Clinical trial NCT02637856
Conditions: Multiple Sclerosis, Relapsing-Remitting
Sponsor: Genentech, Inc.
Start date: 2016-02-11; Completion date: 2019-05-03
Enrollment: 608 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will evaluate the efficacy and safety of ocrelizumab in participants with RRMS who have had a suboptimal response to an adequate course of DMT. Participants will receive ocrelizumab as an initial dose of two 300-milligrams (mg) intravenous (IV) infusions (600 mg total) separated by 14 days followed by one 600-mg IV infusion for a maximum of 4 doses (up to 96 weeks). Anticipated time on study treatment is 96 weeks.

Detailed description:
Participants who complete their Week 72 ocrelizumab infusion and do not experience any serious infusion related reaction (IRR) throughout the main study will be eligible to enroll in an optional, open-label, non-randomized substudy to MN30035 and receive one additional shorter infusion of ocrelizumab at the Week 96 visit. This substudy will enroll approximately 100 patients from MN30035 main study.

Arms: arm 1: Participants will receive ocrelizumab as an initial dose of two 300-mg IV infusions (600 mg total) separated by 14 days (on Days 1 and 15) followed by one 600-mg IV infusion every 24 weeks for a maximum of 4 doses (up to 96 weeks). arm 2: Participants with no serious IRR throughout the main study will be eligible to enroll in an optional substudy and receive one additional shorter infusion of ocrelizumab at the Week 96 visit. Ocrelizumab will be administered IV as a single 600-mg dose at a shorter infusion rate (approximately 2 hours instead of 3.5 hours)
Interventions: intervention 1: Ocrelizumab intervention 2: Ocrelizumab
Intervention descriptions: intervention 1: Participants will receive ocrelizumab as an initial dose of two 300-mg IV infusions (600 mg total) separated by 14 days (on Days 1 and 15) followed by one 600-mg IV infusion every 24 weeks for a maximum of 4 doses (up to 96 weeks). intervention 2: Participants will receive an additional single 600-mg dose IV infusion at a shorter infusion rate (approximately 2 hours instead of 3.5 hours)

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
 
AN OPEN-LABEL STUDY TO EVALUATE THE 
EFFECTIVENESS AND SAFETY OF 
OCRELIZUMAB IN PATIENTS WITH RELAPSING 
REMITTING MULTIPLE SCLEROSIS WHO HAVE 
HAD A SUBOPTIMAL RESPONSE TO AN 
ADEQUATE COURSE OF DISEASE-MODIFYING TREATMENT 
NCT Number: 
NCT02637856   
Document Date: 
Protocol Version 5: 19-June-2018 
 
 
 


FINAL PROTOCOL APPROVAL
CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (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 Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered.
Ocrelizumab—Genentech, Inc.
Protocol MN30035, Version 5
PROTOCOL
TITLE:
AN OPEN-LABEL STUDY TO EVALUATE THE 
EFFECTIVENESS AND SAFETY OF 
OCRELIZUMAB IN PATIENTS WITH RELAPSING 
REMITTING MULTIPLE SCLEROSIS WHO HAVE 
HAD A SUBOPTIMAL RESPONSE TO AN 
ADEQUATE COURSE OF DISEASE-MODIFYING 
TREATMENT
PROTOCOL NUMBER:
MN30035
VERSION NUMBER:
5
EUDRACT NUMBER:
Not applicable
IND NUMBER:
100,593
TEST PRODUCT:
Ocrelizumab (RO4964913)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
Genentech, Inc.
DATE FINAL:
Version 1:  4 December 2015
DATES AMENDED:
Version 2:  4 March 2016
Version 3:  12 December 2016
Version 4:  19 October 2017
Version 5:  See electronic date stamp below
 
19-Jun-2018 09:04:49
Title
Approver's Name
Date and Time (UTC)
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PROTOCOL AMENDMENT, VERSION 5:
RATIONALE
Protocol MN30035 was amended primarily to include an optional shorter infusion 
substudy.  In this substudy, eligible patients enrolled in the main study will have the 
option to receive a dose of 600-mg ocrelizumab at Week 96 infused over a shorter time 
period than the approved administration rate.  The current FDA-approved Ocrevus
(ocrelizumab) labeling recommends that the 600-mg ocrelizumab dose be infused at a 
maximum rate of 200 mL per hour for a duration of 3.5 hours or longer.  Administration 
of ocrelizumab over a shorter infusion time would help convenience of use and 
compliance for both patients and healthcare practices (Sections 1.4, 3.4, and 3.6; and 
Appendix 2).
Additional changes to the protocol, along with a rationale for each change, are 
summarized below:

Because ocrelizumab is now approved by the FDA, the Safety Follow-up Period in 
the main study has been shortened throughout the protocol from 24 and 48 weeks 
after the last dose of ocrelizumab in the study to only 24 weeks after the last dose.  
Thus, the main study will not exceed 96 weeks in duration.  Additionally, B-cell 
monitoring has been removed throughout the protocol. 

Birth control requirements for women in the study have been revised to include 
certain “acceptable” forms of birth control, as “highly effective” birth control methods, 
which are more stringent, are no longer required (Section 4.1.1). 

Premedication information for methylprednisolone (or equivalent steroid) has been 
revised to remove the need for slow infusion over approximately 15 minutes, in 
order to align with the global ocrelizumab program (Section 4.3.2.1, Section 4.3.3, 
and Appendix 1).

Safety language has been added to the protocol to indicate that women who 
accidentally become pregnant during the study will no longer be required to 
permanently discontinue ocrelizumab infusions.  Given that there are insufficient, 
well-controlled data from studies testing the use of ocrelizumab in pregnant or 
breastfeeding women, ocrelizumab infusions are not permitted while a patient is 
pregnant or breastfeeding.  However, patients may now resume infusions 
following a thorough benefitrisk discussion with their investigator after the 
patient’s pregnancy and breastfeeding are finished.  Patients who have already 
permanently discontinued from the study because of pregnancy (or for any other 
reason) may not be re-enrolled in the study (Sections 4.6.2, 4.6.3, and 5.4.3.1).

Information has been updated on risks associated with ocrelizumab 
(Section 5.1.3).

The Medical Monitor has been changed to 
, M.D., Ph.D. 
(Section 5.4.1).

To further strengthen safety monitoring for special situations that may or may not 
result in an adverse event, instructions have been added regarding the reporting of 
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medication errors and accidental overdose (Section 5.4.4) and the prior, less 
specific text on the topic has been deleted (Section 5.3.5.12).
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.
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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 10
PROTOCOL SYNOPSIS .................................................................................... 11
1.
BACKGROUND .......................................................................................... 18
1.1
Background on Multiple Sclerosis.......................................... 18
1.2
Background on Ocrelizumab ................................................. 19
1.2.1
Summary of Clinical Studies of Ocrelizumab in 
Multiple Sclerosis................................................................... 19
1.2.1.1
Clinical Studies...................................................................... 19
1.2.1.2
Clinical Safety........................................................................ 20
1.2.1.3
Clinical Activity....................................................................... 22
1.3
Study Rationale and Benefit-Risk Assessment...................... 23
1.4
Substudy Rationale ............................................................... 23
2.
OBJECTIVES AND ENDPOINTS ............................................................... 24
2.1
Primary Objective .................................................................. 24
2.2
Secondary Objective ............................................................. 24
2.3
Exploratory Objective............................................................. 24
3.
STUDY DESIGN......................................................................................... 24
3.1
Description of the Study......................................................... 24
3.2
Screening .............................................................................. 25
3.3
Treatment Period................................................................... 25
3.4
Optional Shorter Infusion Substudy....................................... 26
3.5
Safety Follow-up Period......................................................... 26
3.6
End of Study and Length of Study......................................... 27
3.7
Planned Total Sample Size ................................................... 27
3.8
Rationale for Study Design.................................................... 27
3.8.1
Rationale for Ocrelizumab Dose and Schedule..................... 27
4.
MATERIALS AND METHODS .................................................................... 27
4.1
Patients.................................................................................. 27
4.1.1
Inclusion Criteria.................................................................... 27
4.1.2
Exclusion Criteria................................................................... 28
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4.2
Method of Treatment Assignment and Blinding..................... 31
4.3
Study Treatment.................................................................... 31
4.3.1
Formulation, Packaging, and Handling.................................. 31
4.3.1.1
Ocrelizumab .......................................................................... 31
4.3.2
Dosage, Administration, and Compliance.............................. 32
4.3.2.1
Ocrelizumab .......................................................................... 32
4.3.3
Mandatory Premedication:  Methylprednisolone 
and Antihistaminic Drug......................................................... 34
4.3.4
Other Prophylactic Treatment................................................ 34
4.3.5
Investigational Medicinal Product Accountability ................... 34
4.3.6
Post-Trial Access to Ocrelizumab.......................................... 35
4.4
Concomitant Therapy ............................................................ 35
4.4.1
Permitted Therapy................................................................. 35
4.4.2
Prohibited Therapy ................................................................ 35
4.5
Study Assessments ............................................................... 36
4.5.1
Informed Consent Forms and Screening Log........................ 36
4.5.2
Medical History and Demographic Data ................................ 36
4.5.3
Physical Examinations........................................................... 36
4.5.4
Neurological Examinations .................................................... 36
4.5.5
Vital Signs.............................................................................. 37
4.5.6
Assessment of Disability........................................................ 37
4.5.7
Brain Magnetic Resonance Imaging...................................... 38
4.5.8
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 38
4.5.9
Patient-Reported Outcomes .................................................. 39
4.5.10
Safety Follow-up Period......................................................... 39
4.6
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 40
4.6.1
Patient Discontinuation.......................................................... 40
4.6.2
Criteria for Re-Treatment with Ocrelizumab .......................... 40
4.6.3
Study Treatment Discontinuation........................................... 40
4.6.4
Study and Site Discontinuation.............................................. 41
5.
ASSESSMENT OF SAFETY....................................................................... 41
5.1
Safety Plan ............................................................................ 41
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5.1.1
Risks Associated with Corticosteroids ................................... 42
5.1.2
Risks Associated with Antihistamines.................................... 42
5.1.3
Risks Associated with Ocrelizumab....................................... 42
5.1.3.1
Identified Risks and Adverse Drug Reactions........................ 42
5.1.3.2
Potential Risks....................................................................... 44
5.1.4
Management of Patients Who Experience 
Specific Adverse Events........................................................ 45
5.2
Safety Parameters and Definitions ........................................ 46
5.2.1
Adverse Events ..................................................................... 46
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 46
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 47
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 48
5.3.1
Adverse Event Reporting Period ........................................... 48
5.3.2
Eliciting Adverse Event Information....................................... 48
5.3.3
Assessment of Severity of Adverse Events ........................... 48
5.3.4
Assessment of Causality of Adverse Events ......................... 49
5.3.5
Procedures for Recording Adverse Events............................ 50
5.3.5.1
Infusion-Related Reactions.................................................... 50
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 51
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 51
5.3.5.4
Persistent or Recurrent Adverse Events................................ 51
5.3.5.5
Abnormal Laboratory Values ................................................. 52
5.3.5.6
Abnormal Vital Sign Values ................................................... 52
5.3.5.7
Abnormal Liver Function Tests.............................................. 53
5.3.5.8
Deaths ................................................................................... 53
5.3.5.9
Preexisting Medical Conditions.............................................. 54
5.3.5.10
Lack of Efficacy or Worsening of Relapsing 
Remitting Multiple Sclerosis................................................... 54
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 54
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 55
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5.4.1
Emergency Medical Contacts................................................ 55
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 55
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 55
5.4.2.2
Events That Occur after Study Drug Initiation........................ 56
5.4.3
Reporting Requirements for Pregnancies.............................. 56
5.4.3.1
Pregnancies in Female Patients............................................ 56
5.4.3.2
Congenital Anomalies/Birth Defects and 
Abortions ............................................................................... 57
5.4.4
Reporting Requirements for Cases of 
Ocrelizumab Accidental Overdose or Medication 
Error....................................................................................... 57
5.5
Follow-Up of Patients after Adverse Events .......................... 58
5.5.1
Investigator Follow-Up........................................................... 58
5.5.2
Sponsor Follow-Up ................................................................ 58
5.6
Post-Study Adverse Events................................................... 59
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 59
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 59
6.1
Determination of Sample Size ............................................... 60
6.2
Summaries of Conduct of Study............................................ 61
6.3
Summaries of Demographic and Baseline 
Characteristics....................................................................... 62
6.4
Analysis Populations ............................................................. 62
6.4.1
Intent-to-Treat Population...................................................... 62
6.4.2
Per-Protocol Population......................................................... 62
6.4.3
Safety Population .................................................................. 62
6.5
Efficacy Analyses .................................................................. 62
6.5.1
Primary Efficacy Outcome Measures .................................... 62
6.5.2
Secondary Efficacy Outcome Measures................................ 63
6.5.3
Exploratory Outcomes ........................................................... 63
6.5.4
Analysis Methods .................................................................. 63
6.6
Safety Analyses..................................................................... 64
6.6.1
Safety Outcome Measures .................................................... 64
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6.6.2
Safety Analyses..................................................................... 64
6.7
Handling of Missing Data....................................................... 65
6.8
Interim Analyses .................................................................... 65
7.
DATA COLLECTION AND MANAGEMENT ............................................... 65
7.1
Data Quality Assurance......................................................... 65
7.2
Electronic Case Report Forms............................................... 66
7.3
Source Data Documentation.................................................. 66
7.4
Use of Computerized Systems .............................................. 67
7.5
Retention of Records............................................................. 67
8.
ETHICAL CONSIDERATIONS.................................................................... 67
8.1
Compliance with Laws and Regulations ................................ 67
8.2
Informed Consent.................................................................. 68
8.3
Institutional Review Board or Ethics Committee.................... 69
8.4
Confidentiality........................................................................ 69
8.5
Financial Disclosure .............................................................. 70
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 70
9.1
Study Documentation ............................................................ 70
9.2
Protocol Deviations................................................................ 70
9.3
Site Inspections ..................................................................... 70
9.4
Administrative Structure......................................................... 70
9.5
Publication of Data and Protection of Trade 
Secrets .................................................................................. 71
9.6
Protocol Amendments ........................................................... 71
10. REFERENCES ........................................................................................... 73
LIST OF TABLES
Table 1
Overview of Ocrelizumab Dosing................................................ 33
Table 2
Guidelines for Management of Specific Adverse Events ............ 45
Table 3
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 49
Table 4
Causal Attribution Guidance ....................................................... 50
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LIST OF FIGURES
Figure 1
Overview of Study Procedures.................................................... 25
Figure 2
Safety Follow-up:  Variable B-Cell Monitoring Period ................. 26
Figure 3
Prob(Half-width of 95% CI4%) with Sample Size if 
Expected Proportion30%50% ................................................. 61
Figure 4
Prob(Half-width of 95% CI5%) with Sample Size if 
Expected Proportion30%50% ................................................. 61
LIST OF APPENDICES
Appendix 1
Schedule of Activities.................................................................. 75
Appendix 2
Optional Shorter Infusion Substudy ............................................ 79
Appendix 3
Expanded Disability Status Scale (EDSS) .................................. 87
Appendix 4
2010 Revised McDonald Diagnostic Criteria for Multiple 
Sclerosis ..................................................................................... 89
Appendix 5
New York Heart Association Classification of 
Functional Cardiac Capacity ....................................................... 91
Appendix 6
Guidance for Diagnosis of Progressive Multifocal 
Leukoencephalopathy................................................................. 92
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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
AN OPEN-LABEL STUDY TO EVALUATE THE 
EFFECTIVENESS AND SAFETY OF OCRELIZUMAB 
IN PATIENTS WITH RELAPSING REMITTING 
MULTIPLE SCLEROSIS WHO HAVE HAD A 
SUBOPTIMAL RESPONSE TO AN ADEQUATE 
COURSE OF DISEASE-MODIFYING TREATMENT
PROTOCOL NUMBER:
MN30035
VERSION NUMBER:
5
EUDRACT NUMBER:
Not applicable
IND NUMBER:
100,593
TEST PRODUCT:
Ocrelizumab (RO4964913)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
Genentech, Inc.
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 the CRO.
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PROTOCOL SYNOPSIS
TITLE:
AN OPEN-LABEL STUDY TO EVALUATE THE EFFECTIVENESS 
AND SAFETY OF OCRELIZUMAB IN PATIENTS WITH 
RELAPSING REMITTING MULTIPLE SCLEROSIS WHO HAVE 
HAD A SUBOPTIMAL RESPONSE TO AN ADEQUATE COURSE 
OF DISEASE-MODIFYING TREATMENT
PROTOCOL NUMBER:
MN30035
VERSION NUMBER:
5
EUDRACT NUMBER:
Not applicable
IND NUMBER:
100,593
TEST PRODUCT:
Ocrelizumab (RO4964913)
PHASE:
IIIb 
INDICATION:
Relapsing remitting multiple sclerosis
SPONSOR:
Genentech, Inc.
Objectives and Endpoints
Primary Objective
The primary objective of this study is to assess the effectiveness of ocrelizumab 600 mg 
intravenously (IV) every 24 weeks over 96 weeks in patients with relapsing remitting multiple 
sclerosis (RRMS) who have had a suboptimal response to an adequate course of a 
disease-modifying treatment (DMT).  
A suboptimal response is defined by having one or more clinically reported relapse(s), OR one 
or more T1 gadolinium (Gd)-enhanced lesion(s), OR two or more new or enlarging T2 lesions 
on magnetic resonance image (MRI) despite being on a stable dose of the same DMT for at 
least 6 months.  In addition, in patients receiving stable doses of the same approved DMT for 
more than a year, the event must have occurred within the last 12 months of treatment with this 
DMT.  
Secondary Objective
The secondary objective of this study is to evaluate the safety and tolerability of ocrelizumab 
600 mg IV given every 24 weeks in patients with RRMS who have had a suboptimal response 
to an adequate course of a DMT as measured by the nature and incidence of adverse events.
Exploratory Objective
The exploratory objective of this study is to further assess the effectiveness of ocrelizumab by 
monitoring patient-reported outcomes (PROs) related to quality of life and treatment satisfaction.
Study Design
Description of the Study
This study is a prospective, multicenter, open-label, effectiveness, and safety study in patients 
with RRMS who have had a suboptimal response to an adequate course of a DMT.  This study 
will be conducted in North America.  An adequate course of prior DMT is defined as the same 
DMT administered for at least 6 months.  Ocrelizumab will be administered as an initial dose of 
two 300-mg infusions (600 mg total) separated by 14 days (i.e., Days 1 and 15) followed by one 
600-mg infusion every 24 weeks for the study duration.  
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Patients will be assessed for effectiveness and safety every 24 weeks.  The study will consist of 
the following periods, described in detail below:

Screening Period:  Up to 4 weeks

Treatment Period:  Open-label treatment period of 72 weeks (4 doses)

Safety Follow-up Period:  Observation 24 weeks after the last infusion of study drug for 
patients who discontinue or who chose not to continue with commercially available 
ocrelizumab at the end of study
Eligible patients may choose to participate in an optional shorter infusion substudy at the
Week 96 visit, during which they will receive ocrelizumab infused over a shorter time period 
than the approved administration rate (Appendix 2).  
Number of Patients
This study will enroll approximately 600 patients with RRMS who have had a suboptimal 
response to an adequate course of a DMT.  
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Able to comply with the study protocol, in the investigator’s judgment

Age 1855 years, inclusive

Have a definite diagnosis of multiple sclerosis (MS), confirmed per the revised 2010 
McDonald criteria (Polman et al. 2011; Appendix 4), and have the relapsing remitting form 
of MS

Have a length of disease duration, from first symptom, of 12 years

Have been treated with an adequate course of treatment with no more than three prior 
DMTs  

Adequate treatment is defined as 6 months on a DMT.

Discontinuation of the most recent adequately used DMT must have been due to 
suboptimal response as defined below.

Suboptimal response while on his/her last adequately used DMT (for 6 months); a 
suboptimal response is defined by having one of the following qualifying events despite 
being on a stable dose of the same DMT for at least 6 months:

One or more clinically reported relapse(s)

OR one or more T1 Gd-enhanced lesion(s)

OR two or more new or enlarging T2 lesions on MRI
These qualifying events must have occurred while on the last adequately used DMT.  In 
addition, in patients receiving stable doses of the same approved DMT for more than a 
year, the event must have occurred within the last 12 months of treatment with this DMT
from the date of screening.

Expanded Disability Status Scale (EDSS) of 0 to 5.5, inclusive, at screening

For women of childbearing potential:  agreement to use an acceptable birth control method: 

Progesterone-only oral hormonal contraception, where inhibition of ovulation is not 
the primary mode of action

Male or female condom with or without spermicide

Cap, diaphragm, or sponge with spermicide

A combination of male condom with either cap, diaphragm, or sponge with spermicide 
(double-barrier methods are also considered acceptable, but not highly effective, birth 
control methods)
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Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

History of primary progressive multiple sclerosis (PPMS), progressive relapsing multiple 
sclerosis (PRMS), or secondary progressive multiple sclerosis (SPMS)

Inability to complete an MRI (contraindications for MRI include but are not restricted to 
claustrophobia, weight, pacemaker, cochlear implants, presence of foreign substances in 
the eye, intracranial vascular clips, surgery within 6 weeks of entry into the study, coronary 
stent implanted within 8 weeks prior to the time of the intended MRI, inability to tolerate 
Gd-enhancing ligands, etc.).

Known presence of other neurological 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 central nervous system (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; MELAS [mitochondrial myopathy, encephalopathy, lactic acidosis, stroke] 
syndrome)

Neuromyelitis optica

History or known presence of systemic autoimmune disorders potentially causing 
progressive neurologic disease (e.g., lupus, anti-phospholipid antibody syndrome, 
Sjogren’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 (PML)

Pregnancy or lactation, or intention to become pregnant during the study

Women of childbearing potential must have a negative serum or urine pregnancy test 
result within 14 days prior to initiation of study drug.

Any concomitant disease that may require chronic treatment with systemic corticosteroids 
or immunosuppressants during the course of the study

Lack of peripheral venous access

Significant, uncontrolled disease, such as cardiovascular (including cardiac arrhythmia), 
pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine, and 
gastrointestinal or any other significant disease that may preclude patient from participating 
in the study

Congestive heart failure (New York Heart Association [NYHA] Class III/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 severe 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 of or currently active primary or secondary immunodeficiency

History or known presence of recurrent or chronic infection (e.g., HIV, syphilis, TB)

History of recurrent aspiration pneumonia requiring antibiotic therapy
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
History of malignancy, including solid tumors and hematological malignancies, except basal 
cell, in situ squamous cell carcinoma of the skin, and in situ carcinoma of the cervix of the 
uterus that have been excised with clear margins

History of severe allergic or anaphylactic reactions to humanized or murine monoclonal 
antibodies

History of coagulation disorders

History of alcohol or drug abuse within 24 weeks prior to screening

Previous treatment with natalizumab within 12 months prior to screening unless failure was 
due to confirmed, persistent anti-drug antibodies 

Patients previously treated with natalizumab will be eligible for this study only if duration 
of treatment with natalizumab was 1 year and natalizumab was not used in the 12 
months prior to screening.  Anti-JCV antibody status (positive or negative) and titer (both 
assessed within the year of screening) must be documented prior to enrollment.  When 
assessed, anti-JCV antibody status should be determined using an analytically and 
clinically validated immunoassay (e.g., ELISA).

