with a history of each disease 
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• 
Concomitant diseases (other than MS) by SOC and PT:  number and percentage of 
patients with concomitant non-MS diseases, and number and percentage of patients 
with each disease 
 
A glossary listing of SOC terms, PTs, and verbatim terms for all diseases will also be 
provided. 
4.3.4 
Previous and Concomitant Treatments 
Summaries of previous and concomitant treatments will be presented for the Safety 
Population only.  The number of treatments and number and percentages of patients 
receiving treatments will be presented. 
Treatments for MS 
The following treatments for MS will be summarized: 
• 
Previous treatments for MS by superclass term and PT 
• 
IFN-β concomitant treatment allowed for MS during the ISP for patients in Group B  
• 
Concomitant treatments for MS starting during the SFU Period following the ISP by 
PT for patients who did not enter the OOE   
• 
Concomitant treatments for MS starting during the SFU Period following the OOE by 
PT   
 
A listing of previous MS treatments by PT will be presented. 
Other Treatments 
The following other treatments will be analyzed: 
• 
Previous treatments by superclass term and PT 
• 
Previous procedures/surgeries by superclass term and PT  
• 
Concomitant treatment present at baseline by superclass term and PT 
• 
Procedures/surgeries present at baseline by superclass term and PT 
 
A glossary listing of superclass terms, PTs, and verbatim terms for all medications and 
procedures will be provided.  A glossary listing of grouping (procedures category), 
superclass terms, and PTs will also be provided. 
4.3.5 
Passive Immunization History and Vaccination History 
The following information on passive immunization history and vaccination history will be 
analyzed: 
• 
Passive immunization history:  number and percentage of patients (yes or no) who 
have received the following passive immunizations:  tetanus immunoglobulin, 
hepatitis B immunoglobulin, hepatitis A immunoglobulin, rabies antiserum, varicella 
zoster immunoglobulin, and other 
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• 
Vaccination history:  number and percentage of patients (yes or no) who have 
received the following vaccinations:  tetanus, pneumococcus polysaccharide, 
pneumococcal booster, diphtheria, influenza, KLH, varicella, measles, mumps, 
rubella, hepatitis B, hepatitis A, bacillus Calmette-Guerin, polio, pertussis, 
haemophilus influenza B, meningococcal, typhoid, yellow fever, smallpox, rotavirus, 
human papilloma virus, herpes zoster, and other.  For tetanus, the number of years 
since prior tetanus vaccination will be summarized (summary statistics: mean, 
median, SD, minimum, and maximum). 
 
Listings of passive immunization history and vaccination history will also be provided. 
4.3.6 
Expanded Disability Status Scale 
The following characteristics of baseline Expanded Disability Status Scale (EDSS) (pre-
dose) will be analyzed: 
• 
Number and percentage of patients in each EDSS category (< 4.0, and ≥ 4.0) 
• 
Summary statistics, including mean, median, SD, minimum, and maximum  
 
A listing of all EDSS assessments made during the whole study will be provided.  Since 
an EDSS assessment should be performed if progressive multifocal 
leukoencephalopathy (PML) is suspected, this listing will include all available EDSS 
assessments, i.e., baseline and postbaseline. 
4.3.7 
Pre-Vaccination/Pre-Immunization Immunology Assessments 
For the OC Population, the following pre-vaccination/pre-immunization immunology 
assessments will be summarized descriptively (note that, by design, some of these pre-
vaccination/pre-immunization assessments are taken after baseline [Day 1]): 
• 
Levels of anti-tetanus antibodies in patients measured prior to booster TT vaccine 
administration (prior to the start of ocrelizumab treatment) 
• 
Levels of anti-pneumococcal antibody (μg/mL) against each of the 23 different 
serotypes (see Section 4.4.2.2) measured prior to administration of the 23-PPV 
vaccine 
• 
Levels of anti-pneumococcal antibody (μg/mL) against each of the 23 different 
serotypes (see Section 4.4.2.2) measured 4 weeks after administration of the 23-
PPV vaccine (which, for Group A1 patients, is prior to administration of the 13-PCV 
booster vaccine) 
• 
Levels of anti-KLH antibody IgG measured immediately prior to first KLH 
administration (prior to the start of ocrelizumab treatment) 
• 
In Groups A2 and B only, strain-specific GMTs measured immediately prior to 
immunization with the influenza vaccine (which can occur prior to or after the start of 
ocrelizumab treatment) 
 
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Each assessment listed above will be summarized descriptively by treatment group (as 
individually specified for each assessment) for the following summary statistics: 
• 
Number and percentage of patients with values ≤ lower limit of quantification (LLQ) 
• 
Number and percentage of patients with values > LLQ 
• 
Geometric mean of known values > LLQ 
• 
95% CI for geometric mean of known values > LLQ, calculated using a normal 
approximation method on the log scale and then back-transformed to the original 
scale 
• 
Geometric mean of all nonmissing values, imputing LLQ ÷ 2 for values ≤ LLQ 
• 
95% CI for geometric mean of all nonmissing values, imputing LLQ ÷ 2 for values 
≤ LLQ, calculated using a normal approximation method on the log scale and then 
back-transformed to the original scale 
• 
Median of known values > LLQ 
• 
Median of all nonmissing values, imputing LLQ ÷ 2 for values ≤ LLQ 
 