Previous treatment with systemic cyclophosphamide, azathioprine, mycophenolate mofetil, 
cyclosporine, or methotrexate

Treatment with IV immunoglobulin within 12 weeks prior to baseline

Treatment with dalfampridine (Ampyra) unless on stable dose for 30 days prior to 
screening

Wherever possible, patients should remain on stable doses throughout the treatment 
period.

Receipt of a live vaccine within 6 weeks prior to baseline; in rare cases when patient 
requires vaccination with a live vaccine, the screening period may need to be extended but 
cannot exceed 8 weeks

Systemic corticosteroid therapy within 4 weeks prior to screening

The screening period may be extended (but cannot exceed 8 weeks) for patients who 
have used systemic corticosteroids for their MS before screening.  

There should be 4 weeks from last dose of systemic corticosteroid therapy prior to first 
infusion.

Previous treatment with fingolimod (Gilenya®) or dimethyl fumarate (Tecfidera) in patients 
whose lymphocyte count is below the lower limit of normal (LLN)

Contraindications to or intolerance of oral or IV corticosteroids, including IV 
methylprednisolone (or equivalent steroid) administered according to the country label, 
including:

Psychosis not yet controlled by a treatment

Hypersensitivity to any of the constituents preceding

Treatment with alemtuzumab (Lemtrada)

Treatment with a B-cell targeted therapies (e.g., rituximab, ocrelizumab, atacicept, 
belimumab, or ofatumumab)

Treatment with a drug that is experimental (Exception:  treatment with an experimental drug 
that was subsequently approved in the patient’s country is allowed.)

Laboratory test results as follows:

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)

Lymphocyte count below LLN

CD4 count300/L

AST or ALT 3.0the upper limit of normal (ULN)
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
Platelet count100,000/L (100109/L)

Total neutrophil count below LLN
Re-testing before baseline:  in rare cases in which the screening laboratory 
samples are rejected by the laboratory (e.g., hemolyzed sample) or the results are 
not assessable (e.g., indeterminate) or abnormal, the tests need to be repeated.  
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 enrollment must meet study criteria.  In such circumstances, 
the screening period may need to be prolonged but should not exceed 8 weeks.
End of Study
The end of the treatment period is defined as the date when the last patient, last visit (LPLV) at 
96 weeks occurs (or at Week 100 in the substudy). 
Length of Study
The total length of the study is expected to be approximately 4 years from the first patient 
enrolled to LPLV.
The end of study is defined as the LPLV of the safety follow-up.
Investigational Medicinal Products
Test Product (Investigational Drug)
Dose 1 of ocrelizumab will be administered as two 300-mg IV infusions (600 mg total) separated 
by 14 days (i.e., Days 1 and 15).  Subsequent doses will be administered as one 600-mg IV 
infusion every 24 weeks, for a maximum of 4 doses.
Non-Investigational Medicinal Products
Premedicate with 100-mg methylprednisolone (or equivalent) completed approximately 
30 minutes prior to each ocrelizumab infusion and with an antihistaminic drug (e.g., 
diphenhydramine) approximately 30 60 minutes before each infusion of ocrelizumab to reduce 
the frequency and severity of infusion-related reactions (IRRs).
The addition of an antipyretic (e.g., acetaminophen/paracetamol) may also be considered to 
further reduce the frequency and severity of IRRs.
Statistical Methods
Primary Efficacy Outcome Measures
The primary efficacy assessment will be the proportion of patients who are free of any 
protocol-defined events during a 96-week period.  The definition of a protocol-defined event is 
the occurrence of at least one of the following while on treatment with ocrelizumab:

A protocol-defined relapse 

A T1 Gd-enhanced lesion on brain MRI

A new and/or enlarging T2 lesion on brain MRI

Confirmed disability progression (24 weeks)
Determination of Sample Size  
Assuming a) the expected proportion of patients who will be event free during 96 weeks is 45%; 
b) the type one error rate is 5% and the half-width of 95% confidence interval (CI) for the 
proportion is 4%; c) the probability that half-width of 95% CI is at most 4% is 80%, then the 
required sample size will be n600.
Interim Analyses 
It is estimated that two to three interim analyses will be performed during the course of the 
study, according to patient enrollment and availability of data of interest.  Interim analyses may 
be used for internal decision making, hypothesis generation, abstraction/publication for major 
MS conferences, or other purposes, as applicable.  Details on the timing and scope of interim 
analyses will be described in the Statistical Analysis Plan.
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LIST OF ABBREVIATIONS
Abbreviation
Definition
ADA
anti-drug antibody
ADR
adverse drug reaction
ARR
annual relapse rate
-hCG
beta subunit human chorionic gonadotropin
CDP
confirmed disability progression
CI
confidence interval
CNS
central nervous system
CRO
contract research organization
CTCAE
Common Terminology Criteria for Adverse Events
DMT
disease-modifying treatment
EC
Ethics Committee
ECG
electrocardiogram
eCRF
electronic Case Report Form
EDC
electronic data capture
EDSS
Expanded Disability Status Scale
FACS
Fluorescence-activated cell sorting
FDA
Food and Drug Administration
FLAIR
fluid-attenuated inversion-recovery
FSS
Functional Systems Score
GA
glatiramer acetate
Gd
gadolinium
HAM
HTLV-1 associated myelopathy
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HepCAb
hepatitis C antibody
HIPAA
Health Insurance Portability and Accountability Act
HTLV-1
human T-lymphotropic virus 1
ICH
International Council on Harmonisation
IFN-
interferon beta
IMP
investigational medicinal product
IRR
infusion-related reaction
IND
Investigational New Drug (application)
IRB
Institutional Review Board
ITT
intent-to-treat
IV
intravenous
IxRS
interactive voice/Web response system
KLH
keyhole limpet haemocyanin
LDH
lactate dehydrogenase
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Abbreviation
Definition
LLN
lower limit of normal
LPLV
last patient, last visit
MELAS
mitochondrial myopathy, encephalopathy, lactic acidosis, stroke
MMRM
mixed model with repeated measure
MRI
magnetic resonance image 
MS
multiple sclerosis
MSIS-29
Multiple Sclerosis Impact Scale (29-item scale)
NCI
National Cancer Institute
NEDA
no evidence of disease activity
NK
natural killer
NYHA
New York Heart Association
PCR
polymerase chain reaction
PML
progressive multifocal leukoencephalopathy
PP
per-protocol
PPMS
primary progressive multiple sclerosis
PRMS
progressive relapsing multiple sclerosis
PRO
patient-reported outcome
PY
patient years
QOL
quality of life
RA
rheumatoid arthritis
RMS
relapsing multiple sclerosis
RR
relative reduction
RRMS
relapsing remitting multiple sclerosis
SAP
statistical analysis plan
SD
standard deviation
SPMS
secondary progressive multiple sclerosis
TB
tuberculosis
ULN
upper limit of normal
U.S.
United States
USP
United States Pharmacopeia
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1.
BACKGROUND
1.1
BACKGROUND ON MULTIPLE SCLEROSIS
Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, and degenerative 
disease of the central nervous system (CNS) that affects approximately 400,000 people 
in the United States (U.S.) and 2.3 million worldwide (National Multiple Sclerosis 
Society).  MS primarily affects young adults, with 70%80% of patients having an age of 
onset (i.e., initial clinical presentation to a physician) between 20 and 40 years 
(Anderson et al. 1992; Noonan et al. 2002), and has a strong gender bias, with 
approximately 64%70% of diagnosed patients being women (Goodin 2014).  
MS is clinically subcategorized into four phenotypic disease patterns distinguished by 
the occurrence and timing of relapses relative to disease onset and disability 
progression.  These include relapsing remitting MS (RRMS), primary progressive MS 
(PPMS), progressive relapsing MS (PRMS), and secondary progressive MS (SPMS) 
(Lublin et al. 1996).  Accumulated disability is the fate of most patients with MS when a 
20- to 25-year perspective is considered (Trojano et al. 2003).
Approximately 85% of MS patients initially present with RRMS (Confavreaux et al. 2000; 
Leray et al. 2015).  The majority of RRMS patients will transition into SPMS within 
2025 years (Trojano et al. 2003).  
Over the past two decades, there has been a substantial increase in the number and 
type of available treatments for RRMS.  Yet, despite suboptimal response to an 
adequate course of treatment with a disease-modifying treatment (DMT), defined as the 
same DMT administered for at least 6 months, a significant proportion of treated patients 
with RRMS will show signs of disease activity. Suboptimal responses, defined in this 
protocol as one or more clinically reported relapse(s), one or more T1 gadolinium
(Gd)-enhanced lesion(s), OR two or more new or enlarging T2 lesions on brain magnetic 
resonance imaging (MRI) despite being on a stable dose of the same DMT for at least 
6 months, are reported in approximately one-third of patients receiving interferon beta 
(IFN-) therapy (Bergvall et al. 2014; Durelli et al. 2008; Fernández et al. 2005; 
Waubant et al. 2003).  Disease activity while receiving a DMT is associated with poorer 
long-term outcomes (Bermel et al. 2013), thus subsequent treatment with a more 
effective therapy may be warranted in patients with breakthrough signs and symptoms.  
Consequently, reported rates of treatment switching for suboptimal responses range 
from 20%35% of patients (Rio et al. 2012; Gajofatto et al. 2009; Teter et al. 2014).  
While clinical experience and retrospective studies suggest that better disease control is 
obtained by escalating to a higher-efficacy therapy, few prospective studies have been 
conducted.  A prospective, observational study evaluated the outcomes of patients who 
failed first-line treatment with IFN-or glatiramer acetate (GA) who were subsequently 
treated with a different IFN-formulation or GA or were escalated to natalizumab
(Prosperini et al. 2012).  At 1 year, no significant differences in disease activity were 
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observed between the two groups.  However, after 2 years, significantly greater 
proportions of patients escalated to natalizumab were free from relapse, disability
progression, MRI activity, and combined activity than patients who were treated with 
IFN-or GA.  In the Phase III trial (CARE-MS II) published by Coles and colleagues, 
patients who had one or more relapses while receiving IFN-or GA therapy were 
randomized to receive either IFN-or alemtuzumab.  Significant reductions in relapse 
rates and the accumulation of disabilities were reported with alemtuzumab compared to 
IFN-at 1 year (Coles et al. 2012).  However, more data from large-scale, prospective 
studies assessing patients who are subsequently treated with higher-efficacy therapies 
following suboptimal control with first-line treatment are needed. 
A Phase II study provided initial evidence that ocrelizumab could be effective at further 
reducing MS disease activity (i.e., annual relapse rate [ARR] and MRI activity) following 
initial IFN-therapy.  Additional data are also available on previously treated patients in 
two completed Phase III studies (Studies WA21092 [OPERA I] and WA21093 [OPERA 
II]), but only in a subgroup of patients. Therefore, this prospective study was designed 
to specifically evaluate the effectiveness and safety of using ocrelizumab in patients who 
show a suboptimal response to an adequate course of a DMT.
1.2
BACKGROUND ON OCRELIZUMAB
Ocrelizumab is a recombinant humanized monoclonal antibody that selectively targets 
CD20-expressing B cells (Klein et al. 2013), which are believed to play a critical role 
in MS.    
CD20 is a cell surface antigen found on pre-B cells, mature B cells, and memory B cells,
but it is not expressed on lymphoid stem cells and plasma cells (Stashenko et al. 1980; 
Loken et al. 1987; Tedder and Engel 1994).  While ocrelizumab selectively depletes 
CD20-expressing B cells (Kappos et al. 2011), the capacity of B-cell reconstitution and 
pre-existing humoral immunity are preserved (Martin and Chan 2006; DiLillo et al. 2008).  
In addition, innate immunity and total T-cell numbers are not affected (WA21493 Clinical 
Study Report).
See the Ocrelizumab Investigator's Brochure for additional details on nonclinical and 
clinical studies.
1.2.1
Summary of Clinical Studies of Ocrelizumab in Multiple 
Sclerosis
1.2.1.1
Clinical Studies
Current studies of ocrelizumab include four ongoing controlled clinical trials in patients 
with MS:  three Phase III studies (pivotal Studies WA21092 and WA21093 and 
Study WA25046) and one Phase II study (Study WA21493).  
Studies WA21092 and WA21093 are multicenter, randomized, parallel-group, 
double-blind, double-dummy, active-comparator studies of ocrelizumab in patients with 
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relapsing multiple sclerosis (RMS).  Patients receive 600 mg intravenous (IV) 
ocrelizumab every 24 weeks or 44 g IFN--1a subcutaneously three times per week.  
The primary endpoint is the protocol-defined ARR at 2 years (96 weeks).  
Study WA25046 is a multicenter, randomized, parallel-group, placebo-controlled study in 
patients with PPMS.  Patients receive 600 mg IV ocrelizumab every 24 weeks as two 
300-mg infusions 2 weeks apart or placebo.  The primary objective of this study is to 
evaluate the effectiveness and safety of ocrelizumab compared with placebo.  The 
primary endpoint in this study is the time to onset of confirmed disability progression 
(CDP) as measured by a pre-specified increase in Expanded Disability Status Scale 
(EDSS) score (see Appendix 3), sustained for at least 12 weeks.  
Study WA21493 was a Phase II, multicenter, randomized, parallel-group, partially 
blinded, placebo and Avonex (IFN--1a) controlled, dose-finding study to evaluate the 
effectiveness, as measured by brain MRI lesions, and safety of two dose regimens of 
ocrelizumab in patients with RRMS.  Results from the completed Phase II study showed 
that, at Week 24, ocrelizumab significantly reduced the number of Gd-enhancing lesions 
on T1-weighted brain MRI and ARR compared with both placebo and the active 
comparator.  
See the Ocrelizumab Investigator’s Brochure for additional information.  
1.2.1.2
Clinical Safety
Safety in Multiple Sclerosis
The safety data included are from three Phase III studies in RMS (Studies WA21092 and 
WA21093) and PPMS (Study WA25046) and one Phase II study in RRMS 
(Study WA21493). 
Studies WA21092, WA21093, WA25046, and WA21493 have completed the controlled 
treatment period and are in open-label extension phase.
In the two RMS Phase III studies (pooled data of Studies WA21092 and WA21093) 
during the 96-week controlled treatment period, ocrelizumab was well tolerated with 
lower rates of treatment discontinuations for adverse events in patients treated with 
ocrelizumab 600 mg (3.5%) than in patients receiving IFN -1a (6.2%).  The proportion 
of patients with adverse events (83.3% in both groups) as well as the total number of 
adverse events were similar in the ocrelizumab and the IFN -1a treatment groups over 
the 96-week treatment period.  The proportion of patients reporting infections was higher 
in the ocrelizumab group compared with the IFN -1a group (58.4% vs. 52.4%, 
respectively).  In addition, there were more events of infection in the ocrelizumab group 
(1224 events) compared with the IFN group (948 events) and these were primarily upper 
respiratory tract infections of Grade 1 or 2 intensity.  The proportion of patients with 
serious adverse events was lower in the ocrelizumab treatment group than in the 
IFN -1a treatment group (6.9% in the ocrelizumab treatment group vs. 8.7% in the 
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IFN -1a treatment group).  Overall, the proportion of patients with serious infections 
was lower in the ocrelizumab group (1.3%) than in the IFN -1a group (2.9%).  Two 
serious infusion-related reactions (IRRs) were reported; one in the IFN -1a group 
(Grade 3) and one in the ocrelizumab group (Grade 4).  As expected, the proportion of 
patients experiencing IRRs were increased in the ocrelizumab group (34.3%) compared 
with the active control group (9.7%) who received dummy infusions.  During the 96-week 
controlled treatment period, a total of 6 malignancies were reported, 2 events (1 mantle 
cell lymphoma and 1 squamous cell carcinoma) occurred in 2 patients (0.2%) in the 
IFN -1a treatment group and 4 events (2 invasive ductal breast carcinoma, 1 renal 
cancer, and 1 malignant melanoma) occurred in 4 patients (0.5%) in the ocrelizumab 
treatment group.  During the 96-week controlled treatment period, three deaths occurred 
in Studies WA21092 and WA21093; 2 patients (suicide and mechanical ileus) in the IFN 
-1 treatment group and 1 patient (suicide) in the ocrelizumab treatment group.
In the PPMS Phase III, double-blind, placebo-controlled Study WA25046, ocrelizumab 
was well tolerated with a similar proportion of patients with adverse events leading to 
discontinuation from treatment (4.1%) compared with the placebo group (3.3%).  The 
proportion of patients who experienced at least one adverse event was 90% in the 
placebo group compared with 95% in the ocrelizumab group.  Taking into account that 
twice as many patients were randomized to ocrelizumab than placebo, the number of 
adverse events experienced by patients with an adverse event was similar (1762 events 
in the placebo group and 3690 events in the ocrelizumab group).  The proportion of 
patients who experienced an infection was 69.8% in the ocrelizumab group compared 
with 67.8% in the placebo group.  The proportion of patients with serious infections was 
similar in both groups:  5.9% in the placebo group compared with 6.2% in the 
ocrelizumab group.  As expected, the proportion of patients who reported an IRR was 
higher in the ocrelizumab group (39.9%) compared with placebo (25.5%).  Overall, 
5 patients (1.0%) experienced a serious IRR in the ocrelizumab group.  During the 
96-week controlled treatment period, a total of 15 malignancies in 13 patients were 
reported:  2 events (basal cell carcinoma and adenocarcinoma of the cervix) occurred in 
2 patients (0.8%) in the placebo group and 13 events (5 basal cell carcinoma, 2 invasive 
ductal breast carcinoma, 1 anaplastic large-cell lymphoma, 1 breast cancer, 
1 endometrial cancer, 1 invasive breast carcinoma, 1 malignant fibrous histiocytoma, 
1 pancreatic carcinoma metastatic) occurred in 11 patients (2.3%) in the ocrelizumab 
group.  The proportion of patients with serious adverse events (22.2% in the placebo 
group compared with 20.4% in the ocrelizumab group) was similar in both groups.  
There were 5 deaths during the controlled treatment period, one in the placebo group 
(road traffic accident) and 4 in the ocrelizumab group (pulmonary embolism, pneumonia, 
pancreatic carcinoma, pneumonia aspiration).
In the RRMS Phase II study WA21493, treatment with 300 mg2 and 1000 mg2 
ocrelizumab was generally well tolerated.  The single most common adverse event by 
Preferred Term was IRR, reported by more ocrelizumab-treated patients compared with 
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placebo.  The proportion of patients reporting IRRs was higher in ocrelizumab-treated 
patients after the first infusion on Day 1 of the study (9.3% in placebo arm, 34.5% in the 
300-mg2 arm, and 43.6% in the 1000-mg2 arm).  Rates of infections and serious 
infections were similar in the ocrelizumab arms compared with placebo.  The rate of 
infections remained consistent throughout the study, including the treatment period (up 
to Week 96) and the treatment-free period (up to Week 144).  There was one 
malignancy (breast cancer) reported in Study WA21493 in the ocrelizumab group.  The 
adverse event profile of ocrelizumab during the open-label treatment period up to 
Week 96 and during follow-up and monitoring/observation periods up to Week 144 was 
consistent with observations during the first 24 weeks.  
A total of 3 deaths were reported in RRMS Study WA21493 up to the time of the 
Investigator’s Brochure update in November 2015.  Two fatalities occurred after 
completion of the study treatment and during the Safety Follow-up Period when B cells 
had already repleted.
See the Ocrelizumab Investigator’s Brochure for additional information regarding safety.
1.2.1.3
Clinical Activity
Study WA25046 met its primary endpoint of CDP sustained for at least 12 weeks, 
showing that treatment with ocrelizumab significantly reduced the progression of clinical 
disability for 12 weeks compared with placebo (risk reduction:  24%; hazard ratio:  0.76; 
95% confidence interval [CI]:  0.590.98; p0.0321).  The study also met its key 
secondary endpoints.  Time to CDP sustained for 24 weeks was significantly (p0.0365) 
reduced with ocrelizumab compared with placebo (risk reduction:  25%).  Change in the 
25-foot timed walk from baseline to Week 120 had a significantly (p0.0404) reduction 
of 29% with ocrelizumab.  Percent change in total volume of T2 lesions on MRI from 
baseline to Week 120 was significantly (p0.0001) improved with ocrelizumab 
(decrease of 3.4%) compared with placebo (increase of 7.4%).  Finally, percent change 
in whole brain volume from Week 24 to Week 120 was significantly (p0.0206) 
improved with ocrelizumab (17.5% reduction) compared with placebo.
Study WA21493 results at Week 24 demonstrated that both doses of ocrelizumab 
achieved the primary endpoint by significantly reducing the number of Gd-enhancing 
lesions compared with placebo (p0.0001).  Both ocrelizumab dose groups showed 
statistically significant reductions in ARR compared with the placebo group (ARR0.125 
for the ocrelizumab 300 mg2 group [p0.0005] and ARR0.169 for the ocrelizumab
1000 mg2 group [p0.0014]) compared with ARR0.637 for the placebo group, 
representing a relative reduction (RR) of 80% and 73% in ARR versus placebo group for 
the low- and high-dose ocrelizumab groups, respectively.  In exploratory analyses, both 
ocrelizumab groups were superior to the IFN--1a group for the primary endpoint 
(p0.0001) and the 300 mg2 group for ARR (ARR0.364 for the IFN--1a group, 
representing an RR of 66% in ARR [p0.03] for the ocrelizumab 300 mg2 group 
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versus the IFN--1a group and an RR of 53.6% in ARR [p0.086] for the ocrelizumab 
1000 mg2 group versus the IFN--1a group) (Kappos et al. 2011).
Patients from both the placebo and IFN--1a groups switched to ocrelizumab 300 mg2 
after Week 24.  By 48 weeks, the level of benefit of ocrelizumab in reduction of ARR was 
maintained, where the patients in the ocrelizumab 300 mg2 group continued to have a 
suppressed ARR of 0.086 from Week 24 to 48, and patients who switched to 
ocrelizumab from either placebo or IFN--1a derived a similar degree of efficacy to those 
randomized to ocrelizumab from onset (ARR for placebo to ocrelizumab0.161 and for 
IFN--1a to ocrelizumab0.137 after the switch, representing an RR of 74% and 62.4% 
compared with ARR before the switch, respectively).  From baseline to Week 72, 
patients originally randomized to ocrelizumab 300 mg2 maintained clinical efficacy, 
with an ARR of 0.186.
In studies WA21092 and WA21093, ocrelizumab was superior to IFN--1a in reducing 
the three major markers of disease activity over the two-year controlled treatment period.  
The studies met their primary endpoint of significantly reducing ARR, with a 50% 
reduction in the ocrelizumab group compared with the IFN--1a group over the two-year 
period.  Additionally, the studies met their secondary endpoints of significantly delaying 
CDP (loss of physical abilities, measured by the EDSS) by approximately 40% sustained 
for both 12 and 24 weeks with ocrelizumab compared with IFN--1a in pre-specified,
pooled analyses of the two studies (p0.0006 and p0.0025, respectively).  Patients in 
the ocrelizumab group also had significantly reduced acute multiple sclerosis MS-related 
inflammation and brain injury (total number of T1 Gd-enhancing lesions measured by 
MRI) at 24, 48, and 96 weeks by more than 90% and the emergence of more chronic or 
growing areas of MS-related brain injury (T2 hyperintense lesions) at 24, 48, and 96 
weeks by approximately 80% compared with patients in the IFN--1a group.
See the Ocrelizumab Investigator’s Brochure for additional information regarding 
efficacy.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
This study will evaluate the effectiveness and safety of using ocrelizumab in patients
with RRMS who show a suboptimal response to an adequate course of a DMT.  
1.4
SUBSTUDY RATIONALE
The optional shorter infusion substudy will evaluate the safety and tolerability of 
ocrelizumab infused over a shorter time period than the approved administration rate.
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2.
OBJECTIVES AND ENDPOINTS
2.1
PRIMARY OBJECTIVE
The primary objective of this study is to assess the effectiveness of ocrelizumab 600 mg 
IV every 24 weeks over 96 weeks in patients with RRMS who have had a suboptimal 
response to an adequate course of a DMT.  
A suboptimal response is defined by having one or more clinically reported relapse(s), 
OR one or more T1 Gd-enhanced lesion(s), OR two or more new or enlarging T2 lesions 
on MRI despite being on a stable dose of the same DMT for at least 6 months.  In 
addition, in patients receiving stable doses of the same approved DMT for more than a 
year, the event must have occurred within the last 12 months of treatment with this DMT.  
2.2
SECONDARY OBJECTIVE
The secondary objective of this study is to evaluate the safety and tolerability of 
ocrelizumab 600 mg IV given every 24 weeks in patients with RRMS who have had a 
suboptimal response to an adequate course of a DMT as measured by the nature and 
incidence of adverse events.
2.3
EXPLORATORY OBJECTIVE
The exploratory objective of this study is to further assess the effectiveness of 
ocrelizumab by monitoring patient-reported outcomes (PROs) related to quality of life 
and treatment satisfaction.  
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This study is a prospective, multicenter, open-label, effectiveness and safety study in 
patients with RRMS who have had a suboptimal response to an adequate course of a 
DMT.  This study will be conducted in North America.  An adequate course of prior DMT 
is defined as the same DMT administered for at least 6 months.  Ocrelizumab will be 
administered as an initial dose of two 300-mg infusions (600 mg total) separated by 
14 days (i.e., Days 1 and 15) followed by one 600-mg infusion every 24 weeks for the 
study duration.  
Patients will be assessed for effectiveness and safety every 24 weeks as described in 
the schedule of activities presented in Appendix 1.  
The study will consist of the following periods, described in detail below:

Screening Period:  Up to 4 weeks

Treatment Period:  Open-label treatment period of 72 weeks (4 doses)
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
Safety Follow-up Period:  Observation 24 weeks after the last infusion of study drug
for patients who discontinue or who choose not to continue with commercially 
available ocrelizumab at the end of study
Figure 1 presents an overview of the study procedures.  A schedule of activities is 
provided in Appendix 1.
Figure 1
Overview of Study Procedures
IVintravenous; OCRocrelizumab.
Note:  The screening period will last up to 4 weeks, but it may be prolonged for up to 8 weeks for 
relevant clinical, administrative, or operational reasons.  Baseline MRI results must be available 
prior to the first infusion.
3.2
SCREENING
Patients screened for this study should not be withdrawn from their current therapies for 
the sole purpose of meeting eligibility for the trial.  Patients who discontinue their current 
therapy for non-medical reasons should be informed of other approved treatment options 
before deciding to enroll in the study.
After providing written informed consent, patients will enter a screening period to be 
evaluated for eligibility.  The screening period will last up to 4 weeks, but it may be 
prolonged for up to 8 weeks for relevant clinical, administrative, or operational reasons.  
Re-screening of a patient is allowed once.  See Appendix 1 for the assessments to be 
performed at screening.
3.3
TREATMENT PERIOD
Eligible patients will be treated with an initial 600-mg dose as two 300-mg infusions 
separated by 14 days (i.e., Days 1 and 15) with subsequent doses administered as one 
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600-mg infusion every 24 weeks for the study duration. A total of 4 doses will be 
administered to study participants during the treatment period.
3.4
OPTIONAL SHORTER INFUSION SUBSTUDY
Eligible patients may choose to participate in an optional shorter infusion substudy at 
the Week 96 visit, during which they will receive ocrelizumab infused over a shorter 
time period than the approved administration rate.  See Appendix 2 for substudy 
details.
3.5
SAFETY FOLLOW-UP PERIOD
Patients who complete their infusion at Week 72 or who discontinue from treatment 
early should enter the Safety Follow-up Period and be assessed at 24 weeks. If the 
peripheral blood B-cell count remains depleted after 6 months from the date of the last 
infusion, the investigator may want to continue monitoring the B-cell count until it has 
returned to the baseline value or to the lower limit of the normal range, whichever is 
lower.  During the Safety Follow-up Period, patients who receive other B-cell targeted 
therapies will only be followed for an additional period of approximately 24 weeks from 
the start of the alternative MS treatment.
Figure 2 provides an overview of the Safety Follow-up Period, which is the variable 
B-cell monitoring period.  
Figure 2
Safety Follow-up:  Variable B-Cell Monitoring Period
Note:  Patients who complete their infusion at Week 72 or who discontinue from treatment 
early should enter the Safety Follow-up Period and be assessed at 24 weeks.  If the peripheral 
blood B-cell count remains depleted after 6 months from the date of the last infusion, the 
investigator may want to continue monitoring the B-cell count until it has returned to the 
baseline value or to the lower limit of the normal range, whichever is lower.  During the Safety 
Follow-up Period, patients who receive other B-cell targeted therapies will only be followed for an 
additional period of approximately 24 weeks from the start of the alternative MS treatment.  
During the Safety Follow-up Period, patients will be formally assessed at a clinical visit 
24 weeks after their last infusion.  Any data (i.e., from scheduled or unscheduled visits) 
collected after the patient withdrew from study treatment until the patient completes the 
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24-week Safety Follow-up Period, or until the patient decides to discontinue from the 
study entirely, is considered to be safety follow-up.  If the peripheral blood B-cell count 
remains depleted after 6 months from the date of the last infusion, the investigator may 
want to continue monitoring the B-cell count until it has returned to the baseline value 
or to the lower limit of the normal range, whichever is lower.  See Appendix 1 for 
further details.
Every effort should be made to have patients withdrawing from the treatment complete 
the 24-week Safety Follow-up Period and all related assessments.
3.6
END OF STUDY AND LENGTH OF STUDY
The end of the treatment period is defined as the date when the last patient, last visit 
(LPLV) at 96 weeks occurs.  For patients who enter the substudy, the end of the 
treatment period occurs approximately at Week 100.   
The total length of the study is expected to be approximately 4 years from the first 
patient enrolled to LPLV.
The end of study is defined as the LPLV of the safety follow-up.  
3.7
PLANNED TOTAL SAMPLE SIZE 
This study will enroll approximately 600 patients. Please refer to Section 6.1 for more 
details.  
3.8
RATIONALE FOR STUDY DESIGN
3.8.1
Rationale for Ocrelizumab Dose and Schedule
The first dose of ocrelizumab will be administered as two 300-mg IV infusions separated 
by 14 days, to reduce IRRs.   The remaining doses will be administered as single 
600-mg doses every 24 weeks.  
This dosing regimen is anticipated to be well tolerated and is consistent with the dosing 
regimen used in Studies WA21092 and WA21093 in patients with RMS
(see Section 1.2.1).  
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 600 patients with RRMS who fulfill the eligibility criteria listed below may 
participate in this study.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form
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
Able to comply with the study protocol, in the investigator’s judgment

Age 1855 years, inclusive

Have a definite diagnosis of MS, confirmed per the revised 2010 McDonald criteria 
(Polman et al. 2011; Appendix 4), and have the relapsing remitting form of MS

Have a length of disease duration, from first symptom, of 12 years

Have been treated with an adequate course of treatment with no more than three 
prior DMTs 

Adequate treatment is defined as 6 months on a DMT.

Discontinuation of the most recent adequately used DMT must have been due 
to suboptimal response as defined below.  

Suboptimal response while on his/her last adequately used DMT (for 6 months); a 
suboptimal response is defined by having one of the following qualifying events 
despite being on a stable dose of the same DMT for at least 6 months:

One or more clinically reported relapse(s)

OR one or more T1 Gd-enhanced lesion(s)

OR two or more new or enlarging T2 lesions on MRI
These qualifying events must have occurred while on the last adequately used 
DMT.  In addition, in patients receiving stable doses of the same approved DMT for 
more than a year, the event must have occurred within the last 12 months of 
treatment with this DMT from the date of screening.

EDSS of 0 to 5.5, inclusive, at screening

For women of childbearing potential:  agreement to use an acceptable birth control 
method: 

Progesterone-only oral hormonal contraception, where inhibition of ovulation 
is not the primary mode of action

Male or female condom with or without spermicide

Cap, diaphragm, or sponge with spermicide

A combination of male condom with either cap, diaphragm, or sponge with 
spermicide (double-barrier methods are also considered acceptable, but not 
highly effective, birth control methods)
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

History of PPMS, PRMS, or SPMS

Inability to complete an MRI (contraindications for MRI include but are not restricted 
to claustrophobia, weight, pacemaker, cochlear implants, presence of foreign 
substances in the eye, intracranial vascular clips, surgery within 6 weeks of entry 
into the study, coronary stent implanted within 8 weeks prior to the time of the 
intended MRI, inability to tolerate Gd-enhancing ligands, etc.).
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
Known presence of other neurological 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; MELAS [mitochondrial myopathy, encephalopathy, 
lactic acidosis, stroke] syndrome)

Neuromyelitis optica

History or known presence of systemic autoimmune disorders potentially 
causing progressive neurologic disease (e.g., lupus, anti-phospholipid antibody 
syndrome, Sjogren’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 (PML)

Pregnancy or lactation, or intention to become pregnant during the study

Women of childbearing potential must have a negative serum or urine 
pregnancy test result within 14 days prior to initiation of study drug.

Any concomitant disease that may require chronic treatment with systemic 
corticosteroids or immunosuppressants during the course of the study

Lack of peripheral venous access

Significant, uncontrolled disease, such as cardiovascular (including cardiac 
arrhythmia), pulmonary (including obstructive pulmonary disease), renal, hepatic, 
endocrine, and gastrointestinal or any other significant disease that may preclude 
patient from participating in the study

Congestive heart failure (New York Heart Association [NYHA] Class III/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 severe 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 of or currently active primary or secondary immunodeficiency
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
History or known presence of recurrent or chronic infection (e.g., HIV, syphilis, 
tuberculosis)

History of recurrent aspiration pneumonia requiring antibiotic therapy

History of malignancy, including solid tumors and hematological malignancies, 
except basal cell, in situ squamous cell carcinoma of the skin, and in situ carcinoma 
of the cervix of the uterus that have been excised with clear margins

History of severe allergic or anaphylactic reactions to humanized or murine 
monoclonal antibodies

History of coagulation disorders

History of alcohol or drug abuse within 24 weeks prior to screening

Previous treatment with natalizumab within 12 months prior to screening unless 
failure was due to confirmed, persistent ADAs  

Patients previously treated with natalizumab will be eligible for this study only if 
duration of treatment with natalizumab was 1 year and natalizumab was not 
used in the 12 months prior to screening.  Anti-JCV antibody status (positive or 
negative) and titer (both assessed within the year of screening) must be 
documented prior to enrollment.  When assessed, anti-JCV antibody status 
should be determined using an analytically and clinically validated 
immunoassay (e.g., ELISA).

Previous treatment with systemic cyclophosphamide, azathioprine, mycophenolate 
mofetil, cyclosporine, or methotrexate

Treatment with IV immunoglobulin within 12 weeks prior to baseline

Treatment with dalfampridine (Ampyra) unless on stable dose for30 days prior to 
screening

Wherever possible, patients should remain on stable doses throughout the 
treatment period.

Receipt of a live vaccine within 6 weeks prior to baseline; in rare cases when patient 
requires vaccination with a live vaccine, the screening period may need to be
extended but cannot exceed 8 weeks

Systemic corticosteroid therapy within 4 weeks prior to screening

The screening period may be extended (but cannot exceed 8 weeks) for 
patients who have used systemic corticosteroids for their MS before screening.  

There should be 4 weeks from last dose of systemic corticosteroid therapy prior 
to first infusion.  

Previous treatment with fingolimod (Gilenya®) or dimethyl fumarate (Tecfidera) in 
patients whose lymphocyte count is below the lower limit of normal (LLN)

Contraindications to or intolerance of oral or IV corticosteroids, including IV 
methylprednisolone (or equivalent steroid) administered according to the country 
label, including:

Psychosis not yet controlled by a treatment
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
Hypersensitivity to any of the constituents preceding

Treatment with alemtuzumab (Lemtrada)

Treatment with a B-cell targeted therapies (e.g., rituximab, ocrelizumab, atacicept, 
belimumab, or ofatumumab)

Treatment with a drug that is experimental (Exception:  treatment with an 
experimental drug that was subsequently approved in the patient’s country is 
allowed.)

Laboratory test results as follows:

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)

Lymphocyte count below LLN

CD4 count 300/L

AST or ALT 3.0the upper limit of normal (ULN)

Platelet count 100,000/L (100109/L)

Total neutrophil count below LLN
Re-testing before baseline:  in rare cases in which the screening laboratory 
samples are rejected by the laboratory (e.g., hemolyzed sample) or the 
results are not assessable (e.g., indeterminate) or abnormal, the tests need 
to be repeated.  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 enrollment must 
meet study criteria.  In such circumstances, the screening period may need
to be prolonged but should not exceed 8 weeks.
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is an open-label study in which all patients will receive the 600-mg dose of 
ocrelizumab following the 24-week regimen.  Therefore, no randomization or blinding will 
be used in this study.  
4.3
STUDY TREATMENT 
The investigational medicinal product (IMP) for this study is ocrelizumab.
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Ocrelizumab
Ocrelizumab will be supplied by the Sponsor as a liquid formulation containing 
30-mg/mL ocrelizumab in 20 mM sodium acetate at pH 5.3, with 4% trehalose dihydrate 
and 0.02% polysorbate 20.  The drug product is provided as a single-use liquid 
formulation in a 15-cc, type I USP, glass vial fitted with a 20-mm, fluoro-resin, laminated 
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stopper and an aluminum seal with a flip-off plastic cap and contains a nominal 300 mg 
ocrelizumab.  No preservative is used as each vial is designed for single use.
The ocrelizumab drug product must be diluted before administration.  Solutions of 
ocrelizumab 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 to 
2 mg/mL.
Ocrelizumab may contain fine translucent and/or reflective particles associated with 
enhanced opalescence.  Do not use the solution if discolored or if the solution contains 
discrete foreign particulate matter.
The infusion solution must be administered using an infusion set with an in-line, sterile, 
non-pyrogenic, low-protein-binding filter (pore size of up to 0.2 micrometer).
The prepared infusion solution of ocrelizumab is physically and chemically stable for 
24 hours at 28C and subsequently 8 hours at room temperature.  The prepared 
infusion solution should be used immediately.  If not used immediately, it can be stored 
up to 24 hours at 28C.  Infusion solution must be completely administered to the 
patient within 32 hours of preparation (not exceeding 24 hours at 2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.
For information on the formulation and handling of ocrelizumab, see the Ocrelizumab
Investigator's Brochure.
4.3.2
Dosage, Administration, and Compliance
4.3.2.1
Ocrelizumab
Dose 1 of ocrelizumab will be administered as two 300-mg IV infusions (600 mg total) 
separated by 14 days (i.e., Days 1 and 15).  Subsequent doses will be administered as
one 600-mg IV infusion every 24 weeks for a maximum of 4 doses.  
Although ocrelizumab may be administered on an outpatient basis, patients may be 
hospitalized for observation at the discretion of the investigator.  Ocrelizumab infusions 
should always be administered in a hospital or clinic environment under close 
supervision of the investigator or a medically qualified staff member.  It is anticipated that 
the patient will need to stay at the hospital or clinic for a full day for the infusion visits.
Each ocrelizumab infusion should be given as a slow IV infusion over approximately 
150 minutes (2.5 hours) for the 300-mg dose and approximately 210 minutes (3.5 hours) 
for the 600-mg dose.  To reduce potential IRRs, all patients will receive prophylactic 
treatment with 100 mg of methylprednisolone (or equivalent steroid), to be completed 
approximately 30 minutes before the start of each ocrelizumab infusion, and with an 
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antihistaminic drug (e.g., diphenhydramine) approximately 3060 minutes before each 
ocrelizumab infusion. 
Refer to Section 5.1.1 and Section 5.1.2 for the risks associated with these mandatory 
premedications.
It is also strongly recommended that the infusion is accompanied by prophylactic 
treatment with an analgesic/antipyretic such as acetaminophen/paracetamol (1 g) 
3060 minutes prior to the start of an infusion to reduce potential IRRs.  
Since transient hypotension may occur during ocrelizumab infusion, the investigator may 
wish to withhold anti-hypertensive medications 12 hours prior to ocrelizumab infusion. 
Ocrelizumab must not be administered as an IV push or bolus.  Well-adjusted infusion 
pumps should be used to control the infusion rate, and ocrelizumab should be infused 
through a dedicated line.  It is important not to use evacuated glass containers, which 
require vented administration sets, to prepare the infusion because this causes foaming 
as air bubbles pass through the solution. 
After completion of the infusion, the IV cannula should remain in situ for at least 1 hour 
to allow for administration of drugs intravenously, if necessary, in the event of a delayed 
reaction.  If no adverse events occur during this period of time, the IV cannula may be 
removed and the patient may be discharged.
See the Ocrelizumab Investigator’s Brochure for detailed instructions on drug 
preparation, storage, and administration.
An overview of the ocrelizumab dosing is presented in Table 1.  
Table 1
Overview of Ocrelizumab Dosing
Group
1st Dose a,c
2nd Dose b,c
3rd Dose c
4th Dose
(Weeks 124)
(Weeks 2448)
(Weeks 4872)
(Weeks 7296)
Day 1 
Infusion
Day 15 
Infusion
Week 24 
Infusion
Week 48 
Infusion
Week 72 
Infusion
Ocrelizumab 
300 mg IV
300 mg IV
600 mg IV
600 mg IV
600 mg IV
IVintravenous.
Note:  Before each infusion of ocrelizumab, 100 mg of methylprednisolone IV and an 
antihistamine will be administered to reduce the potential for IRRs.  Each treatment period has a 
duration of 24 weeks.  The treatment period consists of up to 96 weeks of treatment; patients will 
receive a maximum of 4 treatment cycles.  
a The first dosing will consist of two IV infusions separated by 14 days (i.e., Days 1 and 15).
b Beginning with the second dose, a single infusion of ocrelizumab will be administered.
c Prior to the next infusion, a clinical evaluation will be performed to ensure that the patient 
remains eligible for retreatment.
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Because of possible need to vary infusion rates depending on tolerance of the infusion,
the total infusion time may exceed the time stated. Unless an IRR occurs 
necessitating discontinuation, the entire contents of the infusion bag must be 
administered to the patient.
Guidelines for treatment discontinuation are provided in Section 4.6.3.
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.
4.3.3
Mandatory Premedication:  Methylprednisolone and 
Antihistaminic Drug
Premedicate with 100-mg methylprednisolone (or equivalent) completed approximately 
30 minutes prior to each ocrelizumab infusion and with an antihistaminic drug (e.g., 
diphenhydramine) approximately 3060 minutes before each infusion of ocrelizumab to 
reduce the frequency and severity of IRRs.
Any overdose or incorrect administration of methylprednisolone should be noted on the 
Pre-infusion Treatment eCRF.  Adverse events associated with an overdose or incorrect 
administration of methylprednisolone or antihistamine should be recorded on the 
Adverse Event eCRF, with signs and symptoms also recorded on the dedicated Infusion-
Related Reaction eCRF.
4.3.4
Other Prophylactic Treatment
The addition of an antipyretic (e.g., acetaminophen/paracetamol) may also be 
considered to further reduce the frequency and severity of IRRs.
4.3.5
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (ocrelizumab) will be provided by the 
Sponsor.  The study site will acknowledge receipt of IMPs, using the interactive 
voice/Web response system (IxRS) to confirm the shipment condition and content.  Any 
damaged shipments will be replaced. 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation. The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any unused IMP is 
destroyed, and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log.
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4.3.6
Post-Trial Access to Ocrelizumab
Currently, the Sponsor (Genentech, a member of the Roche Group) does not have any 
plans to provide ocrelizumab or any other study treatments or interventions to patients 
who have completed the study, in accordance with the Roche Global Policy on 
Continued Access to Investigational Medicinal Product, available at the following 
Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient from 4 weeks prior to screening to the study completion/ discontinuation visit.  All 
such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF.
Medications used after treatment discontinuation should be recorded during the 
Safety Follow-up Period (see Appendix 1).
4.4.1
Permitted Therapy 
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use.

Anti-hypertensive medications  

Since transient hypotension may occur during ocrelizumab infusion, the 
investigator may wish to withhold anti-hypertensive medications 12 hours prior 
to ocrelizumab infusion.