Pre-vaccination/pre-immunization assessments for the following exploratory immunology 
endpoints may be summarized descriptively using the same statistics listed above, 
depending on data availability at the time of the primary analysis: 
• 
Overall levels of antibodies to the 23-PPV vaccine, i.e., IgG (using ELISA), 
measured prior to administration of the 23-PPV 
• 
Overall levels of antibodies to the 23-PPV vaccine, i.e., IgM (using ELISA), 
measured prior to administration of the 23-PPV vaccine 
• 
Levels of overall antibody response to the 13-PCV vaccine, i.e., IgG (using ELISA), 
measured 4 weeks after administration of the 23-PPV vaccine (which, for Group A1 
patients, is prior to administration of the 13-PCV booster vaccine) 
• 
Levels of overall antibody response to the 13-PCV vaccine, i.e., IgM ( using ELISA), 
measured 4 weeks after administration of the 23-PPV vaccine (which, for Group A1 
patients, is prior to administration of the 13-PCV booster vaccine) 
 
4.3.8 
Baseline Magnetic Resonance Imaging Data 
The following characteristics of baseline MRI data will be analyzed: 
• 
Volume of T2 lesions at baseline:  summary statistics, including mean, median, SD, 
minimum, and maximum 
• 
Number of T2 lesions at baseline:  summary statistics, including mean, median, SD, 
minimum and maximum, and number and percentage of patients in each category 
(0−5, 6−9, and > 9 T2 lesions at baseline) 
• 
Number of gadolinium (Gd)-enhancing T1 lesions at baseline:  summary statistics, 
including mean, median, SD, minimum and maximum, and number and percentage 
of patients in each category (0, 1, 2, 3, and ≥ 4 Gd-enhancing T1 lesions at baseline) 
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• 
Normalized brain volume at baseline:  summary statistics, including mean, median, 
SD, minimum, and maximum 
• 
White matter volume at baseline:  summary statistics, including mean, median, SD, 
minimum, and maximum 
• 
Cortical grey matter volume at baseline:  summary statistics, including mean, 
median, SD, minimum, and maximum 
• 
Un-enhancing T1-lesion volume at baseline:  summary statistics, including mean, 
median, SD, minimum, and maximum 
• 
Number of T1 hypo-intense lesions (black holes) at baseline:  summary statistics, 
including mean, median, SD, minimum, and maximum 
 
A listing of MRI assessments at baseline will be provided. 
4.4 
OUTCOME ANALYSIS 
No hypothesis testing will be performed. 
For immunology endpoints, pre-immunization levels are those obtained immediately 
prior to administration of a vaccine. 
Patients with missing immunology assessment data will not be included in the 
calculations.  No missing data imputation methods will be applied. 
For immunology endpoints, except where stated, tabular presentations will show Group 
A (Groups A1 and A2 combined) and Group B.  
Summaries will be presented for the OC Population only. 
4.4.1 
Primary Immunology Endpoint 
The primary outcome measure is the proportion of patients in Groups A and B with a 
positive response (IgG) to TT adsorbed vaccine measured 8 weeks after TT booster 
vaccine administration.  Positive response is defined as follows:  
• 
For patients with pre-immunization tetanus antibody titers < 0.1 IU/mL, a positive 
response to the booster TT immunization is defined as an antibody titer ≥ 0.2 IU/mL 
measured 8 weeks after immunization. 
• 
For patients with pre-immunization tetanus antibody titers ≥ 0.1 IU/mL, a positive 
response to the booster TT immunization is defined as a 4-fold increase in antibody 
titers measured 8 weeks after immunization compared with pre-immunization levels. 
 
The number and proportion of patients with a positive response to TT adsorbed vaccine 
will be presented by treatment group.  The difference between treatment groups A and B 
in positive response rates and the associated 95% CI will also be presented using a 
normal approximation method. 
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Levels of anti-tetanus antibody in patients in Groups A and B measured 8 weeks after a 
booster TT vaccine administration will be summarized descriptively by treatment, 
showing the following summary statistics: 
• 
Number and percentage of patients with values ≤ LLQ 
• 
Number and percentage of patients with values > LLQ 
• 
Geometric mean of known values > LLQ 
• 
95% CI for geometric mean of known values > LLQ, calculated using a normal 
approximation method on the log scale and  then back-transformed to the original 
scale 
• 
Geometric mean of all nonmissing values, imputing LLQ ÷ 2 for values ≤ LLQ 
• 
95% CI for geometric mean of all nonmissing values, imputing LLQ ÷ 2 for values 
≤ LLQ, calculated using a normal approximation method on the log scale and then 
back-transformed to the original scale 
• 
Median of known values > LLQ 
• 
Median of all nonmissing values, imputing LLQ ÷ 2 for values ≤ LLQ 
 
To aid comparison back to pre-vaccination levels, the following pre-vaccination summary 
statistics will also be included in the tabular summary at 8 weeks: 
• 
Geometric mean of known pre-vaccination values > LLQ  
• 
Geometric mean of all nonmissing pre-vaccination values, imputing LLQ ÷ 2 for 
values ≤ LLQ  
 
4.4.2 
Secondary Immunology Endpoints 
4.4.2.1 
Tetanus Toxoid Adsorbed Vaccine Response Measured 
4 weeks after Vaccine Administration 
The proportion of patients in Groups A and B with a positive response (IgG) to TT 
vaccine measured 4 weeks after TT vaccine administration will be compared.  Positive 
response is defined as follows (this differs from the definition of response used for the 8-
week assessment above):  
• 
For patients with pre-immunization tetanus antibody titers < 0.1 IU/mL, a positive 
response to the booster TT immunization is defined as an antibody titer ≥ 0.2 IU/mL 
measured 4 weeks after immunization. 
• 
For patients with pre-immunization tetanus antibody titers ≥ 0.1 IU/mL, a positive 
response to the booster TT immunization is defined as a 2-fold increase in antibody 
titers measured 4 weeks after immunization compared with pre-immunization levels. 
 