Corticosteroids

Patients who experience a relapse may receive treatment with IV or oral 
corticosteroids, if judged to be clinically appropriate by the investigator. Such 
patients should not discontinue study treatment solely based on the occurrence 
of a relapse, unless the patient or investigator feels he or she has met the 
criteria for withdrawal (Section 4.6.2).
4.4.2
Prohibited Therapy
Use of the following therapies is prohibited during the program and for at least 7 days 
prior to initiation of ocrelizumab, unless otherwise specified below:

Therapies for MS (see Section 4.1.2 for restrictions prior to initiation of ocrelizumab) 
other than systemic corticosteroids

Immunosuppressants, lymphocyte-depleting agents, or lymphocyte-trafficking 
blockers while patient is B-cell depleted
See the Ocrelizumab Investigator’s Brochure for a more detailed safety profile.
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4.5
STUDY ASSESSMENTS 
Please see Appendix 1 for the schedule of activities to be performed during the study.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures.  Informed Consent Forms for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site.
All screening evaluations must be completed and reviewed by the investigator to confirm 
that patients meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
4.5.2
Medical History and Demographic Data
Medical history includes clinically significant diseases, surgeries, reproductive status, 
and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, nutritional supplements) used by the patient within 4 weeks prior 
to the screening visit.  Demographic data will include age, sex, and self-reported 
race/ethnicity.
4.5.3
Physical Examinations
A full physical examination will be conducted at the screening and early termination visits.  
At all other visits, a limited physical examination will be conducted.  Any abnormality 
identified at baseline should be recorded on the eCRF.  Changes from baseline 
abnormalities should be recorded at each subsequent physical examination.  New or 
worsened clinically significant abnormalities should be recorded as adverse events, if 
appropriate.
Height and weight will be measured at screening only.  See Appendix 1 (schedule of 
activities) for the timing of these assessments.
4.5.4
Neurological Examinations
Neurological examinations will be used to distinguish relapse in MS from another 
neurological (non-MS) disorder.  Potential relapses should be recorded throughout the
study.  See Appendix 1 (schedule of activities) for the timing of these assessments.
A protocol-defined relapse is an occurrence of new or worsening neurological symptoms 
attributable to MS.  Symptoms must persist for 24 hours and should not be attributable 
to confounding clinical factors (e.g., fever, infection, injury, adverse reactions to 
medications) and immediately preceded by a stable or improving neurological state for 
least 30 days.  The new or worsening neurological symptoms must be accompanied by 
objective neurological worsening consistent with an increase of at least half a step on 
the EDSS scale, or 2 points on one of the appropriate Functional Systems Score (FSS), 
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or 1 point on two or more of the appropriate FSS.  The change must affect the selected 
FSS (i.e., pyramidal, ambulation, cerebellar, brainstem, sensory, or visual).  Episodic 
spasms, sexual dysfunction, fatigue, mood change or bladder or bowel urgency or 
incontinence will not suffice to establish a relapse (Please note:  Sexual dysfunction and 
fatigue need not be scored).
Investigators will also screen patients for signs and symptoms of worsening neurological 
function localized to the cerebral cortex, such as cortical symptoms/signs, behavioral 
and neuropsychological alteration, retrochiasmal visual defects, hemiparesis, and 
cerebellar symptoms/signs (e.g., gait abnormalities, limb incoordination).  Patients with 
suspected PML should be withheld from ocrelizumab treatment until PML is ruled out by 
complete clinical evaluation and appropriate diagnostic testing (see Appendix 6).  A 
patient with confirmed PML should be withdrawn from the study.  PML should be 
reported as a serious adverse event (with all available information) with immediate 
notification of the Medical Monitor.
4.5.5
Vital Signs
Vital signs will include measurements of heart rate, temperature, and systolic and 
diastolic blood pressure.
Vital signs should be taken approximately 45 minutes prior to premedication.  In addition, 
vital signs should be obtained prior to the ocrelizumab infusion and then approximately 
every 15 minutes for the first hour, followed by approximately every 30 minutes until 
1 hour after the end of the infusion.  
Patients will be informed about the possibility of delayed post-infusion symptoms and 
instructed to contact their study physician if they develop such symptoms.
4.5.6
Assessment of Disability
Disability in MS will be measured by the EDSS.  See Appendix 1 (schedule of activities) 
for the timing of these assessments.  It is strongly recommended that the same EDSS 
rater is used for each patient throughout the study when possible.  The EDSS should be 
done on the same day or within 24 hours prior to the study drug infusion if both are done 
at the same visit. 
The EDSS is based on a standard neurological examination, incorporating seven 
functional systems (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, 
and cerebral [or mental], plus “other”) rated and scored as FSSs.  Each FSS is an 
ordinal clinical rating scale ranging from 0 to 5 or 6.  These ratings are then used in 
conjunction with observations and information concerning ambulation and use of 
assistive devices to determine the EDSS score.  The EDSS is a disability scale that 
ranges in 0.5-point steps from 0 (normal) to 10 (death) (see Appendix 3).
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Disability progression is defined as a1-point increase in EDSS score from baseline if 
the baseline EDSS score is between 0.0 and 5.5 (inclusive) or a 0.5-increase from 
baseline if the baseline EDSS score is higher than 5.5.  The increase of disability 
progression on EDSS should be confirmed 24 weeks after the time at which the increase 
has been observed.  The initial increase in EDSS can occur at any visit during the 
96-week study.
4.5.7
Brain Magnetic Resonance Imaging
MRI will be used to monitor CNS lesions related to MS pathology and potentially other 
pathology findings.  Brain MRI scans will be obtained at study visits as shown in the 
schedule of activities (see Appendix 1).  The evaluation of scans for incidental pathology 
not related to MS, such as PML, is a local responsibility that should be handled 
according to the local practice.  Any clinically significant findings should be reported on 
the Adverse Event eCRF.
MRI scans will be read by a centralized reading center for efficacy endpoints.  Prior to 
initiation of treatment on Day 1/Baseline, a quality control (QC) report for the patients 
Screening MRI scan must have been received from the centralized reading center 
confirming scan passed QC.  The brain MRI requires approximately 2 business days to 
be quality checked before dosing of ocrelizumab.  Further details on scanning 
acquisition sequences, methods, handling, transmission of the scans, and certification of 
site MRI scanner are described in a separate MRI technical manual.  
Assessments will include T1-weighted scans before and after injection of Gd contrast, 
and may also include, but may not be limited to:  fluid-attenuated inversion-recovery 
(FLAIR), proton density-weighted, and T2-weighted scans.
4.5.8
Laboratory, Biomarker, and Other Biological Samples
Samples for the laboratory tests will collected on the days indicated in the schedule of 
activities (see Appendix 1).
Pre-infusion laboratory test results need to be available for review before each infusion, 
unless otherwise specified.  
Routine safety laboratory assessments will include the following:

Hematology (hemoglobin, hematocrit, RBCs, WBC absolute or differential, ANC, 
and quantitative platelet count)

Serum chemistry (AST, ALT, GGT, total bilirubin, urea or BUN, uric acid, creatinine, 
potassium, sodium, calcium, and phosphorus)

Urinalysis or urine dipstick on site (standard to assess kidney function)

Pregnancy test  

All women of childbearing potential will have a serum or urine pregnancy test at 
screening.  Urine pregnancy tests will be performed at specified subsequent 
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visits.  If a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test.

Viral serology and detection:

Hepatitis B (HBsAg and HBcAb confirmed, if positive, by positive viral DNA 
PCR)

For enrolled patients with negative HBsAg and positive total HBcAb, hepatitis B 
virus (HBV) DNA (by PCR) must be repeated every 24 weeks

Hepatitis C virus (HCV) antibody (performed only at screening)
Additional samples will include the following:

Lymphocyte subtypes

Whole-blood samples will be collected to determine the duration of B-cell 
depletion and recovery (CD19) and T-cell counts (CD4, CD8).
Per local Institutional Review Board (IRB)/Ethics Committees (ECs) requirements, 
additional testing may be required for selected patients or selected centers to exclude 
TB, Lyme disease, HTLV-1 associated myelopathy (HAM), AIDS, hereditary disorders, 
connective tissue disorders, or sarcoidosis.
4.5.9
Patient-Reported Outcomes
PRO data will be elicited from patients in this study to better characterize patient quality 
of life and treatment satisfaction while on ocrelizumab.  PROs completed at baseline 
should be in reference to the last-used DMT prior to enrollment.
The Multiple Sclerosis Impact Scale (MSIS-29) is a 29-item questionnaire designed to 
measure the physical and psychological impact of MS from the patient’s perspective.  
Additionally, the Treatment Satisfaction Questionnaire for Medication (TSQM II) and the 
Treatment Satisfaction with Medicines Questionnaire (SATMED-Q), questionnaires to 
assess patients’ treatment satisfaction, will be administered to patients during the visits 
listed in the schedule of activities (see Appendix 1).
Please note that all PROs are required to be administered prior to administration of 
study drug and prior to any other study assessment(s) to ensure the validity of the 
instruments is not compromised.  Also note that the methods for collecting and analyzing 
PRO data are different from those for the ascertainment of observed or volunteered 
adverse events.  Due to these differences, PRO data will not be reported as adverse 
events and no attempt will be made to resolve any noticeable discrepancies between 
PRO data and observed or volunteered adverse events.
4.5.10
Safety Follow-up Period
Patients who complete their infusion at Week 72 or who discontinue from treatment 
early should enter the Safety Follow-up Period and be assessed at 24 weeks.  If the
peripheral blood B-cell count remains depleted after 6 months from the date of the last 
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infusion, the investigator may want to continue monitoring the B-cell count until it has 
returned to the baseline value or to the lower limit of the normal range, whichever is
lower.  During the Safety Follow-Up Period, patients who receive other B-cell targeted 
therapies will only be followed for an additional period of approximately 24 weeks from 
the start of the alternative MS treatment.  
See Figure 2 for an overview of the Safety Follow-up Period and Appendix 1 for the 
schedule of activities.  
4.6
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.6.1
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

Patient non-compliance, defined as failure to follow dosing instructions or to 
complete program visits
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.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced.
4.6.2
Criteria for Re-Treatment with Ocrelizumab
Prior to re-treatment with ocrelizumab, patients will be evaluated for the following 
conditions and laboratory abnormalities. If any of these are present prior to re-dosing, 
further administration of ocrelizumab should be suspended until these are resolved or 
held indefinitely:

Life-threatening (Grade 4) infusion-related event that occurred during a previous 
ocrelizumab infusion

Any significant or uncontrolled medical condition or treatment-emergent, clinically 
significant laboratory abnormality

Active infection

Ongoing pregnancy or breastfeeding 
4.6.3
Study Treatment Discontinuation
Patients must discontinue study treatment if they experience any of the following:

Life-threating IRR or serious hypersensitivity reaction
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
Active hepatitis B infection

PML

Active TB, either new onset or reactivation
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be
replaced.
4.6.4
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 Council on Harmonisation (ICH) guidelines
for Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Ocrelizumab is currently in clinical development for the treatment of MS.  Identified and 
potential risks associated with ocrelizumab treatment will continue to be closely 
monitored throughout the clinical program.  Patient safety during the ocrelizumab 
program is ensured by targeting the most appropriate patient population, stringent safety 
monitoring by the Sponsor, and protocol-specified ocrelizumab treatment interruption 
criteria.  Patients will be evaluated clinically and with standard laboratory tests before 
and at regular intervals during their participation in this study.  Safety evaluations will 
consist of medical interviews, recording of adverse events, physical examinations, and 
standard laboratory measurements.  Adverse events will be graded according to the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) v4.0.
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Administration of ocrelizumab will be performed in a hospital or clinic environment under 
close supervision of the investigator or a medically qualified staff member.  All adverse 
events and serious adverse events will be recorded during the study for at least
24 weeks after the end of the treatment period and throughout safety follow up.  Safety 
assessments will include the incidence, nature, and severity of (serious) adverse events 
graded per the NCI CTCAE v4.0.  Safety assessments will be conducted per the 
schedule of activities in Appendix 1.  
The identified and potential safety issues anticipated in this study are reported in the 
Ocrelizumab Investigator’s Brochure.  In addition, measures intended to avoid or 
minimize these issues, are outlined in the following sections.
5.1.1
Risks Associated with Corticosteroids
The adverse reactions of corticosteroids may result from unwanted glucocorticoid 
actions, or from inhibition of the hypothalamic-pituitary-adrenal axis.  Please refer to 
local prescribing information.
5.1.2
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.
5.1.3
Risks Associated with Ocrelizumab 
5.1.3.1
Identified Risks and Adverse Drug Reactions
5.1.3.1.1
Infusion-Related Reactions
All CD20depleting agents administered via the intravenous route, including 
ocrelizumab, have been associated with acute IRRs.  Symptoms of IRRs may occur 
during any ocrelizumab infusion, but have been more frequently reported during the first 
infusion.  Physicians should alert patients that IRRs can occur within 24 hours of the 
infusion.  These reactions may present as pruritus, rash, urticaria, erythema, throat 
irritation, oropharyngeal pain, dyspnea, pharyngeal or laryngeal edema, flushing, 
hypotension, pyrexia, fatigue, headache, dizziness, nausea, and tachycardia. 
Patients should be observed for at least one hour after the completion of the infusion for 
any symptom of IRR.  They will 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 infusions.  Therefore, 
withholding of antihypertensive treatments should be considered for 12 hours prior to 
and throughout each ocrelizumab infusion. 
5.1.3.1.2
Infections 
Infection is an identified risk associated with ocrelizumab treatment, predominantly 
involving mild to moderate respiratory tract infections.  Non-disseminated herpes 
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virus-associated infections, mostly mild to moderate, were also reported more frequently 
with ocrelizumab (approximately 5% to 6%, simplex and zoster) than with comparators 
(approximately 3%). 
During the controlled period of the pivotal trials, the proportion of RMS patients with 
serious infections 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 
rheumatoid arthritis (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 by any MS patient treated with ocrelizumab
during the controlled period of the pivotal trials. 
There were no reports of hepatitis B reactivation in MS patients treated with ocrelizumab, 
but it had been reported in one RA patient treated with ocrelizumab.  HBV screening 
should be performed in all patients before initiation of treatment with ocrelizumab as per 
local guidelines.  Patients with active hepatitis B virus should not be treated with 
ocrelizumab.  Patients with positive serology should consult liver disease experts before 
the start of treatment and should be monitored and managed following local medical 
standards to prevent hepatitis B reactivation. 
Delay ocrelizumab administration in patients with an active infection until the infection is 
resolved.  
For PML, see Potential Risks (Section 5.1.3.2).
5.1.3.1.3
Decrease in Immunoglobulins
Treatment with ocrelizumab resulted in a decrease in total immunoglobulins (Igs) over 
the controlled period of the studies, mainly driven by reduction in IgM, with no observed 
association with serious infections.  The proportion of patients with decrease in Igs 
below the 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 Potential Risks, Section 5.1.3.2).
5.1.3.1.4
Delayed Return of Peripheral B Cells
Treatment with ocrelizumab leads to rapid depletion of CD19B cells in blood by 
14 days post-treatment (first timepoint of assessment) as an expected pharmacologic 
effect.  This was sustained throughout the treatment period.  The longest follow-up time 
after the last ocrelizumab infusion from Phase II Study WA21493 in 51 patients indicates 
that the median time to repletion (returned to baseline/LLN, whichever occurred first) of 
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B cells was 72 weeks (range:  27175 weeks).  Patients with prolonged B-cell depletion 
should be monitored until their B cells have repleted.
5.1.3.1.5
Impaired Immunization Response 
The safety of immunization with live or live-attenuated vaccines following ocrelizumab 
therapy has not been studied, and vaccination with live-attenuated or live vaccines is 
not recommended during treatment and until B-cell repletion. 
After treatment with ocrelizumab over 2 years, the proportion of patients with positive 
antibody titers against S. pneumoniae, mumps, rubella, varicella were generally similar 
to the proportions at baseline.
In a randomized, open-label study, RMS patients treated with ocrelizumab were able to 
mount humoral responses, albeit decreased, to tetanus toxoid, 23-valent pneumococcal 
polysaccharide, keyhole limpet hemocyanin neoantigen, and seasonal influenza vaccines.  
It is still recommended to vaccinate patients treated with ocrelizumab with seasonal 
influenza vaccines that are inactivated.
Physicians should review the immunization status of patients before starting treatment 
with ocrelizumab.  Patients who require vaccination should complete their 
immunizations at least 6 weeks prior to initiation of ocrelizumab.  Please see the 
Ocrelizumab Investigator’s Brochure for more details.
5.1.3.2
Potential Risks 
5.1.3.2.1
Progressive Multifocal Leukoencephalopathy
PML is an important potential risk for ocrelizumab and it has only been reported with 
ocrelizumab where the risk for PML was preexisting, specifically because of prior 
natalizumab treatment.  Refer to Appendix 6 for guidance for diagnosis of PML.  See the 
Ocrelizumab Investigator's Brochure for more details.
5.1.3.2.2
Serious Infections Related to Decrease in Immunoglobulins
(particularly in patients previously exposed to 
immunosuppressive/immunomodulatory drugs or with 
pre-existing hypogammaglobulinemia)
Based on additional patient exposure an apparent association between sustained 
decrease in immunoglobulins (IgA, IgG, IgM) and serious infections with ocrelizumab 
treatment was observed.  However, no pattern (e.g., type of infections, safety laboratory 
abnormalities beyond the decrease in Ig, latency, duration) was found that could identify 
a subset of patients at higher risk of serious infections.
5.1.3.2.3
Hypersensitivity Reactions 
No hypersensitivity reactions to ocrelizumab were reported in the controlled clinical trials. 
Hypersensitivity may be difficult to distinguish from IRRs in terms of symptoms.  A 
hypersensitivity reaction may present during any infusion, although typically would not 
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present during the first infusion.  For subsequent infusions, more severe symptoms than 
previously experienced, or new severe symptoms, should prompt consideration of a 
potential hypersensitivity reaction.  If a hypersensitivity reaction is suspected during 
infusion, the infusion must be stopped immediately and permanently.  Patients with 
known IgE-mediated hypersensitivity to ocrelizumab must not be treated.
5.1.3.2.4
Malignancies including Breast Cancer
An increased risk of malignancy with ocrelizumab may exist.  In controlled trials in adults 
with multiple sclerosis, malignancies, including breast cancer, occurred more frequently 
in ocrelizumab-treated patients.  Breast cancer occurred in 6 of 781 females treated with 
ocrelizumab and none of 668 females treated with Rebifor placebo.  Patients should 
follow standard breast cancer screening as per local guidelines.  See the Ocrelizumab 
Investigator's Brochure for more details. 
5.1.3.2.5
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 
were mild to moderate in severity, and approximately 1% of the patients had Grade 3 or 
4 neutropenia; and no temporal association with infections was identified.  
Detailed information for all risks can be found in the current Ocrelizumab Investigator’s 
Brochure.
5.1.4
Management of Patients Who Experience Specific Adverse 
Events
Guidelines for management of specific adverse events are outlined in Table 2.  
Additional guidelines are provided in the subsections below.
Table 2
Guidelines for Management of Specific Adverse Events
Event
Action to Be Taken
Mild to moderate IRR

If the event that a patient experiences is a mild to moderate IRR 
(e.g. headache), the infusion rate should be reduced to half the 
rate at the time of the event.

This reduced rate should be maintained for at least 30 minutes.  
If tolerated, the infusion rate may then be increased according to 
the patient’s initial infusion schedule.
Severe IRR (or complex of 
flushing, fever, and throat 
pain)

If a patient experiences a severe IRR or a complex of flushing, 
fever, and throat pain symptoms, the infusion should be 
interrupted immediately and the patient should receive 
symptomatic treatment.

The infusion should be restarted only after all symptoms have 
resolved.

The initial infusion rate at restart should be half of the infusion 
rate at the time of onset of the reaction.
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Event
Action to Be Taken
Life-threatening or 
disabling IRR (e.g., 
anaphylaxis)

Immediately stop ocrelizumab if there are signs of a 
life-threatening or disabling IRR during an infusion, such as 
acute hypersensitivity or acute respiratory distress syndrome.

The patient should receive appropriate treatment.

Permanently discontinue ocrelizumab in these patients.
IRRinfusion-related reaction.
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 guidelines 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 5.3.5.10   

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)
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
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that had it occurred in a more severe form 
or was allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for
reporting instructions).
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 are identified 
for ocrelizumab in the indicated patient population in Section 5.1.3.1.  Standard adverse 
events of special interest include the following:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see Section 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.
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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Section 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).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, related serious adverse events must be collected and 
reported regardless of the time elapsed from the last study drug administration, even if 
the study has been closed (see Section 5.4.2).
Unrelated serious adverse events must be collected and reported during the study 
through the end of the Safety Follow-Up Period, which is at least 24 weeks after the last 
infusion but may be extended in patients whose B cells take longer to replete. 
Non-serious adverse events have to be reported until the end of the Safety Follow-up 
Period.  
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 an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also
Table 4):

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 
occurrence of the event
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Table 4
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug infusion should be captured as a diagnosis (e.g., 
“infusion-related reaction” or “anaphylactic reaction”) on the Adverse Event eCRF.  If 
possible, avoid ambiguous terms such as “systemic reaction.”  Associated signs and 
symptoms should be recorded on the dedicated Infusion-Related Reaction eCRF.  If a 
patient experiences both a local and systemic reaction to the same dose of study drug, 
each reaction should be recorded separately on the Adverse Event eCRF, with signs 
and symptoms also recorded separately on the dedicated Infusion-Related Reaction 
eCRF.  
Investigators should consider a local IRR for any symptoms affecting the skin and 
localized to only one place. Any other IRR should be considered systemic.
Further details on prevention and management of IRRs are described in 
Section 5.1.3.1.1, Section 5.1.4 (Table 2), and in the Ocrelizumab Investigator’s 
Brochure.
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5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events, 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).
5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
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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 whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
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If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2).
5.3.5.8
Deaths
All deaths that occur during the protocol-specified, adverse event, reporting period 
(see Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of RRMS.
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.  The term "sudden death" should be used only for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without preexisting heart disease, within 1 hour after the onset of acute symptoms or, in 
the case of an unwitnessed death, within 24 hours after the patient was last seen alive 
and stable.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.
If the death is attributed to progression of RRMS, "RRMS progression" should be 
recorded on the Adverse Event eCRF.  
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5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of Relapsing Remitting Multiple 
Sclerosis
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on EDSS score.  In rare cases, the determination of clinical 
progression will be based on symptomatic deterioration.  However, every effort should 
be made to document progression through use of objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any 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.  
The following are not considered serious adverse events:

Elective hospitalizations or surgical procedures that are a result of a patient’s 
pre-existing condition(s) that have not worsened since receiving trial medication. 
Examples may include, but are not limited to, cholecystectomy for gallstones and 
diagnostic testing. Such events should still be recorded as medical procedures in 
the concomitant procedures/treatments eCRF.

Hospitalization to receive trial medication, such as infusions of ocrelizumab, unless 
this is prolonged (more than 24 hours)

Hospitalization following an MS relapse as long as the reason for hospitalization is 
to receive standard treatment with IV methylprednisolone
The following hospitalization scenarios are not considered to be serious adverse events, 
but should be reported as adverse events instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
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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

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 
Genentech Medical Monitor contact information:
Medical Monitor:
, M.D., Ph.D.
Telephone No.:
 (U.S.)
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.
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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 for at least 24 weeks after the last dose of study drug.  
Investigators should record all case details that can be gathered immediately (i.e., within 
24 hours after learning of the event) on the Adverse Event eCRF and submit the report 
via the electronic data capture (EDC) system.  A report will be generated and sent to 
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.  
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 to immediately inform the 
investigator if they become pregnant during the study or within 24 weeks after the last 
dose of study drug.  A Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Pregnancy should not be 
recorded on the Adverse Event eCRF.  The investigator should discontinue study drug 
and counsel the patient, discussing the risks of the pregnancy and the possible effects 
on the fetus.  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.  
Given that there are insufficient, well-controlled data from studies testing the use of 
ocrelizumab in pregnant or breastfeeding women, all infusions of ocrelizumab must be 
suspended until the end of pregnancy and breastfeeding. Pregnant and breastfeeding 
patients should continue to follow the schedule of assessments; however, no infusions 
will occur.  If there is a concern with the ability of a pregnant or breastfeeding patient 
to perform all scheduled assessments, or if an assessment is contraindicated during 
pregnancy, the investigator must contact the Medical Monitor for further discussion.  
Restart of ocrelizumab treatment following pregnancy and breastfeeding will be decided 
as a result of a thorough benefitrisk discussion between the patient and investigator.  
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Patients who have already permanently discontinued from the study because of 
pregnancy (or for any other reason) may not be re-enrolled in the study.
For pregnancies occurring in female patients during treatment with ocrelizumab or within 
6 months after the last dose of ocrelizumab, pregnancy outcome and health status of the 
child will be collected 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.  The data will be reported on dedicated pregnancy outcome and infant health 
information paper questionnaire.
5.4.3.2
Congenital Anomalies/Birth Defects and Abortions
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).  Any abortion should be reported in the same 
fashion (as the Sponsor considers abortions to be medically significant).
5.4.4
Reporting Requirements for Cases of Ocrelizumab Accidental 
Overdose or Medication Error
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is 
higher than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.
Special situations are not in themselves adverse events, but may result in adverse 
events.  All special situations associated with ocrelizumab, regardless of whether they
result in an adverse event, should be recorded on the Adverse Event eCRF and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event).  
Special situations should be recorded as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and 
"accidental overdose" as the event term.  Check the "Accidental overdose" and 
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"Medication error" boxes.  Enter a description of the error in the additional case 
details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.
Each adverse event associated with a special situation should be recorded separately on 
the Adverse Event eCRF.  If the associated adverse event fulfills seriousness criteria, 
the event should be reported to the Sponsor immediately (i.e., no more than 24 hours 
after learning of the event; see Section 5.4.2).  Adverse events associated with special 
situations should be recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose and 
one to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked on both eCRF pages.
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.
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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 
at least 24 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.
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, 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 document:

Ocrelizumab Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
Refer to the Ocrelizumab Investigator’s Brochure for a list of serious adverse drug 
reactions.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
In this single-arm, non-comparative study, the analyses will mostly be descriptive and 
exploratory.  Inferential statistical methods, if applied, will be employed to highlight the 
data aspect of interest.  Unless otherwise specified, statistical tests will be two sided and 
the statistical significance level will be 5%.  Corresponding 95% CIs will be presented as 
appropriate.  No corrections for multiple testing will be applied to the primary endpoint or 
secondary endpoints analyses as well as to the interim analyses.
For continuous variables, descriptive statistics (e.g., mean, median, standard deviation 
[SD], n, 25th and 75th percentiles, minimum, maximum) will be calculated and 
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summarized.  For categorical variables, the number and percentage in each category 
will be displayed.  Full details of all statistical issues and planned statistical analyses will 
be specified in a separate Statistical Analysis Plan (SAP), which will be finalized prior to 
the locking of the study database.
Since the number of previous DMTs used may be related to the treatment outcome, the 
number of previous DMTs used (i.e., 1 vs. 2) will be used as a stratification factor in the 
summary and analysis.  In general, the report will be presented by the number of 
previous DMTs used and overall; the statistical analysis will be stratified or adjusted for 
by the number of previous DMTs used along with the corresponding baseline covariate 
when appropriate.  Other subgroups of interest may also be considered in the statistical 
data analysis.  
After the Week 72 visit of the last patient enrolled, approximately 24 weeks may be 
needed to allow the confirmation of the last protocol-defined event of the 24-week CDP.  
Therefore, the clinical cut-off date will occur approximately 24 weeks after the last 
patient’s Week 72 visit when the status is clarified for each patient.  The sites and EDSS 
raters will remain available until approximately 24 weeks after the Week 72 visit of the 
last patient enrolled.
6.1
DETERMINATION OF SAMPLE SIZE
Assuming a) the expected proportion of patients who will be event free during 96 weeks 
is 45%; b) the type one error rate is 5% and the half-width of 95% CI for the proportion is 
4%; c) the probability that half-width of 95% CI is at most 4% is 80%, then the required 
sample size will be n600.
It should be noted that the estimation of the proportion of patients who will be 
protocol-defined event free (45%) is based on the pooled data from Studies WA21092 
and WA21093 (OPERA I and OPERA II, respectively) from all patients who had a 
baseline EDSS of 2.0.  The true proportion could be lower than 45% for 
ocrelizumab-treated patients who would meet the definition of sub-optimal responders as 
specified in this protocol.  However, the required sample size should be lower than 600
patients to achieve the same precision (i.e., maximum half-width of 95% CI) if the true 
proportion is actually lower than 45%.  This is due to the fact that a lower proportion will 
have a smaller variance for the estimated proportion than that from 45% and the 
variance of proportion is maximized when the proportion is 50% (calculation performed 
using SAS software, Version 9.2).  In Figure 3, the sample sizes are displayed from a 
range of proportions (30% to 50%) with an 80% probability that half-width of 95% CI is at 
most 4%.  For example, if the proportion is 45%, the corresponding sample size is 
598.86 (rounded to 600 for recommended number).  The ranges of proportion were 
based on the 2-year proportion of alemtuzumab-treated patients and natalizumab-
treated patients who achieved no evidence of disease activity (NEDA) (32% and 55%, 
respectively).  In Figure 4, the sample sizes are displayed similarly to Figure 3, but the 
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half-width of 95% CI is set as 5% for providing additional information concerning the 
impact of half-width on sample size.   
Figure 3
Prob(Half-width of 95% CI4%) with Sample Size if Expected 
Proportion30%50%
Source:  Hartung et al. 2013; Prosperini et al. 2012; Internal OPERA study data.
CIconfidence interval.
Figure 4
Prob(Half-width of 95% CI5%) with Sample Size if Expected 
Proportion30%50%
Source:  Hartung et al. 2013; Prosperini et al. 2012; Internal OPERA study data.
CIconfidence interval.
6.2
SUMMARIES OF CONDUCT OF STUDY
Enrollment, ocrelizumab administration, and discontinuations from the study will be 
summarized.  Patient disposition and the incidence of treatment discontinuation for 
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reasons other than disease progression will be tabulated.  Major protocol violations, 
including violations of inclusion/exclusion criteria, will also be summarized.
6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Patients’ demographics, medical history, and neurological examination will be 
summarized.  MS disease history (duration since MS first symptom, duration since MS 
diagnosis), MS disease status (MS treatment naïve or experienced), and MS prior 
treatment (for those being treated) will be summarized.  Also, the baseline measures of
MRI, EDSS, or other important endpoints will be summarized.
6.4
ANALYSIS POPULATIONS
The efficacy analyses will be performed using the intent-to-treat (ITT) population. The 
per-protocol (PP) population will be used for supportive efficacy analyses (for the
primary endpoint and selected secondary endpoints) in order to evaluate the influence 
of major protocol violators on key efficacy endpoints. The safety population will be used 
for safety analyses.
6.4.1
Intent-to-Treat Population
All enrolled patients who receive any ocrelizumab will be included in the ITT population. 
Patients who prematurely withdrew from the study for any reason and who did not 
perform any assessment for any reason will still be included in the ITT population.
6.4.2
Per-Protocol Population
The PP population will include all patients in the ITT population who adhere to the 
protocol.  Specific reasons for warranting exclusion will be agreed to by the study team
and documented in the SAP. 
6.4.3
Safety Population
The Safety Population will include all enrolled patients who received any ocrelizumab.
6.5
EFFICACY ANALYSES
6.5.1
Primary Efficacy Outcome Measures
The primary efficacy assessment will be the proportion of patients who are free of any 
protocol-defined events during a 96-week study.  The definition of a protocol-defined 
event is the occurrence of at least one of the following while on treatment with 
ocrelizumab:

A protocol-defined relapse as defined in Section 4.5.4 (Note:  An adjudication of 
protocol-defined relapses will be performed by the Sponsor based on pre-specified 
criteria, applied to data collected by the investigator.)

A T1 Gd-enhanced lesion on brain MRI

A new and/or enlarging T2 lesion on brain MRI
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
CDP (24 weeks) 
6.5.2
Secondary Efficacy Outcome Measures
The secondary efficacy outcome measures are as follows:

The proportion of patients free from a protocol-defined event during a 24-week 
period and a 48-week period

Time to protocol-defined event (see definition above)

Annualized relapse rate at Week 96

The time to onset of first relapse

Time to onset of first T1 Gd-enhanced lesion 

Time to onset of first new and/or enlarging T2 lesion

Time to onset of CDP for at least 24 weeks during the study period 

Total number of T1 Gd-enhanced lesions detected by brain MRI at Weeks 24, 48, 
and 96

Change in total T2 lesion volume detected by brain MRI from baseline to 
Weeks 24, 48, and 96

Total number of new and/or enlarging T2 lesions detected by brain MRI at 
Weeks 24, 48, and 96
6.5.3
Exploratory Outcomes 
The exploratory outcomes will consist of the following: 

PRO

MSIS-29

SATMED-q

TSQM II
6.5.4
Analysis Methods
The proportion of patients who are free from a protocol-defined event during Week 96
(the primary efficacy endpoint) will be calculated, and the two-sided 95% CI will be 
presented.  Data from any unscheduled visit within each respective 24-week interval will 
be included for this endpoint.  Similar analyses will be applied to the proportions of 
patients who are free from a protocol-defined event during Weeks 24 and 48.
The annualized relapse rates by Week 96 will be analyzed using negative binomial 
model, adjusting for the number of previous DMTs used and including the 
log-transformed year of drug exposure time as an “offset” variable.  The adjusted 
annualized relapse rate and the two-sided 95% CI for the relapse rate will be presented. 
The Kaplan-Meier estimator (i.e., the product limit estimator) will be used to estimate the 
survival function for time-to-event data (e.g., time to protocol-defined event; time to onset 
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of first relapse; time to onset of CDP for at least 24 weeks).  The proportion of patients 
with an event and of those censored will be reported; the median survival time and its 
95% CI will be presented.  
The total number of T1 Gd-enhanced lesions will be calculated as the sum of the 
individual number of T1 Gd-enhanced lesions at Weeks 24, 48, and 96.  Data from other 
unscheduled assessments will not be included in this summary or analysis.  A negative 
binomial model will be used to estimate the rate of lesion occurrence.  In order to 
account for patients receiving varying numbers of brain MRI scans during the study, the 
log-transformed number of brain MRI scans received will be included in the model as an 
“offset” variable for appropriate computation.  
The change from baseline in total T2 lesion volume as detected by brain MRI to 
Weeks 24, 48, and 96 will be analyzed through a mixed model with repeated measure 
(MMRM), adjusting the following covariates: baseline score and the number of previous 
DMT use.
The total number of new and/or enlarging T2 lesions will be calculated as the sum of the 
individual number of new and/or enlarging T2 lesions at Weeks 24, 48, and 96.  Data 
from unscheduled assessments will not be included in this summary or analysis.  The 
analysis model will be similar to that used for the total number of T1 Gd-enhanced 
lesions. 
The PRO outcomes and other exploratory endpoints will be descriptively summarized as 
change from baseline at Weeks 24, 48, and 96 if they are continuous variables (e.g., 
MSIS-29) or summarized in the number and percentage of events by each visit if they 
are dichotomized or categorical variables.  To assess the longitudinal treatment effect for 
continuous variable, the mean changes from baseline at Weeks 24, 48, and 96 will be 
analyzed through a MMRM adjusting the following covariates:  baseline score and the 
number of previous DMTs used.
6.6
SAFETY ANALYSES
6.6.1
Safety Outcome Measures
The safety outcome measures comprise the following:  the incidence and nature of all 
adverse events, including findings on vital sign measurements, physical and neurological 
examinations, clinical laboratory tests, locally reviewed MRI for safety (non-MS CNS 
pathology), and concomitant medications.
6.6.2
Safety Analyses
Safety will be assessed through summaries of adverse events (including incidence rates 
and corresponding 95% CIs) and clinical laboratory abnormalities.  
All adverse events occurring on or after treatment on Day 1 will be coded, summarized 
by NCI CTCAE v4.0 grade, and tabulated by body system and Preferred Term for 
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individual adverse events within each body system.  Grade 3 to 5 adverse events, 
serious adverse events, adverse events leading to treatment discontinuation, time to 
withdrawal from the study due to an adverse event, adverse events leading to infusion 
adjustment, and treatment-related adverse events will be summarized.  In addition, all 
serious adverse events and deaths will be listed.
Associated laboratory parameters, such as hepatic function, renal function, and 
hematology values, will be grouped and presented together.  Marked abnormalities will 
also be flagged. 
Ocrelizumab exposure will be summarized, including duration and dosage. 
6.7
HANDLING OF MISSING DATA
The following guideline will be used when dealing with missing data related to the 
protocol-defined event in the primary efficacy endpoint.  Patients who complete the 
treatment period will be considered as having a protocol-defined event if any of the 
following are reported during the 96-week study:  at least one protocol-defined relapse, 
Gd-enhancing T1 lesions, new and/or enlarging T2 lesions, or CDP.  Otherwise, the 
patient will be considered as being protocol-defined event free.
Patients who discontinue treatment early and have at least one event before early 
discontinuation will be considered as having a protocol-defined event.  Details of 
missing data handling for patients who discontinue treatment early and do not have any 
event before early discontinuation will be specified in Statistical Analysis Plan.
6.8
INTERIM ANALYSES
It is estimated that two to three interim analyses will be performed during the course of 
the study, according to patient enrollment and availability of data of interest.  Interim 
analyses may be used for internal decision making, hypothesis generation, 
abstraction/publication for major MS conferences, or other purposes, as applicable.  
Details on the timing and scope of interim analyses will be described in the Statistical 
Analysis Plan.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will supply eCRF specifications for this study.  A contract research 
organization (CRO) 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 CRO will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
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The CRO will produce a Data Quality Plan that describes the quality checking to be 
performed on the data.  Local laboratory data will be sent directly to the CRO, using the 
CRO's standard procedures to handle and process the electronic transfer of these data.
The Sponsor will perform oversight of the data management of this study, including 
approval of the CRO’s data management plans and specifications.  Data will be 
periodically transferred electronically from the CRO to the Sponsor, and the Sponsor’s 
standard procedures will be used 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 at the CRO and records retention for the study data will 
be consistent with the CRO’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.
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 
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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/EC review.  The study site must also allow 
inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic PRO data (if applicable), Informed Consent Forms, 
laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for at least 15 years after completion or discontinuation of the 
study, or for the length of time required by relevant national or local health authorities, 
whichever is longer.  After that period of time, the documents may be destroyed, subject 
to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
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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 (and ancillary sample Informed Consent 
Forms such as a Home Nursing Informed Consent Form, if applicable) will be provided 
to each site.  If applicable, it will be provided in a certified translation of the local 
language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/ECapproved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
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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 
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 national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
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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 
[LPLV]).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.
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 trial will be sponsored by Genentech, a member of the Roche group, and will be 
managed by Genentech and CROs.  CROs will provide clinical operations management, 
data management, biostatistics, and medical monitoring. 
An IxRS will be used to assign patient numbers, monitor enrollment and patient status, 
and to manage study treatment requests and study drug shipments.  
Patient data will be recorded via an EDC system using eCRFs.
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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 Trials Data at the following Web site:  
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.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 
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 
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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.
REFERENCES
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Clinical Study Report for WA21493: Phase II, multicenter, randomized, parallel-group, 
partially blinded, placebo and Avonexcontrolled dose finding study to evaluate 
the efficacy as measured by brain MRI lesions, and safety of 2 dose regimens of 
ocrelizumab in patients with RRMS. Report No. 1034917, November 2012.
Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing 
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multiple sclerosis. N Engl J Med 2000;343:14301438.
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immunotherapy in mice. J Immunol 2008;180:361371.
Durelli L, Barbero P, Bergui M, et al. The OPTimization of Interferon for MS Study: 
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Fernández O, Fernández V, Mayorga C, et al. HLA class II and response to interferon-
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Gajofatto A. Bacchetti P, Grimes B, et al. Switching first-line disease-modifying therapy 
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Goodin DS. The epidemiology of multiple sclerosis: insights to disease pathogenesis. 
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Hartung H, Vollmer T, Arnold D, et al. Alemtuzumab reduces MS disease activity in 
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prior therapy. Neurology 2013;80(Meeting Abstracts 1):P07093.
Kappos L, Li D, Calabresi PA, et al. Ocrelizumab in relapsing-remitting multiple 
sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet 
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Klein C, Lammens A, Schafer W, et al. Epitope interactions of monoclonal antibodies 
targeting CD20 and their relationship to functional properties. MAbs 2013;5:2233.
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Trojano M, Paolicelli D, Bellacosa A, et al. The transition from relapsing-remitting MS to 
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Waubant E, Vukusic S, Gignoux L, et al. Clinical characteristics of responders to 
interferon therapy for relapsing MS. Neurology 2003;61(2):184189.
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Appendix 1
Schedule of Activities
Screening
Treatment Period
Safety 
Follow-up 
Visit b
Early 
Withdrawal 
Visit c
Unscheduled 
Visit
(due to 
relapse) d
Visit Number
1
2
3
4
5
6
7
Week
4 a

2 
24 
48 
72 
96 
Study Day
(window in days)
28
1
Baseline
15
(2)
169
(14)
337
(14)
505
(14)
673
(14)
Informed consent e
x
Medical history and demographic data f
x
Review inclusion and exclusion criteria
x
x
Physical examination g
x
x
x
x
x
x
x
x
x
Height
x
Weight
x
Vital signs h
x
x
x
x
x
x
x
x
x
Laboratory Assessments i
Hematology, chemistry, urinalysis j
x
x k
x
x
x
x
x
Pregnancy test l
x
x
x
x
x
x
x
x
Hepatitis screening m
x
Hepatitis B virus DNA test m
x
x
x
x
x
x
Lymphocyte subtypes n
x
x
x
x
x
x
EDSS score
x
x k
x o
x o
x o
x
x
x
Neurological examination p
x
x
x
x
x
x
x
x
x
Patient-Reported Outcome Assessmentsq
x
x
x
x
x
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Appendix 1
Schedule of Activities (cont.)
Ocrelizumab—Genentech, Inc.
76/ Protocol MN30035, Version 5
Screening
Treatment Period
Safety 
Follow-up 
Visit b
Early 
Withdrawal 
Visit c
Unscheduled 
Visit
(due to 
relapse) d
Visit Number
1
2
3
4
5
6
7
Week
4 a