The number and proportion of patients with a positive response to TT adsorbed vaccine 
will be presented by treatment group.  The difference between treatment groups A and B 
in positive response rates and the associated 95% CI will also be presented using a 
normal approximation method. 
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Levels of anti-tetanus antibody in patients in Groups A and B measured 4 weeks after a 
booster vaccine will be summarized descriptively by treatment group using the same 
summary statistics as presented above for the primary immunology endpoint at 8 weeks 
after vaccine administration. 
4.4.2.2 
23-Valent Pneumococcal Polysaccharide Vaccine and 
Pneumococcal Conjugate Booster 
The 23-PPV vaccine is assessed by measurement of 23 anti-pneumococcal antibody 
serotypes (1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 
20, 22F, 23F, and 33F).  The 13-PCV vaccine acts as a booster to the 23-PPV vaccine, 
and the 13-PCV vaccine is assessed by measurement of 13 anti-pneumococcal antibody 
serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F).  At the time this SAP 
was prepared, it is known that no data can be reported for Serotype 6A.  Therefore only 
12 of the planned 13 serotypes can be analysed for the 13-PCV booster, and all of these 
12 serotypes are included in the 23 serotypes which make up the 23-PPV assessments. 
Group A1:  Patients in Group A1 receive the 23-PPV vaccine at Week 16 and also the 
13-PCV booster vaccination 4 weeks later at Week 20.  All 23 serotypes are assessed 
immediately prior to 23-PPV vaccination at Week 16, again prior to the 13-PCV “booster” 
4 weeks later at Week 20, and then again 4 weeks after that at Week 24. 
Group A2:  Patients in Group A2 receive the 23-PPV vaccine at Week 16, but do not 
receive the 13-PCV “booster”.  All 23 serotypes are assessed immediately prior to 23-
PPV vaccination at Week 16, again 4 weeks later at Week 20 and again 4 weeks after 
that at Week 24. 
Group B:  Patients in Group B follow a similar schedule to Group A2, but earlier in the 
study.  They receive the 23-PPV vaccine at Week 4, and do not receive the 13-PCV 
“booster”.  All 23 serotypes are assessed immediately prior to 23-PPV vaccination at 
Week 4, again 4 weeks later at Week 8 and again 4 weeks after that at Week 12. 
Summaries will show the following groups separately:  Group A1, Group A2, Group A 
(Groups A1 and A2 combined), and Group B.  Pairwise between-group comparisons will 
show: 
• 
Group A1 versus Group A2 
• 
Group A1 versus Group B 
• 
Group A2 versus Group B 
• 
Group A (A1 and A2 combined) versus Group B 
 
Note that the first 3 of the 4 comparisons above, which involve treatment groups A1 and 
A2 separately, should be interpreted with some caution, since patients were not 
assigned to these 2 treatment groups randomly (patients were randomized to Group A or 
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Group B, and within Group A were non-randomly assigned to Group A1 or A2, based on 
seasonality considerations). 
A positive response against a serotype is defined as developing either a 2-fold increase 
in level or a > 1 μg/mL rise in level, compared with pre-immunization levels. 
At 4 weeks after the 23-PPV vaccine, the number and proportion of patients in Groups 
A1, A2, A (A1 and A2 combined), and B with a positive response (as defined above) 
against each of the 23 serotypes will be presented.  For the same 4 pairwise between-
group comparisons described earlier in this section, pairwise between-group differences 
in positive response rates and the associated 95% CI will also be presented for each 
serotype, using a normal approximation method. 
At 4 weeks after the 23-PPV vaccine, the number and proportion of patients in Groups 
A1, A2, A (A1 and A2 combined), and B with positive responses (as defined above) 
against at least 2 of the 23 serotypes will also be presented.  For the same 4 pairwise 
between-group comparisons described earlier in this section, pairwise between-group 
differences in response rates and the associated 95% CI will also be presented, using a 
normal approximation method. 
At 4 weeks after the 23-PPV vaccine, the number and proportion of patients in Groups 
A1, A2, A (A1 and A2 combined), and B with positive responses (as defined above) 
against at least 50% of the serotypes (≥ 12 of 23) will also be presented.  For the same 
4 pairwise between-group comparisons described earlier in this section, pairwise 
between-group differences in response rates and the associated 95% CI will also be 
presented, using a normal approximation method. 
At 8 weeks after the 23-PPV vaccine (which is 4 weeks after Group A1 patients received 
the 13-PCV booster), the number and proportion of patients in Groups A1, A2, A (A1 and 
A2 combined), and B with a positive response (as defined above) against each of the 23 
serotypes will be presented.  For the same 4 pairwise between-group comparisons 
described earlier in this section, pairwise between-group differences in positive response 
rates and the associated 95% CI will also be presented for each serotype, using a 
normal approximation method. 
Levels of anti-pneumococcal antibodies (μg/mL) against each of the 23 different 
serotypes in patients in Groups A1, A2, A (A1 and A2 combined), and B measured 
4 weeks and 8 weeks after administration of 23-PPV (which is 4 weeks after Group A1 
patients received the 13-PCV booster) will be summarized descriptively by group using 
the same summary statistics as presented in Section 4.4.1 for the primary immunology 
endpoint. 
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4.4.2.3 
Keyhole Limpet Hemocyanin 
Levels of anti-KLH antibody IgG in patients in Groups A and B measured at 4, 8, and 12 
weeks after first KLH administration will be summarized descriptively by treatment group 
using the same summary statistics as presented in Section 4.4.1 for the primary 
immunology endpoint. 
Levels of anti-KLH antibody IgM in patients in Groups A and B measured over time at 4, 
8, and 12 weeks after first KLH administration will be summarized descriptively by 
treatment group using the same summary statistics as presented in Section 4.4.1 for the 
primary immunology endpoint. 
 