2 
24 
48 
72 
96 
Study Day
(window in days)
28
1
Baseline
15
(2)
169
(14)
337
(14)
505
(14)
673
(14)
Brain MRI r
x s
x o
x o
x
x c
Recording of potential relapses
x
x
x
x
x
x
x
x
Adverse event assessment t
x
x
x
x
x
x
x
x
Concomitant treatment review
x
x
x
x
x
x u
x
x
Methylprednisolone and antihistamine 
premedication v
x
x
x
x
x
Ocrelizumab administration w
x
x
x
x
x
-hCGbeta human chorionic gonadotropin; eCRF electronic Case Report Form; EDSS Expanded Disability Status Scale; HBcAb hepatitis B 
core antibody; HBsAg hepatitis B surface antigen; HBV hepatitis B virus; HepCAb hepatitis C antibody; IRR infusion-related reaction; 
IV intravenous; MRI magnetic resonance imaging; MS multiple sclerosis; PCR polymerase chain reaction; PML progressive multifocal 
leukoencephalopathy; PRO patient-reported outcome; QC quality control.
a The screening period will last up to 4 weeks, but it may be prolonged for up to 8 weeks for relevant clinical, administrative, or operational reasons.
b The Safety Follow-up Period will begin when the patient completes their infusion at Week 72 or discontinues from treatment early.  Patients will 
be assessed at 24 weeks (at Week 96).  If the peripheral blood B-cell count remains depleted after 6 months from the date of the last infusion, 
the investigator may want to continue monitoring the B-cell count until it has returned to the baseline value or to the lower limit of the normal 
range, whichever is lower.  During the Safety Follow-up Period, patients who receive other B-cell targeted therapies will only be followed for an 
additional period of approximately 24 weeks from the start of the alternative MS treatment.
c When a patient discontinues treatment, all assessments must be completed/obtained, except for MRI if done within the past 8 weeks unless 
clinically indicated.
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Appendix 1
Schedule of Activities (cont.)
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d Additional assessments may be conducted, as determined by the investigator, in order to investigate adverse events.
e Written informed consent will be obtained from all patients during screening in order to be eligible for the study.
f
Medical history includes clinically significant diseases, surgeries, reproductive status, smoking history, and all medications (e.g., prescription 
drugs, over-the-counter drugs, herbal or homeopathic remedies, and nutritional supplements) used by the patient within 4 weeks prior to the 
screening visit.  Demographic data will include age, sex, and self‑reported race/ethnicity.
g A full physical examination will be conducted at the screening and early termination visits.  At all other visits, a limited physical examination will 
be conducted.  Any abnormality identified at baseline should be recorded on the eCRF.  Changes from baseline abnormalities should be 
recorded at each subsequent physical examination.  New or worsened clinically significant abnormalities should be recorded as adverse events, 
if appropriate.
h Vital signs will include the measurements of heart rate, systolic and diastolic blood pressures, and temperature.  Vital signs should be taken 
approximately 45 minutes prior to the premedication methylprednisolone infusion.  In addition, vital signs should be obtained prior to the 
ocrelizumab infusion then approximately every 15 minutes for the first hour, followed by approximately every 30 minutes until 1 hour after the 
end of the infusion.  
i
Needs to be available prior to dosing (to be taken up to 14 days prior to dosing).  In rare cases in which the result is not assessable (e.g., 
indeterminate) or is abnormal, the tests need to be repeated.  Any abnormal screening laboratory value that is clinically relevant should be 
retested in order to rule out any progressive or uncontrolled underlying condition.    
j
Hematology will include hemoglobin, hematocrit, RBCs, WBC absolute or differential, ANC, and quantitative platelet count.  Chemistry will 
include AST, ALT, GGT, total bilirubin, urea or BUN, uric acid, creatinine, potassium, sodium, calcium, and phosphorus.  Urinalysis or urine 
dipstick will be used to assess kidney function.
k If the screening assessments have been conducted/obtained within 14 days prior to dosing, respective baseline assessments do not need to be 
repeated prior to dosing.
l
Serum or urine -hCG must be performed at screening in women of childbearing potential within 14 days prior to initiation of study drug.  
Subsequently, urine -hCG (sensitivity 25 mIU/mL) must be collected.  On infusion visits, the urine pregnancy test should be performed prior to 
premedication in all women of childbearing potential.  If positive, ocrelizumab should be withheld and pregnancy status confirmed.  
m All patients must have negative HBsAg result and negative HepCAb screening tests prior to enrollment in the study.  If the total HBcAb is positive 
at screening, HBV DNA measured by PCR must be negative in order for a patient to be eligible for the study.  For enrolled patients with negative 
HBsAg and positive total HBcAb, HBV DNA (by PCR) must be repeated every 24 weeks.
n Whole-blood samples will be collected to determine the duration of B-cell depletion and recovery (CD19) and T-cell counts (CD4, CD8).  
o To be obtained/performed before administration of ocrelizumab (i.e., pre-dose).
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Appendix 1
Schedule of Activities (cont.)
Ocrelizumab—Genentech, Inc.
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p Neurological examinations will be used to distinguish relapse in MS from another neurological (non-MS) disorder.  Potential relapses should be 
recorded throughout the treatment period.  Investigators will also screen patients for signs and symptoms of worsening neurological function 
localized to the cerebral cortex, such as cortical symptoms/signs, behavioral and neuropsychological alteration, retrochiasmal visual defects, 
hemiparesis, cerebellar symptoms/sings (e.g., gait abnormalities, limb incoordination).  Patients with suspected PML should be withheld from 
ocrelizumab treatment until PML is ruled out by complete clinical evaluation and appropriate diagnostic testing (see Appendix 6).  A patient with 
confirmed PML should be withdrawn from the study.  
q PRO assessments will consist of the following:  Multiple Sclerosis Impact Scale 29 (MSIS-29), the Treatment Satisfaction Questionnaire for 
Medication (TSQM II), and the Treatment Satisfaction with Medicines Questionnaire (SATMED-Q).  PROs completed at baseline should be in 
reference to the last-used DMT prior to enrollment.  Please note that all PROs are required to be administered prior to administration of study 
drug and prior to any other study assessment(s) to ensure the validity of the instruments is not compromised.  
r
Should only be done at scheduled visits unless PML is suspected.  
s MRI has to be conducted before the baseline visit, and results must be available prior to treatment.  Prior to initiation of treatment on 
Day 1/Baseline, a QC report for the baseline MRI scan must have been received from the centralized reading center confirming scan passed 
QC.  The brain MRI requires approximately 2 business days to be quality checked before dosing of ocrelizumab.  
t
After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention (e.g., invasive procedures such as biopsies, discontinuation of medications) should be reported.  After initiation of study drug, related 
serious adverse events must be collected and reported regardless of the time elapsed from the last study drug administration, even if the study 
has been closed.  Unrelated serious adverse events must be collected and reported during the study through the end of the Safety Follow-up 
period, which is at least 24 weeks after the last infusion but may be extended in patients whose B cells take longer to replete. Non-serious 
adverse events have to be reported until the end of the Safety Follow-up Period.  
u Medications used after treatment discontinuation should be recorded during the Safety Follow-up Period.
v All patients must receive prophylactic treatment with 100 mg methylprednisolone (or equivalent), to be completed approximately 30 minutes 
before the start of each ocrelizumab infusion, and with an antihistaminic drug (e.g., diphenhydramine) approximately 30 60 minutes before each 
infusion of ocrelizumab.  Prophylactic treatment with an analgesic/antipyretic (e.g., 1 g acetaminophen) is strongly recommended 3060 minutes 
prior to the start of ocrelizumab infusion to reduce the risk of IRRs.
w Dose 1 of ocrelizumab will be administered as two 300-mg IV infusions (600 mg total) separated by 14 days (i.e., Days 1 and 15).  Subsequent 
doses will be administered as one 600-mg IV infusion every 24 weeks for a maximum of 4 doses.
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Appendix 2
Optional Shorter Infusion Substudy
BACKGROUND AND RATIONALE
Ocrevus(ocrelizumab) is approved by the U.S. Food and Drug Administration (FDA) 
for the treatment of adults with primary progressive multiple sclerosis (PPMS) and 
relapsing multiple sclerosis (RMS).  According to the currently approved U.S. label, 
ocrelizumab must be administered at a 600-mg dose through slow intravenous (IV) 
infusion.  The first dose is given as two doses, separated by 14 days, and administered 
as two 300-mg infusions over the course of 2.5 hours, while subsequent doses are given 
as a single 600-mg infusion over 3.5 hours.  This substudy will explore the effect of a 
shorter infusion of ocrelizumab on the rate and severity of IRRs. 
The most common safety events reported with ocrelizumab are IRRs.  IRRs occur more 
frequently during the first infusion of the first dose.  The majority of IRRs (90% of 
patients reporting IRRs) were of mild to moderate intensity, and the intensity of IRRs 
decreased with subsequent dosing.  The most frequently reported IRR symptoms during 
infusion in the ocrelizumab group were pruritus, rash, throat irritation, and flushing 
(33.0%, 29.2%, 29.8%, and 16.8% of patients with IRR, respectively) (see the 
Ocrelizumab Investigator’s Brochure).  
A Phase II, parallel-group, dose-finding trial (WA21493) evaluated ocrelizumab 
compared with placebo and Avonex(interferon-β1a) in patients with RRMS for up to 
96 weeks. In this study, both the 600-mg and 1000-mg dose were administered over 
4 cycles.  After the first cycle, during which only the 600-mg dose was divided in half 
and given over a 15-day interval, subsequent cycles involved administration as a single, 
undivided dose.  Doses were administered over approximately 240 minutes.  The 
infusion schedule in this study shows that, both for the 600- and 1000-mg dose, 
approximately 400 mg of ocrelizumab were infused within 2 to 2.5 hours.  However, in 
the remaining 1.5 to 2 hours of the infusion, only 200 mg remained to be infused for the 
lower dose, while in the 1000-mg dose, 600 mg were given within the same timeframe.  
Based on this infusion schedule, a dose/infusion rate/IRR relationship was not clearly 
observed.
The lack of dose/infusion rate/IRR relationship based on the current clinical data is 
supportive of the hypothesis that administration of ocrelizumab over a shorter infusion 
time should not pose a potential additional risk to patients in terms of increased risk of 
IRRs, but would help convenience of use and compliance for both patients and 
healthcare practices.  In addition, procedures are in place to further mitigate risk of IRR, 
such as a pre-treatment schedule and guidance around infusion adjustment, if required.  
After the infusion, patients will be followed for safety, per the substudy schedule of 
activities, to monitor for any effects of the shorter administration.  
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Appendix 2
Optional Shorter Infusion Substudy (cont.)
Ocrelizumab—Genentech, Inc.
80/ Protocol MN30035, Version 5
OBJECTIVES
The primary objective of this study is to evaluate the rate and severity of 
infusion-related reactions (IRRs) of the ocrelizumab 600-mg infusion administered over 
the course of 2 hours, instead of the currently approved duration of 3.5 hours, in 
patients with MS who have had prior treatment with ocrelizumab in MN30035 
(CHORDS), as measured by the rate and frequency of National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0) 
Grade 3 and 4 IRRs.  
STUDY DESIGN 
This is an open-label, non-randomized substudy to MN30035 designed to evaluate the 
safety and tolerability of ocrelizumab infused over a shorter time period than the 
approved administration rate.  Patients who complete their Week 72 ocrelizumab 
infusion and do not experience any serious IRR (see Section 5.2.2 for seriousness 
criteria) throughout the main study will be eligible to enroll in this optional substudy 
and receive one additional shorter infusion of ocrelizumab at the Week 96 visit.  
Premedication in the substudy will be administered per the main study methods 
(Section 4.3.3).  Ocrelizumab will then be administered as a single 600-mg dose at a 
shorter infusion rate (i.e., over the course of approximately 2 hours instead of 3.5 hours) 
than in the main study.  
Ocrelizumab infusion rate will be slowed and/or stopped if a patient experiences a 
Grade 3 or higher IRR or other serious adverse event.  
Patients who received ocrelizumab at a shorter infusion rate at the Week 96 visit will 
return for a substudy follow-up visit approximately 30 days after treatment. 
The end of the treatment period in the substudy is defined as the date when the last 
patient in the substudy completes the substudy follow-up visit (Week 100).
Planned Total Sample Size
This substudy will enroll approximately 100 patients from MN30035 who did not 
experience any serious IRR throughout the main study.
OUTCOME MEASURES 
Safety Outcome Measures

Rate and frequency of Grade 3 or 4 IRRs with onset on or after the shorter
ocrelizumab infusion at Week 96 and at the substudy follow-up

Changes in physical findings and vital signs with onset on or after the shorter
ocrelizumab infusion at Week 96 and at the substudy follow-up
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Appendix 2
Optional Shorter Infusion Substudy (cont.)
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SAFETY PLAN 
Identified and potential risks associated with ocrelizumab treatment will continue to be 
closely monitored throughout the substudy.  Patient safety will be ensured by targeting 
the most appropriate patient population, stringent safety monitoring by the Sponsor, 
and protocol-specified ocrelizumab treatment interruption criteria. Patients will be 
evaluated clinically before and during their participation in this substudy.  Safety 
evaluations will consist of medical interviews, recording of adverse events, and physical 
examinations.  Adverse events will be graded according to NCI CTCAE v4.0.
Administration of ocrelizumab will be performed in a hospital or clinic environment 
under close supervision of the investigator or a medically qualified staff member.  All 
adverse events and serious adverse events will be recorded during the substudy for at 
least 30 days after treatment (i.e., the substudy follow-up period).  Safety assessments 
will include the incidence, nature, and severity of (serious) adverse events graded per 
the NCI CTCAE v4.0.  Safety assessments will be conducted per the substudy schedule 
of activities.  
The identified and potential safety issues anticipated in this substudy, including IRRs, 
are reported in the Ocrelizumab Investigator’s Brochure.  Guidelines for the 
management of patients who experience specific adverse events are also included in the 
Ocrelizumab Investigator’s Brochure. 
PATIENT SELECTION CRITERIA 
Inclusion Criteria
Patients must continue to meet the following:

Actively enrolled in the main study

Completed Week 72 infusion

Signed substudy Informed Consent Form prior to the Week 96 infusion

Able to comply with the substudy protocol, in the investigator’s judgment
Exclusion Criteria
Patients who become ineligible for any reason in the main study, in addition to the 
following:

Any documented serious IRR at any time during the main study
TRIAL DRUG
Dosage, Administration, and Storage
Patients will receive 600-mg IV ocrelizumab per a shorter infusion protocol (see 
Table 1).   
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Appendix 2
Optional Shorter Infusion Substudy (cont.)
Ocrelizumab—Genentech, Inc.
82/ Protocol MN30035, Version 5
Table 1:  Infusion Rates for 600-mg Ocrelizumab Shorter Dose
Time (min)
Infusion rate
(mL/hr)
Infusion rate
(mg/hr)
Max Dose per 
Interval  (mg)
Cumulative 
Dose
(mg)
015
100
120
30
30
1530
200
240
60
90
3060
250
300
150
240
6090
300
360
180
420
90120
300
360
180
600
Infusion time:  120 min.  
Preparation per U.S. label:  600 mg ocrelizumab/500 mL normal saline toward a drug concentration of 
approximately 1.2 mg/mL.
Although ocrelizumab may be administered on an outpatient basis, patients may be 
hospitalized for observation at the discretion of the investigator.  Ocrelizumab 
infusions should always be administered in a hospital or clinic environment under close 
supervision of the investigator or a medically qualified staff member.  
To reduce potential IRRs, all patients will receive prophylactic treatment with 100 mg 
of methylprednisolone (or equivalent steroid), to be completed approximately 
30 minutes before the start of each ocrelizumab infusion, and with an antihistaminic 
drug (e.g., diphenhydramine) approximately 3060 minutes before each ocrelizumab 
infusion. 
It is also strongly recommended that the infusion is accompanied by prophylactic 
treatment with an analgesic/antipyretic such as acetaminophen/paracetamol (1 g) 
3060 minutes prior to the start of an infusion to reduce potential IRRs.  
Since transient hypotension may occur during ocrelizumab infusion, the investigator 
may wish to withhold anti-hypertensive medications 12 hours prior to ocrelizumab 
infusion. 
Ocrelizumab must not be administered as an IV push or bolus.  Well-adjusted infusion 
pumps should be used to control the infusion rate, and ocrelizumab should be infused 
through a dedicated line.  It is important not to use evacuated glass containers, which 
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Appendix 2
Optional Shorter Infusion Substudy (cont.)
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require vented administration sets, to prepare the infusion because this causes foaming 
as air bubbles pass through the solution. 
After completion of the infusion, the IV cannula should remain in situ for at least 1 
hour to allow for administration of drugs intravenously, if necessary, in the event of a 
delayed reaction.  If no adverse events occur during this period of time, the IV cannula 
may be removed and the patient may be discharged.
See the Ocrelizumab IB for detailed instructions on drug preparation, storage, and 
approved administration.
Dosage Modification 
Unless an IRR occurs necessitating discontinuation, the entire contents of the infusion bag must 
be administered to the patient.
Patients must discontinue study treatment if they experience any of the following:

Life-threating IRR or serious hypersensitivity reaction

Active hepatitis B infection

Progressive multifocal leukoencephalopathy (PML)

Active tuberculosis, either new onset or reactivation
SUBSTUDY ASSESSMENTS 
Substudy assessments will be performed according to the schedule of activities in 
Table 3.
Informed Consent Forms and Screening Log
Written informed consent for participation in the substudy must be obtained before 
performing any substudy-related procedures.  
Physical Examinations
A limited physical examination will be conducted at the substudy treatment visit.  Any 
abnormality identified prior to treatment administration in the substudy should be 
recorded on the eCRF.  New or worsened clinically significant abnormalities after 
treatment administration should be recorded as adverse events, if appropriate.
Vital Signs
Vital signs will include measurements of heart rate, temperature, and systolic and 
diastolic blood pressure.
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Appendix 2
Optional Shorter Infusion Substudy (cont.)
Ocrelizumab—Genentech, Inc.
84/ Protocol MN30035, Version 5
Vital signs should be taken approximately 45 minutes prior to premedication.  In 
addition, vital signs should be obtained prior to the ocrelizumab infusion and then 
approximately every 15 minutes for the first hour, followed by approximately every 
30 minutes until 1 hour after the end of the infusion.  
Patients will be informed about the possibility of delayed post-infusion symptoms and 
instructed to contact their study physician if they develop such symptoms.
SUBSTUDY FOLLOW-UP
Patients should have substudy follow-up 30 days after the date of the last infusion of 
ocrelizumab in this substudy, consisting of one clinic visit.  After 30 days, patients 
may continue to be followed per the main study safety follow-up if they do not continue 
onto commercial ocrelizumab.  
STATISTICAL METHODS
Safety Analyses
Safety analyses will include all patients who received any amount of study treatment in 
the substudy. 
Safety will be summarized using descriptive statistics.  Continuous variables will be 
summarized using n (sample size), mean, standard deviation, median, minimum, and 
maximum.  Frequency distributions (patient counts and associated percentages) will be 
used to summarize categorical variables.  When applicable, 95% confidence intervals 
(CIs) will be provided for the mean and proportion.  The Clopper and Pearson method 
will be used to calculate exact CIs for proportion when applicable.  
All adverse events occurring on or after treatment will be coded, summarized by NCI 
CTCAE v4.0 grade, and tabulated by body system and Preferred Term for individual 
adverse events within each body system.  Grade 3 to 5 adverse events, serious adverse 
events, adverse events leading to treatment discontinuation, time to withdrawal from 
the study due to an adverse event, adverse events leading to infusion adjustment, and 
treatment-related adverse events will be summarized.  In addition, all serious adverse 
events and deaths will be listed.
Associated laboratory parameters, such as hepatic function, renal function, and 
hematology values, will be grouped and presented together.  Marked abnormalities will 
also be flagged. 
Ocrelizumab exposure will be summarized, including rate of infusion and dosage. 
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Appendix 2
Optional Shorter Infusion Substudy (cont.)
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Handling of Missing Data
For adverse events with a missing onset date, data will be imputed.  
Missing assessments for continuous variables, such as physical examinations and vital 
signs, will not be imputed.
Determination of Sample Size
Based on the sample size of 100 patients used for analysis, the 95% CIs for some 
assumed Grade 3 or 4 IRRs are provided in Table 2.
Table 2:  Determination of Substudy Sample Size
Number of Patients with 
Grade 3 or 4 IRRs
Grade 3 or 4 IRRs (%)
(N100)
95% CIs for Grade 3 or 4 
IRRs (%)
1
1.00
(0.03, 5.45)
2
2.00
(0.24, 7.04)
3
3.00
(0.62, 8.52)
4
4.00
(1.10, 9.93)
5
5.00
(1.64, 11.28)
6
6.00
(2.23, 12.60)
7
7.00
(2.86, 13.89)
The 95% CIs for the IRR (%) are calculated based on the Clopper and Pearson method.
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Appendix 2
Optional Shorter Infusion Substudy (cont.)
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Table 3:  Substudy Schedule of Activities
Week 96 
Treatment Visit
(14 days)
Substudy 
Follow-up Visit 
(3014 days later) a
Informed consent b
x
Review inclusion and exclusion criteria
x
Physical examination c
x
x
Weight
x
Vital signs d
x
x
Brain MRI e
x
Pregnancy test f
x
Adverse event assessment g
x
x
Concomitant treatment review
x
x h
Methylprednisolone and antihistamine
premedication i
x
Ocrelizumab administration
x
eCRFelectronic case report form; IRRinfusion-related reaction; IVintravenous; MRImagnetic 
resonance imaging; PMLprogressive multifocal leukoencephalopathy.
a Conducted 30 days after the shorter infusion with ocrelizumab.  
b Written informed consent will be obtained from all patients in order to be eligible for the study and prior 
to any study procedures.
c
A limited physical examination may be conducted.  Any abnormality identified should be recorded on 
the eCRF.  New or worsened clinically significant abnormalities should be recorded as adverse events, if 
appropriate
d Vital signs will include the measurements of heart rate, systolic and diastolic blood pressures, and 
temperature.  Vital signs should be taken approximately 45 minutes prior to the premedication 
methylprednisolone infusion.  In addition, vital signs should be obtained prior to the ocrelizumab 
infusion then approximately every 15 minutes for the first hour, followed by approximately every 
30 minutes until 1 hour after the end of the infusion.
e
Should only be done if PML is suspected, and should not be done in addition to an MRI at Week 96 
conducted in the main study.  If needed, should be done pre-dose.
f
Pregnancy test should not be done in addition to the pregnancy test at Week 96 conducted in the main 
study.   If needed, should be done pre-dose. 
g After informed consent has been obtained but prior to initiation of study drug, only serious adverse 
events caused by a protocol-mandated intervention (e.g., invasive procedures such as biopsies, 
discontinuation of medications) should be reported.  After initiation of study drug, related serious 
adverse events must be collected and reported regardless of the time elapsed from the study drug 
administration, even if the substudy has been closed.  Unrelated serious adverse events must be collected 
and reported during the substudy and substudy follow-up.  Non-serious adverse events have to be 
reported until the end of substudy follow-up.  
h Medications used after treatment discontinuation should be recorded during substudy follow-up.
i
All patients must receive prophylactic treatment with 100 mg methylprednisolone (or equivalent), to be 
completed approximately 30 minutes before the start of each ocrelizumab infusion, and with an 
antihistaminic drug (e.g., diphenhydramine) approximately 3060 minutes before each infusion of 
ocrelizumab.  Prophylactic treatment with an analgesic/antipyretic (e.g., 1 g acetaminophen) is strongly 
recommended 3060 minutes prior to the start of ocrelizumab infusion to reduce the risk of IRRs.
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Appendix 3
Expanded Disability Status Scale (EDSS)
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Appendix 3
Expanded Disability Status Scale (EDSS) (cont.)
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Source:  http://www.nationalmssociety.org/For-Professionals/Researchers/Resources-for-
Researchers/Clinical-Study-Measures/Functional-Systems-Scores-(FSS)-and-Expanded-Disab
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Appendix 4
2010 Revised McDonald Diagnostic Criteria for Multiple 
Sclerosis
Clinical 
(attacks) 
Lesions 
Additional Criteria to Make Diagnosis 
2 or more 
Objective clinical evidence of 2 or 
more lesions or objective clinical 
evidence of 1 lesion with 
reasonable historical evidence of a 
prior attack 
None.  Clinical evidence alone will suffice; 
additional evidence desirable but must be 
consistent with MS 
2 or more 
Objective clinical evidence of 1 
lesion 
Dissemination in space, demonstrated by

1 T2 lesion in at least two MS typical 
CNS regions (periventricular, 
juxtacortical, infratorial, spinal cord); 
OR 

Await further clinical attack implicating a 
different CNS site
1 
Objective clinical evidence of 2 or 
more lesions 
Dissemination in time, demonstrated by

Simultaneous asymptomatic contrast-
enhancing and non-enhancing lesions 
at any time; 
OR 

A new T2 and/or contrast-enhancing 
lesions(s) on follow-up MRI, irrespective 
of its timing; 
OR 

Await a second clinical attack
1 
Objective clinical evidence of 1 
lesion 
Dissemination in space, demonstrated by 

1 T2 lesion in at least two MS typical 
CNS regions (periventricular, 
juxtacortical, infratentorial, spinal cord); 
OR 

Await further clinical attack implicating a 
different CNS site 
AND
Dissemination in time, demonstrated by 

Simultaneous asymptomatic contrast-
enhancing and non-enhancing lesions 
at any time; 
OR 

A new T2 and/or contrast-enhancing 
lesions(s) on follow-up MIR, irrespective 
of its timing; 
OR 

Await a second clinical attack
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Appendix 4
2010 Revised McDonald Diagnostic Criteria for Multiple 
Sclerosis (cont.)
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Clinical 
(attacks) 
Lesions 
Additional Criteria to Make Diagnosis 
0 
(progression 
from onset) 
One year of disease progression 
(retrospective or prospective) AND at least 2 
out of 3 criteria: 

Dissemination in space in the brain 
based on 1 T2 lesion in 
periventricular, juxtacortical or 
infratentorial regions; 

Dissemination in space in the spinal 
cord based on 2 T2 lesions; 
OR

Positive CSF
2 or more 
Objective clinical evidence of 2 or 
more lesions or objective clinical 
evidence of 1 lesion with 
reasonable historical evidence of a 
prior attack 
None.  Clinical evidence alone will suffice; 
additional evidence desirable but must be 
consistent with MS
CNScentral nervous system; CSF cerebrospinal fluid; MRImagnetic resonance imaging; 
MSmultiple sclerosis.
Sources: 
http://www.nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/Brochures/Paper-
TipSheet_-2010-Revisions-to-the-McDonald-Criteria-for-the-Diagnosis-of-MS.pdf
Polman et al. 2011.
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Appendix 5
New York Heart Association Classification of 
Functional Cardiac Capacity
Class
Description
I
No limitation:  Ordinary physical activity does not cause undue fatigue, 
dyspnea, or palpitation.
II
Slight limitation of physical activity:  Such patients are comfortable at rest.  
Ordinary physical activity results in fatigue, palpitations, dyspnea, 
or angina.
III
Marked limitation of physical activity:  Although patients are comfortable at 
rest, less than ordinary physical activity will lead to symptoms.
IV
Inability to carry on physical activity without discomfort:  Symptoms of 
congestive heart failure are present even at rest.  With any physical 
activity, increased discomfort is experienced.
From:  Criteria Committee, New York Heart Association, Inc. Diseases of the heart 
and blood vessels. Nomenclature and criteria for diagnosis. 6th ed. Boston, Little, 
Brown and Co, 1964:114.
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Appendix 6
Guidance for Diagnosis of Progressive Multifocal 
Leukoencephalopathy
ACTION STEPS IF PROGRESSIVE MULTIFOCAL 
LEUKOENCEPHALOPATHY (PML) IS SUSPECTED: 

If the clinical presentation is suggestive of PML, further investigations should include 
brain magnetic resonance imaging (MRI) evaluation as soon as possible.  If MRI 
evaluation reveals lesions suspicious for PML (see Figure 1), a lumbar puncture 
with evaluation of the cerebrospinal fluid (CSF) for the detection of JC virus (JCV) 
DNA using a validated 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. 

There is no known treatment or cure for PML.  Treatment considerations are 
discussed in the medical literature (Calabrese et al. 2007).
MRI ASSESSMENT 

Although there are no pathognomonic findings that differentiate PML from MS, a 
brain MRI scan that includes fluid-attenuated inversion recovery (FLAIR) and 
T2-weighted and T1-weighted sequences, with and without gadolinium, should be 
performed to assess patients with neurological changes suggestive of PML (see 
Figure 1). 