4.4.2.4 
Influenza Vaccine Response 
Between-group comparisons of influenza vaccine response require comparison of 
Groups A2 and B.  As noted above in Section 4.4.2.2, comparisons between Groups A2 
and B should be interpreted with some caution, since patients were not assigned to 
Group A2 randomly (patients were randomized to Group A or B, and within Group A 
were non-randomly assigned to Group A1 or A2, based on seasonality considerations). 
The number and percentage of patients in Groups A2 and B who achieve seroprotection, 
defined as specific HI titers > 40 at 4 weeks after vaccination, will be presented by 
treatment group.  The difference between Groups A2 and B in seroprotection rates, and 
the associated 95% CI will also be presented using a normal approximation method. 
The number and percentage of patients in Groups A2 and B who achieve a 2-fold 
increase in specific HI titers at 4 weeks after vaccination will be presented by treatment 
group.  The difference between Groups A2 and B in the proportion of patients achieving 
a 2-fold increase, and the associated 95% CI will also be presented using a normal 
approximation method. 
The number and percentage of patients in Groups A2 and B who achieve a 4-fold 
increase in specific HI titers at 4 weeks after vaccination will be presented by treatment 
group.  The difference between Groups A2 and B in the proportion of patients achieving 
a 4-fold increase, and the associated 95% CI will also be presented using a normal 
approximation method. 
The number and percentage of patients in Groups A2 and B who achieve 
seroconversion at 4 weeks after vaccination, defined as a pre-vaccination antibody 
titer < 10 and a HI titer > 40 at 4 weeks after vaccination, will be presented by treatment 
group.  The difference between Froups A2 and B in seroconversion rates, and the 
associated 95% CI will also be presented using a normal approximation method. 
Strain-specific GMTs in patients in Groups A2 and B measured 4 weeks after 
vaccination will be summarized descriptively by treatment group using the same 
summary statistics as presented in Section 4.4.1 for the primary immunology endpoint. 
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Strain-specific GMT ratio (post-vaccination:pre-vaccination) in patients in Groups A2 and 
B will be summarized descriptively by treatment group; summary statistics calculated will 
include mean, median, SD, minimum, and maximum. 
4.4.3 
Other Secondary Endpoints (Magnetic Resonance Imaging) 
After baseline, MRI assessments are taken at Years 1, 2, 3, 4, and 5 and at early 
termination.  As the ISP is the main focus for this primary analysis, postbaseline MRI 
assessments will be presented only in a data listing and not summarized or analyzed at 
this stage.  These postbaseline MRI assessments may be summarized or analyzed in a 
future analysis when more mature OOE data are available.  The postbaseline MRI 
assessments are as follows: 
• 
T2 lesion volume 
• 
Number of new and/or enlarging T2 lesions since previous MRI 
• 
Number of Gd-enhancing lesions 
• 
Change from baseline in percent brain volume  
• 
Change from baseline in cortical grey matter volume 
• 
Change from baseline in white matter volume 
• 
Unenhancing T1 lesion volume 
• 
Number of Gd-enhancing lesions evolving to black holes since previous MRI 
• 
Number of new T1 hypo-intense (unenhancing) lesions since previous MRI 
 
4.4.4 
Exploratory Immunology Endpoints 
Between-group comparisons of the exploratory immunology endpoints described below 
require comparison of Groups A1 and A2, A1 and B, A1 and A2, and A and B.  As noted 
in Section 4.4.2.2 above, the first three of these four comparisons should be interpreted 
with some caution, since patients were not assigned to Groups A1 and A2 randomly 
(patients were randomized to Group A or Group B, and within Group A were non-
randomly assigned to Group A1 or A2, based on seasonality considerations). 
4.4.4.1 
Overall Antibody Response to 23-PPV Vaccine 
The following analyses will be considered exploratory and may be undertaken, 
depending on data availability at the time of the primary analysis. 
Levels of overall antibody response to the 23-PPV vaccine, IgG (using ELISA) and IgM 
(using ELISA), measured 4 weeks after administration of the 23-PPV vaccine, and 8 
weeks after administration of the 23-PPV vaccine (which is 4 weeks after Group A1 
patients received the 13-PCV booster) for patients in Groups A1, A2, A (A1 and A2 
combined) and B will be summarized descriptively by treatment group using the same 
summary statistics as presented in Section 4.4.1 for the primary immunology endpoint. 
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4.4.4.2 
Overall Antibody Response to 13-PCV Vaccine 
The following analyses will be considered exploratory and may be undertaken, 
depending on data availability at the time of the primary analysis. 
Levels of overall antibody response to the 13-PCV vaccine, IgG (using ELISA) and IgM 
(using ELISA), measured 8 weeks after administration of the 23-PPV vaccine (which is 4 
weeks after Group A1 patients received the 13-PCV booster) for patients in Groups A1, 
A2, A (A1 and A2 combined), and B will be summarized descriptively by treatment group 
using the same summary statistics as presented in Section 4.4.1 for the primary 
immunology endpoint. 
4.4.5 
Sensitivity Analyses 
If there are any reported major protocol deviations relating to, or other issues reported 
which may affect data quality or analysis interpretability for a specific primary or 
secondary immunology endpoint, then as sensitivity analyses, the summaries and 
analyses specified above for that specific endpoint may be repeated excluding those 
patients with major protocol deviations/other issues. 
4.4.6 
Subgroup Analyses 
No subgroup analysis is currently planned but may be performed if deemed necessary. 
4.5 
IMMUNOPHENOTYPING ANALYSES 
For immunophenotyping analyses, data will be presented for Groups A1 and A2 
separately as well as for Group A (Groups A1 and A2 combined) and Group B.  
Summaries will be presented separately within the following study periods:  
• 
ISP  
• 
SFU Period after the ISP (these patients did not enter the OOE) 
• 
OOE 
• 
SFU Period after completing the OOE 
 
The humoral and cellular immunity outcome measures in this study are as follows: 
• 
Flow cytometry, which will include (but is not limited to) the following cells: 
Total B cells (CD19+) 
B-cell subsets (e.g., memory B cells, naïve B cells, and plasma cells) 
Total T cells (CD3+) 
T helper cells (CD3+ and CD4+) 
Cytotoxic lymphocyte T (CD3+ and CD8+) 
Natural killer cells (CD3− and CD16/56+) 
• 
Quantitative Ig:Ig levels (including total Ig, IgG, IgG subtypes, IgM, and IgA) 
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For each flow cytometry parameters, the absolute values and change from baseline 
(Day 1) will be summarized over time by treatment group.  Summary statistics calculated 
will include mean, median, SD, minimum, and maximum.  For CD19 cells, the number 
and percentage of patients whose CD19 counts have repleted will be presented at each 
timepoint.  Repletion is defined as the CD19-cell count having returned to their baseline 
value (Day 1) or lower limit of normal (≥ 80 cells/μL), whichever is lowest.  The median 
CD19-cell count will be displayed graphically over time from the start of study treatment. 
For immunoglobulin levels (IgG, IgM, and total Ig), the absolute values and change from 
baseline will be summarized over time by treatment group.  Summary statistics 
calculated will include mean, median, SD, minimum, and maximum.  At each timepoint, 
the number and percentage of patients with immunoglobulin levels lower than the lower 
limit of normal will be presented.  For each immunoglobulin, the number and percentage 
of patients with single and replicated laboratory abnormalities will be summarized by 
treatment group.  The mean immunoglobulin levels (IgG, IgM, and total Ig) will be 
displayed graphically over time from the start of study treatment. 
4.6 
SAFETY ANALYSES 
For safety analyses, data will be presented for Groups A1 and A2 separately as well as 
for Group A (Groups A1 and A2 combined) and B. 
All summaries of safety data will be based on the Safety Population. 
4.6.1 
Exposure to Study Medication (Ocrelizumab) 
4.6.1.1 
Exposure to Ocrelizumab during the ISP 
Patients will be considered to have received a dose of ocrelizumab treatment if at least 
one part of one infusion of that dose (i.e., either Day 1 or 15 for dual infusions) was 
given. 
Treatment duration for ocrelizumab-treated patients in the ISP will be calculated as the 
date of the last recorded observation during the ISP (the date reported on the ISP 
Completion/Early Discontinuation electronic Case Report Form [eCRF]) minus the date 
of first dose of ocrelizumab.  If protocol requirements are followed exactly, this duration 
should be 168 days (24 weeks) for patients who do not withdraw/discontinue early. 
Exposure to ocrelizumab for patients in Groups A1, A2, and A (Groups A1 and A2 
combined) during the ISP will be summarized as follows: 
• 
Dose received on Day 1:  number and percentage of patients who received 
ocrelizumab dose 
• 
Dose received on Day 15:  number and percentage of patients who received 
ocrelizumab dose 
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• 
Total cumulative dose of ocrelizumab (mg; Day 1 + Day 15):  summary statistics, 
including mean, median, SD, minimum, and maximum 
• 
Receiving < 80% and ≥ 80% of the planned infusion on Day 1:  number and 
percentage of such patients 
• 
Receiving < 80% and ≥ 80% of the planned infusion on Day 15:  number and 
percentage of such patients 
• 
Pretreatment with steroids on Day 1:  number and percentage of patients pretreated 
on Day 1 
• 
Pretreatment with steroids on Day 15:  number and percentage of patients 
pretreated on Day 15 
• 
Pretreatment with antihistamines on Day 1:  number and percentage of patients 
pretreated on Day 1 
• 
Pretreatment with antihistamines on Day 15:  number and percentage of patients 
pretreated on Day 15 
 
A listing of information relating to exposure to ocrelizumab will be provided. 
4.6.1.2 
Exposure to Ocrelizumab during the OOE 
Patients will be considered to have received a dose of ocrelizumab treatment if at least 
one part of one infusion of that dose (i.e., either Day 1 or 15 for dual infusions) was 
given. 
The duration of observation for a patient will be calculated as:  
(Date of the day prior to the infusion of the last dose in OOE − date of the first 
infusion in the dose given during the ISP) + 1 
 
Exposure to ocrelizumab for patients in Groups A1, A2, A (Groups A1 and A2 combined), 
and B during the OOE will be summarized as follows: 
• 
Treatment duration:  number and percentage of patients who received 0−23 weeks 
of treatment, 24−47 weeks of treatment, 48−71 weeks of treatment, 72−95 weeks of 
treatment, etc. 
• 
Number of ocrelizumab doses:  number and percentage of patients receiving 1, 2, 3, 
4, etc. doses and summary statistics for the number of ocrelizumab doses (mean, 
SD, and median) 
• 
Total cumulative dose of ocrelizumab during OOE (mg):  summary statistics, 
including mean, median, SD, minimum, and maximum 
 