Comparison with a baseline scan may assist with interpretation of the findings on 
the newly acquired MRI (see Table 2 for differences in lesion characteristics that 
may help differentiate between PML and multiple sclerosis [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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Appendix 6
Guidance for Diagnosis of Progressive Multifocal 
Leukoencephalopathy (cont.)
CSFcerebrospinal fluid; JCVJC virus; MRImagnetic resonance imaging; MS multiple 
sclerosis; PMLprogressive multifocal leukoencephalopathy.
Table 1
Source:  Kappos et al. 2007.
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Appendix 6
Guidance for Diagnosis of Progressive Multifocal 
Leukoencephalopathy (cont.)
Table 2
MRI Lesion Characteristics Typical of PML and MS
Source:  Yousry et al. 2006.
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SAP_001.pdf: 
 
Official Title: 
 
AN OPEN-LABEL STUDY TO EVALUATE THE 
EFFECTIVENESS AND SAFETY OF 
OCRELIZUMAB IN PATIENTS WITH RELAPSING 
REMITTING MULTIPLE SCLEROSIS WHO HAVE 
HAD A SUBOPTIMAL RESPONSE TO AN 
ADEQUATE COURSE OF DISEASE-MODIFYING TREATMENT 
NCT Number: 
NCT02637856   
Document Date: 
SAP Version 2: 30-April-2019 
 
 
 




STATISTICAL ANALYSIS PLAN AENDMENT APPROVAL 
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CONFIDENTIAL 
 
This is a Genentech, Inc. document that contains confidential information.  Nothing herein is to be 
disclosed without written consent from Genentech, Inc. 
Ocrelizumab—Genentech, Inc. 
Statistical Analysis Plan MN30035 
STATISTICAL ANALYSIS PLAN 
TITLE: 
AN OPEN-LABEL STUDY TO EVALUATE THE 
EFFECTIVENESS AND SAFETY OF OCRELIZUMAB IN 
PATIENTS WITH RELAPSING REMITTING MULTIPLE 
SCLEROSIS WHO HAVE HAD A SUBOPTIMAL RESPONSE 
TO AN ADEQUATE COURSE OF DISEASE-MODIFYING 
TREATMENT 
PROTOCOL NUMBER: 
MN30035 
STUDY DRUG: 
Ocrelizumab (RO4964913) 
VERSION NUMBER: 
2 
IND NUMBER: 
100,593 
EUDRACT NUMBER: 
Not applicable 
 
SPONSOR: 
Genentech, Inc. 
PLAN PREPARED BY: 
, PhD 
DATE FINAL: 
Version 1: May 31, 2016 
DATE(S) AMENDED: 
Version 2: Apr 30, 2019 


 
 
Ocrelizumab—Genentech, Inc. 
2/Statistical Analysis Plan MN30035 
 
STATISTICAL ANALYSIS PLAN AMENDMENT 
RATIONALE 
April 2019 
 
In this version of Statistical Analysis Plan (SAP), updates have been made following the 
approval of version 1 of the SAP: 
 
Study design section has been updated to reflect the protocol version 5 updates 
including removing the B cell monitoring after Week 96, and the shorter infusion 
substudy. 
 
Analysis plan of the shorter infusion substudy was added in Appendix 6. 
 
Sensitivity analysis plan of the primary endpoint has been specified including per 
protocol analysis and sensitivity analysis for missing data. 
 
Preferred terms of the AESIs (AE of Special Interest) have been updated per 
MedDRA coding latest version.  
Additional minor changes have been made to improve clarity and consistency.   
 
 


 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE ............................. 2 
1. 
BACKGROUND ............................................................................................ 5 
2. 
STUDY DESIGN ........................................................................................... 6 
2.1 
Protocol Synopsis .................................................................... 7 
2.2 
Outcome Measures ............................................................... 13 
2.2.1 
Primary Efficacy Outcome Measures .................................... 13 
2.2.2 
Secondary Efficacy Outcome Measures ................................ 13 
2.2.3 
Exploratory Efficacy Outcome Measures ............................... 14 
2.2.4 
Pharmacokinetic Efficacy Outcome Measures ...................... 14 
2.2.5 
Safety Outcome Measures .................................................... 14 
2.3 
Determination of Sample Size ............................................... 15 
2.4 
Analysis Timing ..................................................................... 16 
3. 
STUDY CONDUCT ..................................................................................... 16 
3.1 
Randomization ....................................................................... 16 
3.2 
Independent Review Facility .................................................. 16 
3.3 
Data Monitoring ..................................................................... 16 
4. 
STATISTICAL METHODS .......................................................................... 16 
4.1 
Analysis Populations ............................................................. 16 
4.1.1 
Intent-to-Treat Population ...................................................... 16 
4.1.2 
Modified Intent-to-Treat Population ....................................... 17 
4.1.3 
Per Protocol Population ......................................................... 17 
4.1.4 
Pharmacokinetic-Evaluable Population ................................. 17 
4.1.5 
Safety Population .................................................................. 17 
4.2 
Analysis of Study Conduct ..................................................... 17 
4.3 
Analysis of Demographics and Baseline 
Characteristics ....................................................................... 17 
4.4 
Efficacy Analysis .................................................................... 19 
4.4.1 
Primary Efficacy Endpoint ...................................................... 19 
4.4.2 
Secondary Efficacy Endpoints ............................................... 20 
4.4.3 
Exploratory Efficacy Endpoints .............................................. 23 


 
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4.4.4 
Sensitivity Analyses ............................................................... 24 
4.4.5 
Subgroup Analyses ............................................................... 24 
4.5 
Pharmacokinetic and Pharmacodynamic 
Analyses ................................................................................ 24 
4.6 
PATIENT REPORTED OUTCOME ANALYSES ................... 24 
4.6.1 
MSIS-29 ................................................................................. 24 
4.6.2 
SATMED-q ............................................................................ 25 
4.6.3 
TSQM II ................................................................................. 26 
4.7 
Safety Analyses ..................................................................... 27 
4.7.1 
Exposure of Study Medication ............................................... 28 
4.7.2 
Adverse Events ..................................................................... 28 
4.7.3 
Laboratory Data ..................................................................... 29 
4.7.4 
Vital Signs .............................................................................. 29 
4.7.5 
Safety Endpoints of Special Interest ...................................... 29 
4.8 
Missing Data .......................................................................... 29 
4.9 
Interim Analyses .................................................................... 29 
5. 
REFERENCES ........................................................................................... 30 
 
 
LIST OF TABLES 
No table of figures entries found. 
 
LIST OF APPENDICES 
Appendix 1 
 Protocol Synopsis ...................................................................... 31 
Appendix 2 
 Schedule of Assessments .......................................................... 36 
Appendix 3 
 Data Handling Rules .................................................................. 40 
Appendix 4 
 Programming Codes for Statistical Analyses ............................. 41 
Appendix 5 
 Reasons for Exclusion from the Per-Protocol Population .......... 42 
Appendix 6 
 Statistical Analysis Plan for Shorter Infusion Substudy .............. 43 


 
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1. 
BACKGROUND 
Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, and degenerative 
disease of the central nervous system (CNS) that affects approximately 400,000 people 
in the United States (U.S.) and 2.3 million worldwide (National Multiple Sclerosis 
Society).  MS is clinically subcategorized into four phenotypic disease patterns 
distinguished by the occurrence and timing of relapses relative to disease onset and 
disability progression.  These include relapsing remitting MS (RRMS), primary 
progressive MS (PPMS), progressive relapsing MS (PRMS), and secondary progressive 
MS (SPMS) (Lublin et al. 1996).  Accumulated disability is the fate of most patients with 
MS when a 20- to 25-year perspective is considered (Trojano et al. 2003).  
Approximately 85% of MS patients initially present with RRMS (Confavreaux et al. 2000; 
Leray et al. 2015).   
Over the past two decades, there has been a substantial increase in the number and 
type of available treatments for RRMS.  Yet, despite suboptimal response to an 
adequate course of treatment with a disease-modifying treatment (DMT) that is defined 
as the same DMT administered for at least 6 months, a significant proportion of treated 
patients with RRMS will show signs of disease activity.  Suboptimal responses, defined 
in this protocol as one or more clinically reported relapse(s), one or more T1 gadolinium 
(Gd)-enhanced lesion(s), or two or more new or enlarging T2 lesions on brain magnetic 
resonance imaging (MRI) despite being on a stable dose of the same DMT for at least 
6 months, are reported in approximately one-third of patients receiving interferon beta 
(IFN-) therapy (Bergvall et al. 2014; Durelli et al. 2008; Fernández et al. 2005; 
Waubant et al. 2003).  Disease activity while receiving a DMT is associated with worse 
long-term outcomes (Bermel et al. 2013), thus subsequent treatment with a more 
effective therapy may be warranted in patients with breakthrough signs and symptoms.  
Consequently, reported rates of treatment switching for suboptimal responses range 
from 20%  35% of patients (Rio et al. 2012; Gajofatto et al. 2009; Teter et al. 2014).   
While clinical experience and retrospective studies suggest that better disease control is 
obtained by escalating to a higher-efficacy therapy, few prospective studies have been 
conducted.  A prospective, observational study evaluated the outcomes of patients who 
failed first-line treatment with IFN- or glatiramer acetate (GA) who were subsequently 
treated with a different IFN- formulation or GA, or were escalated to natalizumab 
(Prosperini et al. 2012).  At 1 year, no significant differences in disease activity were 
observed between the two groups.  However, after 2 years, significantly greater 
proportions of patients escalated to natalizumab were free from relapse, disability 
progression, MRI activity, and combined activity than patients who were treated with 
IFN- or GA.  In the Phase III trial (CARE-MS II) published by Coles and colleagues, 
patients who had one or more relapses while receiving IFN- or GA therapy were 
randomized to receive either IFN- or alemtuzumab.  Significant reductions in relapse 
rates and the accumulation of disabilities were reported with alemtuzumab compared to 


 
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IFN- at 1 year (Coles et al. 2012).  However, more data from large-scale, prospective 
studies assessing patients who are subsequently treated with higher-efficacy therapies 
following suboptimal control with first-line treatment are needed.  
A Phase II study provided initial evidence that ocrelizumab could be effective at further 
reducing MS disease activity (i.e., annual relapse rate [ARR] and MRI activity) following 
initial IFN- therapy.  Additional data will also be available on previously treated patients 
in two completed Phase III studies (Studies WA21092 [OPERA I] and WA21093 
[OPERA II]), but only in a subgroup of patients.  Therefore, this prospective study was 
designed to specifically evaluate the effectiveness and safety of using ocrelizumab in 
patients who show a suboptimal response to an adequate course of a DMT. 
Please refer to the protocol for the references cited above and for further details on 
ocrelizumab background. 
2. 
STUDY DESIGN 
This study is a prospective, multicenter, open-label, effectiveness and safety study in 
patients with RRMS who have had a suboptimal response to an adequate course of a 
DMT.  This study will be conducted in North America.   
An adequate course of prior DMT is defined as the same DMT administered for at least 
6 months.  Ocrelizumab will be administered as an initial dose of two 300-mg infusions 
(600 mg total) separated by 14 days (i.e., Days 1 and 15) followed by one 600-mg 
infusion every 24 weeks for the study duration.   
Patients will be assessed for effectiveness and safety every 24 weeks as described in 
the schedule of assessment in Appendix 2. 
The study will consist of the following periods, described in detail below: 
1. Screening period:  up to 4 weeks. 
2. Treatment period:  open-label treatment period of 96 weeks (4 doses). 
3. Safety follow-up period (additional B cell monitoring not applicable to protocol v5 
patients):  observation after the last infusion of study drug for patients who 
discontinue or who chose not to continue with commercially available 
ocrelizumab (if approved) at the end of study. 
4. Eligible patients can be enrolled into an optional shorter infusion substudy to 
explore the effect of a shorter infusion of ocrelizumab on the rate and severity of 
IRRs. 


 
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Detailed study design, outcome measures and statistical analysis plan of the shorter 
infusion substudy will be described in Appendix 6. 
2.1 
PROTOCOL SYNOPSIS 
Please refer to the Protocol for study synopsis and schedule of activities (Protocol 
Section 6.1). 
Figure 1 below presents an overview of the study procedures of the main study.   
Figure 1 Overview of Study Procedures 
 
IV 
 intravenous; OCR  ocrelizumab. 
Note:  The screening period will last up to 4 weeks, but it may be prolonged for up to 8 
weeks for relevant clinical, administrative, or operational reasons.  Baseline MRI 
results must be available prior to the first infusion. 
 
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedule of 
Assessments in  
TITLE: 
An Open-Label Study To Evaluate the Effectiveness and 
Safety of Ocrelizumab in Patients With Relapsing Remitting 
Multiple Sclerosis Who Have Had A Suboptimal Response to 
an Adequate Course of Disease-Modifying Treatment 
PROTOCOL 
NUMBER: 
MN30035 
VERSION NUMBER: 
5 
Eudract Number: 
Not applicable 


 
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IND NUMBER: 
100,593 
TEST PRODUCT: 
Ocrelizumab (RO4964913) 
PHASE: 
IIIb  
INDICATION: 
Relapsing remitting multiple sclerosis 
SPONSOR: 
Genentech, Inc. 
 
Objectives and Endpoints 
Primary Objective 
The primary objective of this study is to assess the effectiveness of ocrelizumab 600 
mg intravenously (IV) every 24 weeks over 96 weeks in patients with relapsing 
remitting multiple sclerosis (RRMS) who have had a suboptimal response to an 
adequate course of a disease-modifying treatment (DMT).   
A suboptimal response is defined by having one or more clinically reported relapse(s), 
OR one or more T1 gadolinium (Gd)-enhanced lesion(s), OR two or more new or 
enlarging T2 lesions on magnetic resonance image (MRI) despite being on a stable 
dose of the same DMT for at least 6 months.  In addition, in patients receiving stable 
doses of the same approved DMT for more than a year, the event must have occurred 
within the last 12 months of treatment with this DMT.   
Secondary Objective 
The secondary objective of this study is to evaluate the safety and tolerability of 
ocrelizumab 600 mg IV given every 24 weeks in patients with RRMS who have had a 
suboptimal response to an adequate course of a DMT as measured by the nature and 
incidence of adverse events. 
Exploratory Objective 
The exploratory objective of this study is to further assess the effectiveness of 
ocrelizumab by monitoring patient-reported outcomes (PROs) related to quality of life 
and treatment satisfaction. 
Study Design 
Description of the Study 
This study is a prospective, multicenter, open-label, effectiveness, and safety study in 
patients with RRMS who have had a suboptimal response to an adequate course of a 
DMT.  This study will be conducted in North America.  An adequate course of prior 
DMT is defined as the same DMT administered for at least 6 months.  Ocrelizumab will 
be administered as an initial dose of two 300-mg infusions (600 mg total) separated by 
14 days (i.e., Days 1 and 15) followed by one 600-mg infusion every 24 weeks for the 
study duration.   
Patients will be assessed for effectiveness and safety every 24 weeks.  The study will 
consist of the following periods, described in detail below: 
 Screening Period:  Up to 4 weeks 
 Treatment Period:  Open-label treatment period of 72 weeks (4 doses) 
 Safety Follow-up Period:  Observation 24 weeks after the last infusion of study drug 
for patients who discontinue or who chose not to continue with commercially 
available ocrelizumab at the end of study 
 
Eligible patients may choose to participate in an optional shorter infusion substudy at 
the Week 96 visit, during which they will receive ocrelizumab infused over a shorter 
time period than the approved administration rate (Appendix 2).   


 
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Number of Patients 
This study will enroll approximately 600 patients with RRMS who have had a 
suboptimal response to an adequate course of a DMT.   
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 Signed Informed Consent Form 
 Able to comply with the study protocol, in the investigator’s judgment 
 Age 1855 years, inclusive 
 Have a definite diagnosis of multiple sclerosis (MS), confirmed per the revised 2010 
McDonald criteria (Polman et al. 2011; Appendix 4), and have the relapsing 
remitting form of MS 
 Have a length of disease duration, from first symptom, of  12 years 
 Have been treated with an adequate course of treatment with no more than three 
prior DMTs   
 Adequate treatment is defined as  6 months on a DMT. 
 Discontinuation of the most recent adequately used DMT must have been due to 
suboptimal response as defined below. 
 Suboptimal response while on his/her last adequately used DMT (for  6 months); 
a suboptimal response is defined by having one of the following qualifying events 
despite being on a stable dose of the same DMT for at least 6 months: 
 
One or more clinically reported relapse(s) 
 
OR one or more T1 Gd-enhanced lesion(s) 
 
OR two or more new or enlarging T2 lesions on MRI 
These qualifying events must have occurred while on the last adequately used 
DMT.  In addition, in patients receiving stable doses of the same approved DMT for 
more than a year, the event must have occurred within the last 12 months of 
treatment with this DMT from the date of screening. 
 Expanded Disability Status Scale (EDSS) of 0 to 5.5, inclusive, at screening 
 For women of childbearing potential:  agreement to use an acceptable birth control 
method:  
 
Progesterone-only oral hormonal contraception, where inhibition of ovulation is 
not the primary mode of action 
 
Male or female condom with or without spermicide 
 
Cap, diaphragm, or sponge with spermicide 
 
A combination of male condom with either cap, diaphragm, or sponge with 
spermicide (double-barrier methods are also considered acceptable, but not 
highly effective, birth control methods) 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 History of primary progressive multiple sclerosis (PPMS), progressive relapsing 
multiple sclerosis (PRMS), or secondary progressive multiple sclerosis (SPMS) 
 Inability to complete an MRI (contraindications for MRI include but are not restricted 
to claustrophobia, weight, pacemaker, cochlear implants, presence of foreign 
substances in the eye, intracranial vascular clips, surgery within 6 weeks of entry 
into the study, coronary stent implanted within 8 weeks prior to the time of the 
intended MRI, inability to tolerate Gd-enhancing ligands, etc.). 


 
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 Known presence of other neurological 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 central nervous system (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; MELAS [mitochondrial myopathy, encephalopathy, lactic 
acidosis, stroke] syndrome) 
 Neuromyelitis optica 
 History or known presence of systemic autoimmune disorders potentially 
causing progressive neurologic disease (e.g., lupus, anti-phospholipid antibody 
syndrome, Sjogren’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 (PML) 
 Pregnancy or lactation, or intention to become pregnant during the study 
 Women of childbearing potential must have a negative serum or urine 
pregnancy test result within 14 days prior to initiation of study drug. 
 Any concomitant disease that may require chronic treatment with systemic 
corticosteroids or immunosuppressants during the course of the study 
 Lack of peripheral venous access 
 Significant, uncontrolled disease, such as cardiovascular (including cardiac 
arrhythmia), pulmonary (including obstructive pulmonary disease), renal, hepatic, 
endocrine, and gastrointestinal or any other significant disease that may preclude 
patient from participating in the study 
 Congestive heart failure (New York Heart Association [NYHA] Class III/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 severe 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 of or currently active primary or secondary immunodeficiency 
 History or known presence of recurrent or chronic infection (e.g., HIV, syphilis, TB) 
 History of recurrent aspiration pneumonia requiring antibiotic therapy 
 History of malignancy, including solid tumors and hematological malignancies, 
except basal cell, in situ squamous cell carcinoma of the skin, and in situ carcinoma 
of the cervix of the uterus that have been excised with clear margins 
 History of severe allergic or anaphylactic reactions to humanized or murine 
monoclonal antibodies 
 History of coagulation disorders 
 History of alcohol or drug abuse within 24 weeks prior to screening 


 
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 Previous treatment with natalizumab within 12 months prior to screening unless 
failure was due to confirmed, persistent anti-drug antibodies  
 Patients previously treated with natalizumab will be eligible for this study only if 
duration of treatment with natalizumab was  1 year and natalizumab was not 
used in the 12 months prior to screening.  Anti-JCV antibody status (positive or 
negative) and titer (both assessed within the year of screening) must be 
documented prior to enrollment.  When assessed, anti-JCV antibody status 
should be determined using an analytically and clinically validated immunoassay 
(e.g., ELISA). 
 Previous treatment with systemic cyclophosphamide, azathioprine, mycophenolate 
mofetil, cyclosporine, or methotrexate  
 Treatment with IV immunoglobulin within 12 weeks prior to baseline 
 Treatment with dalfampridine (Ampyra) unless on stable dose for  30 days prior 
to screening 
 Wherever possible, patients should remain on stable doses throughout the 
treatment period. 
 Receipt of a live vaccine within 6 weeks prior to baseline; in rare cases when 
patient requires vaccination with a live vaccine, the screening period may need to 
be extended but cannot exceed 8 weeks 
 Systemic corticosteroid therapy within 4 weeks prior to screening 
 The screening period may be extended (but cannot exceed 8 weeks) for patients 
who have used systemic corticosteroids for their MS before screening.   
 There should be 4 weeks from last dose of systemic corticosteroid therapy prior 
to first infusion. 
 Previous treatment with fingolimod (Gilenya®) or dimethyl fumarate (Tecfidera) in 
patients whose lymphocyte count is below the lower limit of normal (LLN) 
 Contraindications to or intolerance of oral or IV corticosteroids, including IV 
methylprednisolone (or equivalent steroid) administered according to the country 
label, including: 
 
Psychosis not yet controlled by a treatment 
 
Hypersensitivity to any of the constituents preceding 
 Treatment with alemtuzumab (Lemtrada) 
 Treatment with a B-cell targeted therapies (e.g., rituximab, ocrelizumab, atacicept, 
belimumab, or ofatumumab) 
 Treatment with a drug that is experimental (Exception:  treatment with an 
experimental drug that was subsequently approved in the patient’s country is 
allowed.) 
 Laboratory test results as follows: 
 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) 
 
Lymphocyte count below LLN 
 
CD4 count  300/L 
 
AST or ALT  3.0  the upper limit of normal (ULN) 
 
Platelet count  100,000/L (  100  109/L) 
 
Total neutrophil count below LLN  
Re-testing before baseline:  in rare cases in which the screening laboratory 
samples are rejected by the laboratory (e.g., hemolyzed sample) or the 
results are not assessable (e.g., indeterminate) or abnormal, the tests need 


 
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to be repeated.  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 enrollment must 
meet study criteria.  In such circumstances, the screening period may need 
to be prolonged but should not exceed 8 weeks. 
 