A listing showing duration of exposure to ocrelizumab during the ISP and OOE will be 
provided. 
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4.6.2 
Adverse Events 
Adverse events will be summarized for the ISP and the OOE.  Adverse events reported 
during the SFU Period or B-cell Monitoring Period will be included in the period of 
previous dose received. 
Safety data from this trial will also be included in pooled safety analyses of MS patients 
treated with ocrelizumab (e.g., malignancy) at interim analyses.  These analyses are not 
described in this document. 
4.6.2.1 
Adverse Events during the ISP 
Adverse events will be defined as all adverse events, except non-serious MS relapses, 
but including infusion-related reactions (IRRs) and serious MS relapses.  Therefore, 
those adverse events recorded on the “adverse event” and “infusion-related reaction 
(IRR)” CRF pages will be included.  
For each adverse event recorded, the term entered by the investigator describing the 
event (the “reported term”) will be assigned a standardized term (the “preferred term”) 
based on the MedDRA WHO dictionary of terms.  All analyses of adverse event data will 
be performed using the PTs unless otherwise specified. 
All adverse events will be mapped to PTs and superclass terms and included in a data 
listing (a separate listing showing relapse information will also be presented).  For all 
summary tables, the adverse events will be sorted by SOC (in decreasing order of 
overall incidence) and then by PT (in decreasing order of overall incidence).  An adverse 
event profile summary table will be presented to provide an overview of adverse events 
reported in the ISP.  Additionally, the most frequent adverse events (≥ 5% in any 
treatment group) will be presented by PT. 
Summaries of adverse events will be generated by summarizing the incidence of 
treatment-emergent adverse events only.  Treatment-emergent events are defined as 
those adverse events with observed or imputed onset date on or after the start date of 
study treatment (ocrelizumab or any vaccinations).  Only where the most extreme 
intensity is greater than the initial intensity will events with an onset date prior to the start 
of study treatment (and with an end date on or after the start of study treatment) be 
considered treatment-emergent.  An adverse event with a completely missing, 
non-imputed start date will be assumed to be treatment-emergent unless the adverse 
event has a complete non-imputed end date that is prior to start of study treatment. 
Adverse events will be assigned to a dose if the adverse event onset date is on or after 
the date of the first infusion of that dose but before the first infusion of the next treatment 
dose.  Adverse events that start prior to the first dose and worsen during treatment (i.e., 
treatment-emergent) will be assigned to the first treatment dose. 
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For each treatment group, the incidence count for each adverse event PT will be defined 
as the number of patients reporting at least 1 treatment-emergent occurrence of the 
event.  The incidence rate will be calculated as the incidence count divided by the total 
number of patients in the population.  Each table will also present the overall number of 
patients experiencing at least 1 adverse event and the total number of adverse events 
reported (multiple occurrences of the same adverse event in one patient will be counted 
only once at the most extreme intensity).  For adverse events leading to death, the most 
extreme intensity will be overwritten by Grade 5 (death). 
Serious adverse events will be defined as all serious adverse events, which includes 
serious MS relapses and serious IRRs.  Serious adverse events will be summarized for 
each treatment group by SOC and PT, and presented in a data listing.  Additionally, the 
most frequent serious adverse events (≥ 1%) will be presented by PT for each treatment 
group.  A separate listing with relapses considered as serious adverse events will be 
presented.  Related adverse events and serious adverse events will be summarized by 
SOC and PT for each treatment group and separately for adverse events related to (or 
suspected to be related to) treatment with each of the following: 
• 
Ocrelizumab 
• 
Methylprednisolone 
• 
KLH  
• 
Tetanus and diphtheria vaccine 
• 
Tetanus, diphtheria, and pertussis vaccine 
• 
23-PPV  
• 
13-PCV  
• 
Influenza vaccine 
 
Concomitant treatments for adverse events (excluding IRRs and MS relapses) will be 
summarized by class and PT.  Also concomitant treatments starting during the ISP or 
during the SFU Period following the ISP will be summarized by class and PT. 
Adverse events and serious adverse events will be summarized by intensity (most 
extreme intensity) and overall, by SOC and PT.  Additionally, adverse events of intensity 
grades 3, 4, or 5 (most extreme intensity) will be summarized by intensity and overall, by 
SOC and PT. 
All patient deaths during the study (all study periods) will be included in a data listing. 
A patient may experience an adverse event that leads to the discontinuation of their 
study treatment.  Discontinuation of study treatment for an adverse event may not 
necessarily lead to discontinuation from the study because patients can enter the SFU 
Periods.  Only adverse events that led to the discontinuation of study treatment are of 
interest.  Patients who withdraw early from the study because of adverse events will be 
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summarized under disposition.  The number of patients who experienced an adverse 
event that led to discontinuation of study treatment will be summarized by SOC and PT 
for each treatment group.  A listing will be presented showing all adverse events which 
led to discontinuation of study treatment. 
The number of patients who experienced an adverse event that led to modification or 
interruption of study drug will be summarized by SOC and PT for each treatment group. 
A glossary of superclass terms, PTs and verbatim terms for adverse events will be 
provided.  Also a glossary of superclass terms and PTs for adverse events baskets will 
be provided. 
To comply with the reporting requirements of www.clinicaltrials.gov, the following two 
tabular summaries will be provided for the ISP.  For the two summaries below, unlike all 
other adverse event summaries in this study, multiple occurrences of the same adverse 
event in an individual are counted separately: 
• 
Non-serious adverse events reported in ≥ 5% of patients in any treatment group will 
be summarized by SOC and PT.  Non-serious relapses will be excluded here.  
Within each treatment group, the number and percentage of patients reporting such 
adverse events, and the number and percentage of events reported, will be 
presented. 
• 
Serious adverse events will be summarized by SOC and PT.  Within each treatment 
group, the number and percentage of patients reporting serious adverse events, and 
the number and percentage of serious adverse events reported, will be presented.  
Further, the total number of serious adverse events in each treatment group that 
were treatment-related, fatal, and treatment-related and fatal will be presented. 
 
4.6.2.2 
Adverse Events during the OOE 
Adverse events during the OOE will be handled and reported using the same general 
approaches as described above for the ISP. 
An adverse event profile summary table will be presented to provide an overview of 
adverse events reported in the OOE.  Adverse events and serious adverse events will 
be summarized by SOC and PT also. 
Concomitant treatments for adverse events will be summarized by class and PT.  Also 
concomitant treatments starting during the OOE or during the SFU Period following the 
OOE will be summarized by class and PT. 
The number of patients who experienced an adverse event within the OOE that led to 
interruption of study drug will be summarized by SOC and PT for each treatment group. 
4.6.2.3 
Adverse Events, All Study Periods 
When presenting adverse events across all study periods, the same general approaches 
to handling and reporting adverse events will be applied, as described above for the ISP. 
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An adverse event profile summary table will be presented to provide an overview of 
adverse events reported in the OOE.  Adverse events and serious adverse events will 
be summarized by SOC and PT also. 
Concomitant treatments for adverse events (excluding IRRs and MS relapses) will be 
summarized by class and PT. 
Concomitant procedures/surgeries will be summarized by class and PT. 
4.6.3 
Selected Adverse Events 
4.6.3.1 
Progressive Multifocal Leukoencephalopathy 
PML will be categorized as a serious adverse event per guidance on the diagnosis of 
PML in protocol.  Patients with PML, if any, will be included in the listing of serious 
adverse events. 
4.6.3.2 
Infections and Serious Infections 
Infections will be defined from the adverse event data using the MedDRA SOC of 
“Infections and Infestations”.  An infection will be defined as serious if the event is a 
serious adverse event. 
A listing of infections (defined using the MedDRA SOC “Infections and Infestations”) with 
pathogen information code will be provided.  An additional listing will display adverse 
events from other SOCs with the pathogen information code.  Also a listing will display 
non-serious infections treated with an intravenous anti-infective. 
Immunization Study Period 
Infections and serious infections will be summarized by SOC and PT.  Infections by 
intensity will be summarized also.  If a patient has multiple events, the most extreme 
intensity will be taken.  Infections and serious infections will also be summarized by 
pathogen type.  The number of infections and serious infections per 100 patient-years 
will be calculated and summarized. 
Optional Ocrelizumab Extension 
The same summaries will be presented for OOE as for ISP, with the exception of 
summaries of infections and serious infections by pathogen type. 
All Periods 
The same summaries will be presented for all study periods as for ISP. 
4.6.3.3 
Infusion-Related Reactions 
An IRR and its corresponding symptoms are collected on the dedicated eCRF. 
The symptom(s) of an IRR and the IRR itself may be of different intensities.  As other 
symptoms can be recorded as free-text on the eCRF page, symptoms will be coded in 
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MedDRA and summarized by PTs.  IRRs are categorized by the time of the event 
occurring during the infusion and within 24 hours of completion of the infusion. 
A listing of patients with at least one IRR will be presented, including associated 
symptoms.  This listing will be repeated to show the subset of patients with at least one 
IRR/symptom at Grade 3 or above (intensity).   
Immunization Study Period 
During the ISP, pretreatments will be summarized by infusion and overall, by class and 
PT (multiple occurrences of the same treatment in one individual are counted once per 
infusion). 
By infusion and overall during the ISP, the number and percentage of patients with at 
least one IRR will be presented (patients with multiple events within an infusion will 
count only once).  In addition, the total number of patients with IRR symptoms will be 
summarized by infusion and overall (multiple occurrences of an IRR symptom in one 
patient at one infusion (or overall) are counted once for that infusion (or overall).  The 
total number of IRR symptoms will also be summarized by infusion and overall.  IRR 
symptoms will be summarized by SOC and PT. 
During the ISP, the number and percentage of patients with IRRs and the total number 
of IRRs will be summarized by intensity and overall, and by infusion.  For patients who 
have multiple IRRs, the most extreme intensity will be taken. 
By infusion and overall during the ISP, the number and percentage of patients with at 
least one serious IRR will be presented (patients with multiple events within an infusion 
will count only once).  In addition, the total number of patients with IRR symptoms 
resulting from serious IRRs will be summarized by infusion and overall (multiple 
occurrences of a serious IRR symptom in one patient at one infusion (or overall) are 
counted once for that infusion (or overall).  The total number of IRR symptoms resulting 
from serious IRRs will also be summarized by infusion and overall.  Serious IRR 
symptoms will be summarized by SOC and PT. 
By infusion and overall during the ISP, the number and percentage of patients with at 
least one IRR, the total number of IRRs, and the number of IRRs will be summarized by 
the time of events (during infusion, within 24 hours after end of infusion).  Multiple 
occurrences of an IRR in one patient within one time period are counted once. 
During the ISP, the number and percentage of patients reporting adverse events on the 
day or the day after an infusion, and the total number of such events will be presented, 
and these adverse events will be summarized by SOC and PT. 
During the ISP, the number and percentage of patients receiving concomitant treatments 
for IRRs and the total number of such treatments will be presented, and these 
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concomitant treatments will be summarized by class and PT (multiple occurrences of the 
same treatment in one individual are counted once). 
IRRs, serious IRRs and symptoms at Day 1, Dose 1 will be summarized separately for 
the 2 different ocrelizumab formulations used in this study (v0.4 and v1.0). 
Optional Ocrelizumab Extension 
By infusion and overall during the OOE, the number and percentage of patients with at 
least one IRR will be presented (patients with multiple events within an infusion will 
count only once).  In addition, the total number of patients with IRR symptoms will be 
summarized by infusion and overall (multiple occurrences of an IRR symptom in one 
patient at one infusion (or overall) are counted once for that infusion (or overall).  The 
total number of IRR symptoms will also be summarized by infusion and overall.  IRR 
symptoms will be summarized by SOC and PT. 
During the OOE, the number and percentage of patients with IRRs and the total number 
of IRRs will be summarized by intensity and overall, and by infusion.  For patients who 
have multiple IRRs, the most extreme intensity will be taken. 
By infusion and overall during the OOE, the number and percentage of patients with at 
least one serious IRR will be presented (patients with multiple events within an infusion 
will count only once).  In addition, the total number of patients with IRR symptoms 
resulting from serious IRRs will be summarized by infusion and overall (multiple 
occurrences of a serious IRR symptom in one patient at one infusion (or overall) are 
counted once for that infusion (or overall).  The total number of IRR symptoms resulting 
from serious IRRs will also be summarized by infusion and overall.  Serious IRR 
symptoms will be summarized by SOC and PT. 
4.6.3.4 
Malignancies and Premalignant Lesions 
Malignancies and premalignant lesions will be listed. 
4.6.4 
Laboratory Data 
4.6.4.1 
General Laboratory Evaluation 
The summaries described below for general laboratory assessments will be produced for 
both the ISP and for the OOE separately. 
For each laboratory test, absolute and changes from baseline values at each visit will be 
summarized by treatment group.  Summary statistics calculated will include mean, 
median, SD, minimum, and maximum.  The baseline value will be the last value prior to 
the first dose of ocrelizumab for patients in Group A and prior to the first immunization 
for patients in Group B.  When laboratory data are presented over time, the laboratory 
values will be time-windowed into a common visit structure.  If multiple values of the 
same laboratory parameter occur within the same time window, the worst value (i.e., the 
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value furthest away from the midpoint of the normal range) will be included in 
calculations of summary statistics. 
For each laboratory test, the number and percentage of patients with single and 
replicated laboratory abnormalities will be summarized by treatment group. 
In addition, for liver laboratory parameters, the number and percentage of patients with 
an elevated postbaseline AST or ALT levels will be summarized by treatment group. 
During the SFU Period after either the ISP or the OOE, for each laboratory test, absolute 
and changes from baseline values at each visit will be summarized by treatment group.  
Summary statistics calculated will include mean, median, SD, minimum, and maximum.  
These summaries will only be presented if there is a sufficient volume of patient data 
available to allow meaningful interpretation. 
Section 6.5.2 of the protocol states that for each laboratory test, individual patient values 
will be listed, and values outside the standard reference range will be flagged.  To 
maintain consistency with the other Phase 3 studies in the ocrelizumab program, this 
data listing will not be prepared.  The summary tables described above are considered 
adequate to describe general laboratory abnormalities, without the need for this data 
listing. 
4.6.4.2 
Anti-Drug Antibodies 
The summaries described below for ADAs will be produced for both the ISP and for the 
OOE separately. 
ADAs will be summarized descriptively.  The baseline prevalence and postbaseline 
incidence of ADAs will be displayed.  The number of patients with treatment-induced 
ADAs and the number of patients with treatment-enhanced ADAs will also be displayed. 
A table will be presented that summarizes ocrelizumab serum concentrations (μg/mL) at 
timepoints when ADA samples were collected and analyzed (summary statistics: mean, 
median, SD, minimum, maximum, coefficient of variation [percentage], geometric mean, 
number, and percentage of samples with concentration ≤ 20 µg/mL). 
A listing by treatment group covering both ISP and OOE showing anti-ocrelizumab 
antibody data will be presented for patients with at least one ADA-sampled datum. 
4.6.5 
Vital Signs and Electrocardiogram 
The summaries for vital sign parameters and ECG results will be presented separately 
within the ISP and OOE study periods. 
The following vital signs parameters will be assessed:  
• 
Systolic blood pressure 
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• 
Diastolic blood pressure 
• 
Pulse rate 
• 
Respiratory rate 
• 
Temperature 
• 
Weight 
 
For each vital signs parameter within each study period (ISP and OOE), absolute and 
change from baseline values will be summarized by treatment group at study visits that 
do not include an ocrelizumab infusion.  For each vital signs parameter within each study 
period (ISP and OOE), absolute values and the value of the change from the pre-
infusion baseline at that visit will be summarized by treatment group at each study visit 
that includes an ocrelizumab infusion (summary statistics:  mean, median, SD, minimum, 
and maximum).  At each visit at which vital signs parameters are assessed, summary 
statistics calculated will include mean, median, SD, minimum, and maximum.  All vital 
signs data will be presented in a data listing by treatment group and covering all study 
periods. 
ECG results will be summarized by treatment group within each study period (ISP and 
OOE) and will show the number and percentage of patients with normal, abnormal (not 
clinically significant), and abnormal (clinically significant) findings at baseline 
cross-tabulated with postbaseline ECG results in a shift table format.  All ECG results 
will be presented in a data listing by treatment group and covering all study periods. 
4.6.6 
Pregnancies 
For any pregnancies that occur during the study, pregnancy information will be 
presented in a data listing. 
4.7 
MISSING DATA 
Missing data will not be imputed. 
4.8 
INTERIM ANALYSES 
No interim analysis of immunology endpoints is planned. 
Analyses of malignancies and other safety analyses of all patients who received at least 
one dose of ocrelizumab may be done as part of pooled MS ocrelizumab analyses 
(including other clinical trials data).  These analyses are not described in this document.  
Interim PK analyses may also be performed during the study (not described here but in a 
separate document). 
 
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