End of Study 
The end of the treatment period is defined as the date when the last patient, last visit 
(LPLV) at 96 weeks occurs (or at Week 100 in the substudy).  
Length of Study 
The total length of the study is expected to be approximately 4 years from the first 
patient enrolled to LPLV. 
The end of study is defined as the LPLV of the safety follow-up. 
Investigational Medicinal Products 
Test Product (Investigational Drug) 
Dose 1 of ocrelizumab will be administered as two 300-mg IV infusions (600 mg total) 
separated by 14 days (i.e., Days 1 and 15).  Subsequent doses will be administered as 
one 600-mg IV infusion every 24 weeks, for a maximum of 4 doses. 
Non-Investigational Medicinal Products 
Premedicate with 100-mg methylprednisolone (or equivalent) completed approximately 
30 minutes prior to each ocrelizumab infusion and with an antihistaminic drug (e.g., 
diphenhydramine) approximately 30  60 minutes before each infusion of ocrelizumab 
to reduce the frequency and severity of infusion-related reactions (IRRs). 
The addition of an antipyretic (e.g., acetaminophen/paracetamol) may also be 
considered to further reduce the frequency and severity of IRRs. 
Statistical Methods 
Primary Efficacy Outcome Measures 
The primary efficacy assessment will be the proportion of patients who are free of any 
protocol-defined events during a 96-week period.  The definition of a protocol-defined 
event is the occurrence of at least one of the following while on treatment with 
ocrelizumab: 
 A protocol-defined relapse  
 A T1 Gd-enhanced lesion on brain MRI 
 A new and/or enlarging T2 lesion on brain MRI 
 Confirmed disability progression (24 weeks) 
 
Determination of Sample Size   
Assuming a) the expected proportion of patients who will be event free during 96 
weeks is 45%; b) the type one error rate is 5% and the half-width of 95% confidence 
interval (CI) for the proportion is 4%; c) the probability that half-width of 95% CI is at 
most 4% is 80%, then the required sample size will be n  600. 
Interim Analyses  
It is estimated that two to three interim analyses will be performed during the course of 
the study, according to patient enrollment and availability of data of interest.  Interim 
analyses may be used for internal decision making, hypothesis generation, 
abstraction/publication for major MS conferences, or other purposes, as applicable.  
Details on the timing and scope of interim analyses will be described in the Statistical 
Analysis Plan 


 
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Appendix 2. 
2.2 
OUTCOME MEASURES 
2.2.1 
Primary Efficacy Outcome Measures 
The primary efficacy assessment is defined as the proportion of patients who are free of 
any protocol-defined events during a 96-week period.  The definition of a protocol-
defined event is the occurrence of at least one of the following while on treatment with 
ocrelizumab: 
1. A protocol-defined relapse (an adjudication of protocol-defined relapses will be 
performed by the sponsor based on pre-specified criteria, applied to data 
collected by the investigator) 
2. A T1 Gd-enhanced lesion on brain MRI 
3. A new and/or enlarging T2 lesion on brain MRI  
4. Confirmed disability progression (24 weeks)  
The evaluation of T1 Gd-enhanced lesions and new and/or enlarging T2 lesions will be 
performed by NeuroRx and detailed in protocol MN30035 imaging review charter. 
2.2.2 
Secondary Efficacy Outcome Measures 
 
The proportion of patients free from a protocol-defined event during a 24-week 
period and a 48-week period 
 
Time to protocol-defined event (as defined in Section 2.2.1 above) 
 
The time to onset of first relapse 
 
Time to onset of first T1 Gd-enhanced lesion  
 
Time to onset of first new and/or enlarging T2 lesion  
 
Time to onset of confirmed disability progression for at least 24 weeks during the 
study period  
 
Annualized relapse rate at week 96 
 
Total number of T1 Gd-enhanced lesions detected by brain MRI at weeks 24, 48, 
and 96 
 
Total number of new and/or enlarging T2 lesions detected by brain MRI at 
weeks 24, 48, and 96 


 
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 
Change in total T2 lesion volume detected by brain MRI from baseline to 
weeks 24, 48, and 96 
2.2.3 
Exploratory Efficacy Outcome Measures 
 
Change in neurological exam score (EDSS) at Weeks 24, 48 and 96 from 
baseline 
 
Percent change in brain volume at Weeks 24, 48, and 96 from baseline 
 
Change in Patients Reported Outcome Scales from baseline: 
o MSIS-29 - The Multiple Sclerosis Impact Scale  
o SATMED-q - The Treatment Satisfaction with Medicines Questionnaire 
o TSQM II - The Treatment Satisfaction Questionnaire for Medication 
Version II 
2.2.4 
Pharmacokinetic Efficacy Outcome Measures 
Not Applicable to this study. 
2.2.5 
Safety Outcome Measures 
 
Frequency of patients with the following events: 
o Treatment emergent adverse events  
o Serious treatment emergent adverse events 
o Adverse events leading to treatment discontinuation (dose withdrawal) 
o Serious adverse events leading to treatment discontinuation (dose 
withdrawal) 
o Adverse events leading to infusion dose modification/interruption 
o Serious adverse events leading to infusion dose modification/interruption 
o Treatment-related adverse events 
o Treatment-related serious adverse events 
o Adverse events with fatal outcome 
o MS Relapses 


 
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o MS relapses classified as serious 
o Infusion-related reactions (IRR): 
 
IRR by infusion (dose 1 day 1, dose 1 day 15, dose 2, dose 3, 
dose 4, overall) 
 
IRR by CTCAE grades  
 
Infusion related reactions by infusion, grade, and by pre-
medication (Methylprednisolone only, Methylprednisolone and 
analgesics/antipyretics, Methylprednisolone and antihistaminics, 
Methylprednisolone and analgesics/antipyretics and 
antihistaminics) 
o Time to withdrawal from the study due to an adverse event 
 
Changes from baseline and select laboratory abnormalities for the following 
assessments:  
o Hematology (hemoglobin, hematocrit, platelet count, RBC count, WBC 
count, percent, and absolute differential count [neutrophils, bands, 
eosinophils, lymphocytes, monocytes, basophils, other cells]) 
o Serum Chemistries (AST, ALT, gamma-glutamyl transpeptidase [GGT], 
total bilirubin, urea, uric acid, creatinine, potassium, sodium, calcium, 
phosphorus)Urinalysis (specific gravity, pH, glucose, protein, ketones, 
and blood) 
o B-cell depletion and recovery (CD19) and T-cell counts (CD4, CD8) 
o HBV DNA 
o Vital signs (infusion and non-infusion visit) 
 
Exposure duration and dose 
 
Summary of previous DMTs and last DMT before switching to ocrelizumab 
2.3 
DETERMINATION OF SAMPLE SIZE 
Assuming a) the expected proportion of patients who will be event free during 96 weeks 
is 45%; b) the type one error rate is 5% and the half-width of 95% confidence interval for 
the proportion is 4%; c) the probability that half-width of 95% confidence interval is at 
most 4% is 80%, the required sample size for this study is n=600. The shorter infusion 


 
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substudy will enroll approximately 100 patients. Please refer to protocol for further 
details.  
2.4 
ANALYSIS TIMING 
The final analysis will be conducted after all patients completed the study visits including 
safety follow-up visit and the optional substudy visits. Database lock will occur several 
weeks after the last patient last visit to clarify all outstanding queries. In addition to the 
final analysis, two interim analyses were performed: 1) when 20% of patients completed 
their 48-week visit, and 2) when all patients completed their 48-week visit. 
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION  
No randomization is planned. All patients will receive ocrelizumab. 
3.2 
INDEPENDENT REVIEW FACILITY 
Not applicable. 
3.3 
DATA MONITORING 
Not applicable. 
4. 
STATISTICAL METHODS  
For continuous variables, descriptive statistics (e.g., mean, median, standard deviation 
[SD], n, 25th and 75th percentiles, minimum, maximum) will be calculated and 
summarized. For categorical variables, the number and percentage in each category will 
be displayed. Statistical methods for analysis of efficacy variables are detailed in the 
Efficacy Analyses section below. 
Planned analyses for the shorter infusion sub-study will be described in Appendix 6. 
4.1 
ANALYSIS POPULATIONS 
The efficacy analyses will be performed using the intent-to-treat (ITT) or modified ITT 
(mITT) population.  The per-protocol (PP) population will be used for sensitivity efficacy 
analyses for the primary endpoint only) in order to evaluate the influence of major 
protocol violators on  efficacy of ocrelizumab. The safety analyses will be performed 
using the safety population.  
4.1.1 
Intent-to-Treat Population 
All enrolled patients who received any ocrelizumab will be included in the ITT population. 
Patients who prematurely withdrew from the study for any reason and who did not have 
any assessments for any reason will still be included in the ITT population as long as 
patient received ocrelizumab. 


 
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4.1.2 
Modified Intent-to-Treat Population 
The modified ITT (mITT) population is a subset of the ITT population which excludes 
patients who discontinued ocrelizumab treatment early without any protocol-defined 
events for reasons other than death and lack of efficacy.  
4.1.3 
Per Protocol Population 
The per-protocol (PP) population will include all patients in the ITT population without 
key major protocol violations.  Key major violations includes key inclusion/exclusion 
criteria or violations of study conduct that are deemed to potentially affect the efficacy of 
study treatment. The list of key major protocol violations is finalized prior to final 
database lock for the study and listed in Appendix 5. 
4.1.4 
Pharmacokinetic-Evaluable Population 
Not applicable. 
4.1.5 
Safety Population 
The Safety Population will include all enrolled patients who received any ocrelizumab. All 
safety analyses will use this population.  
4.2 
ANALYSIS OF STUDY CONDUCT 
The following will be summarized: 
 
Numbers of patients in each of the ITT, mITT, PP, and safety populations, and 
protocol deviations leading to exclusion from the PP population  
 
Number of patients who complete study treatment 
 
Reasons for study treatment discontinuation (separate summary of number and 
percentage of patients who continued onto commercial OCR for patients under 
protocol version 5 and patients under previous versions) 
 
Reasons for study discontinuation (separate summary of number and percentage 
of patients who continued onto commercial OCR for patients under protocol 
version 5 and patients under previous versions) 
 
Number of patients who complete 1, 2, 3, and 4 doses (dose 1 is split to two 
infusions and will be counted as 1 dose) 
 
Summary and Kaplan-Meier plots of time to discontinuation of study treatment 
(patients did not reach week 96) 
4.3 
ANALYSIS OF DEMOGRAPHICS AND BASELINE 
CHARACTERISTICS 
The following demographic and baseline characteristics will be summarized: 


 
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 
Age at first dose (< 40, ≥ 40, also < 18, 18- 40, 40-55, > 55, and continuous) 
 
Sex 
 
Self-reported race and ethnicity 
 
Female and male reproductive statuses 
 
Country (USA, Canada) 
 
Height, weight, and BMI 
History of MS summaries will include: 
 
Duration since MS first symptoms (in years): continuous and categorical (≤ 3 
years, >3 - 5 years, >5 - 10 years, >10-≤12 years, >12 years) 
 
Duration since RRMS diagnosis (in years): continuous and categorical (≤ 2 
years, >2 - 5 years, >5 - 10 years, >10-≤12 years, >12 years)  
 
Baseline EDSS: continuous and categorical (<4 years, ≥4 years, and <2.5 years, 
≥2.5 years) 
 
Time since first MS relapse: continuous and categorical (≤3 months,>3 to ≤6 
months, >6 months) 
 
Qualifying events for enrollment (relapse, T1 Gd-enhanced lesion or new and/or 
enlarging T2 lesion) 
History of prior MS treatment summaries will include: 
 
 
Number and percent of patients taking previous unique DMTs, by number and by 
name of DMT 
 
Number and percent of patients switching previous DMTs 
 
Duration of previous DMT (months) by name of DMT 
 
Reason for discontinuation from each previous DMT by name of DMT 
 
Number and percent of patients taking last DMT before study enrollment by 
name of DMT  


 
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 
Duration between end of last DMT to initiation of ocrelizumab treatment: 
continuous (months) and categorical (≤1 months,>1 to ≤3 months, >3 months), 
and by name of DMT. 
 
Baseline MRI results: number of Gd-enhancing T1 lesions (0, 1, 2, 3, ≥4) and 
normalized brain volume   
General non-MS medical history and baseline conditions 
 
Study sites (number and percent of patients) 
4.4 
EFFICACY ANALYSIS 
Efficacy endpoints will be evaluated for the mITT or ITT population as specified. 
Sensitivity for primary endpoint will be conducted for the PP population. 
For all change from baseline analyses, except for EDSS, baseline will be defined as the 
last non-missing value on or before the first infusion. Unless otherwise specified, the 
baseline EDSS will be defined as (1) the last non-missing value on or before the first 
infusion, for patients who were administered only one EDSS evaluation before the first 
infusion, or (2) the average of the 2 EDSS results pre infusion, for patients who were 
administered an additional evaluation in cases where the screening EDSS was more 
than 14 days prior to the first infusion.  
The baseline EDSS will be rounded to the second decimal point. For analyses that 
stratify by analysis baseline EDSS i.e. (< 2.5 vs. ≥ 2.5), the EDSS values will be rounded 
to the nearest one decimal value. 
Per protocol, unscheduled MRI evaluations conducted for suspected PML will not be 
included in the analysis of efficacy endpoints. 
Visit windows (defined in Module 2) will be applied to key efficacy assessments to 
accurately capture the timing of assessment.   
4.4.1 
Primary Efficacy Endpoint 
The proportion of patients who are free from a protocol-defined event during a 96-week 
period will be calculated and presented along with a two-sided 95% Clopper-Pearson 
exact confidence interval. Data from unscheduled visits within each respective 24-week 
interval will be included in the evaluation of the endpoint. Analyses will be performed for 
the mITT population. Patients are considered to have a protocol-defined event during the 
96-week period if they discontinue due to lack of efficacy or death despite without a 
protocol-defined event as defined below. 
Event definition and Handling of Missing Data 


 
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The definition of a protocol-defined event is the occurrence of at least one of the 
following while on treatment with ocrelizumab: 
 
A protocol-defined relapse defined as an occurrence of new or worsening 
neurological symptoms attributable to MS.  Symptoms must persist for  24 
hours and should not be attributable to confounding clinical factors (e.g., fever, 
infection, injury, adverse reactions to medications), and immediately be preceded 
by a stable or improving neurological state for least 30 days.   
 
A T1 Gd-enhanced lesion on brain MRI 
 
A new and/or enlarging T2 lesion on brain MRI 
 
Confirmed disability progression (24 weeks) 
The new or worsening neurological symptoms must be accompanied by objective 
neurological worsening consistent with an increase of at least half a step on the EDSS 
scale, or two points on one of the appropriate Functional Systems Score (FSS), or one 
point on two or more of the appropriate FSS. The change must affect the selected FSS 
(i.e., pyramidal, ambulation, cerebellar, brainstem, sensory, or visual). Episodic spasms, 
sexual dysfunction, fatigue, mood change or bladder or bowel urgency or incontinence 
will not suffice to establish a relapse.  
Progression is defined a ≥ 1−point increase in EDSS score from a baseline EDSS score 
of 0.0−5.5 inclusive, and a 0.5-increase from a baseline EDSS score higher than 5.5.  
For example, for a patient with a baseline EDSS score of 5.25 or 5.5, the progression is 
defined as an EDSS score of at least 6.5. For a patient with a baseline EDSS score of 
5.75 or 6.0, the progression is defined as an EDSS score of at least 6.5. 
Confirmation of the 24-week disability progression must occur at the regularly scheduled 
visit that is at least 24 weeks (168 days ± 14 days) after initial progression.  
If a patient has a missing EDSS at the scheduled visit occurring at least 168 days after 
an initial progression, the next immediate scheduled or unscheduled EDSS will be used 
to confirm disability progression. In cases where confirmation of disability progression 
during the study is not possible due to missing 24-week assessments, such that 
establishment of the occurrence of a protocol-defined event is not possible, the patient 
will be considered as not having an event. 
4.4.2 
Secondary Efficacy Endpoints 
The mITT population will be used for secondary efficacy endpoints of the proportion of 
patients free from a protocol-defined event during the first 24-week and 48-week period. 


 
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Analyses of all other secondary efficacy endpoints will be performed using the ITT 
population. 
The proportion of patients free from a protocol-defined event during the first 24-week 
and 48-week will be presented along with a two-sided 95% Clopper-Pearson exact 
confidence interval. Same analysis method of the primary efficacy endpoint will be 
applied to the 24-week and 48-week outcomes. Note that event during the first 24-weeks 
will not include CDP events due to no confirmatory EDSS score can be observed within 
the first 24-weeks. A histogram of the percent of patients who are event free at weeks 24, 
48, and 96 will be produced.   
Time-to-event endpoints 
The Kaplan–Meier method (i.e., the product limit estimator) will be used to estimate the 
time to onset of the 5 parameters listed below. Kaplan-Meier plots will be produced. The 
event-free probability at Week 96 will be calculated based on Kaplan-Meier method as 
sensitivity analyses of the primary endpoint, proportion of patients without a protocol-
defined event. 
Time to protocol-defined event 
For patient with an event, it will be defined as the earliest onset time of the following: 
a protocol-defined relapse, T1 Gd-enhanced lesion, new and/or enlarging T2 lesion, 
or confirmed disability progression (see below for the determination of the time to 
onset of confirmed disability progression)  
Patients without an event (either during the complete 96-week study period, or 
before early withdrawal from treatment) will be censored at the last evaluation of a 
protocol defined event, i.e. the maximum time of last MRI or EDSS evaluation 
Time to onset of first relapse 
For patients with an event, it will be determined as the first relapse time reported by 
the patient.  
Patients without any relapse will be censored at the last study visit.  
Time to onset of first T1 Gd-enhanced lesion 
For patient with event, it will be defined as the first time a T1 Gd-enhanced lesion 
was detected post baseline.  
Patients without an event will be censored at the last performed MRI evaluation.  
Time to onset of first new and/or enlarging T2 lesion 


 
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For patient with event, it will be defined as the first time, including at unscheduled 
visits, a new and/or an enlarging T2 lesion was detected.  
Patients without an event will be censored at the last performed MRI evaluation.  
Time to onset of confirmed disability progression determination for at least 24 weeks 
during the study period  
For patient with an event, it will be defined as the initial disability progression time.  
Patients without an event will be censored at the last available EDSS evaluation. 
The adjusted annualized relapse rate at Week 96 will be estimated using a negative 
binomial model, adjusting for the number of previous DMTs (1 or >1), baseline EDSS 
(2.5 vs 2.5), and including the log-transformed years of drug exposure time as an 
“offset” variable. The adjusted rates along with the two-sided 95% confidence interval 
will be presented. SAS proc GENMOD will be applied.  Years of drug exposure will be 
defined as ((earlier of date of Week 96 visit or date of treatment early termination) − date 
of first infusion + 1)/365.25  
The unadjusted annualized relapse rate at Week 96 will be presented. It is defined as 
the total number of relapses for all patients divided by the total years of drug exposure. 
Total number of T1 Gd-enhanced lesions detected by brain MRI at Weeks 24, 48, 
and 96 
The analyses will include patients who have an interpretable MRI at the time point of 
interest. The following analyses will be presented: 
 
Number and percentage of patients having 0, 1, 2, 3, and greater than 3 lesions at 
weeks 24, 48, and 96.   
 
The unadjusted and adjusted rates of lesion occurrence at weeks 24, 48, and 96 
combined will be calculated: 
o The unadjusted rate will be the ratio of the total number of T1 Gd-enhanced 
lesions to the total number of interpretable MRI scans. 
o The adjusted rate will be derived using a negative binomial model. The 
dependent variable in the model will be the total number of T1-Gd-enhanced 
lesions. The model will be adjusted for the following baseline covariates: Gd 
lesion (present or not), EDSS score (< 2.5 vs. ≥ 2.5), and number of previous 
DMTs (1 vs. >1). In order to account for patients potentially receiving varying 
numbers of brain MRI scans during the study, the log-transformed number of 
brain MRI scans received will be included in the model as an “offset”. 


 
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 
Histogram of the count (0, 1, 2, 3, >3) of T1 Gd-enhanced lesions at Weeks 24, 48, 
and 96, and during all visits combined will be produced. 
Total number of new and/or enlarging T2 lesions detected by brain MRI at 
weeks 24, 48, and 96 
The analyses of this outcome will be similar to the analyses of total T1 Gd-enhanced 
lesions as described above.   
The mean change in total T2 lesion volume detected by brain MRI from baseline to 
Weeks 24, 48, and 96 will be analyzed using a longitudinal mixed effects model 
repeated measure (MMRM).  The model’s fixed effects will include visit along with the 
following baseline covariates: baseline T2 lesion volume, number of previous DMTs (1 
vs. >1), baseline T2 lesion volume by visit interaction, and baseline EDSS score (< 2.5 
vs. ≥ 2.5). Visit will be treated as a repeated variable within a patient. Patient and visit 
will be treated as factor variables. An unstructured variance−covariance structure will be 
applied to model the within-patient errors. The model will be fitted using the Restricted 
Maximum Likelihood method (REML). Denominator degrees of freedom will be 
estimated using Satterthwaite’s approximation. Any patient with an interpretable post 
baseline MRI will be included in the model.  
A plot of T2 lesion volume least squares mean changes from baseline over time and 
corresponding 95% confidence intervals will be presented. 
4.4.3 
Exploratory Efficacy Endpoints 
The ITT population will be used for exploratory efficacy endpoints. 
Changes from baseline in EDSS scores at Weeks 24, 48, and 96 will be estimated using 
a longitudinal mixed effects model repeated measure (MMRM). The model’s fixed effects 
will include visit along with the following baseline covariates: baseline EDSS score and 
number of previous DMTs (1 vs. >1), baseline EDSS score by visit interaction. Visit will 
be treated as a repeated variable within a patient. Patient and visit will be treated as 
factor variables. An unstructured variance−covariance structure will be applied to model 
the within-patient errors. The model will be fitted using the Restricted Maximum 
Likelihood method (REML). Denominator degrees of freedom will be estimated using 
Satterthwaite’s approximation. 
A plot of the adjusted mean EDSS changes form baseline will be produced.  
Percent changes from baseline in brain volume at Weeks 24, 48, and 96 will be 
estimated using the same model as the T2 lesion volume in section 4.4.2. 
Change in below PROs from baseline will be estimated using MMRM adjusting for visit 
along with following baseline covariates: baseline score and number of previous DMTs 


 
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(1 vs. >1), baseline EDSS score (<2.5 vs. >=2.5) and baseline PRO score by visit 
interaction. Visit will be treated as a repeated variable within a patient. Patient and visit 
will be treated as factor variables. 
 
MSIS-29 - The Multiple Sclerosis Impact Scale  
 
SATMED-q - The Treatment Satisfaction with Medicines Questionnaire 
 
TSQM II - The Treatment Satisfaction Questionnaire for Medication Version II 
Detailed analysis method for the PRO endpoints will be described in Section 4.6. 
4.4.4 
Sensitivity Analyses 
The analysis of primary efficacy endpoint described in Section 4.4.1 will be performed for 
the PP population as a sensitivity analysis. Per study schedule, the last EDSS 
assessment is at Week 96, such that no subsequent visit with EDSS measurement can 
be used to confirm an initial disability progression at Week 96. A Sensitivity analysis will 
be performed for the mITT population to impute 50% of the patients with an initial 
disability progression at Week 96 as having an event of CDP; the other 50% of these 
patients as having no event of CDP. 
4.4.5 
Subgroup Analyses 
The primary and all secondary outcomes will be analyzed for the following subgroup for 
the mITT population:
Last DMT before enrollment: Fingolimod vs. Other 
4.5 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Not Applicable. 
4.6 
PATIENT REPORTED OUTCOME ANALYSES 
All analyses on the patient reported outcomes (PROs) will be based on the ITT 
population. 
4.6.1 
MSIS-29  
The Multiple Sclerosis Impact Scale (MSIS-29) is a 29-item questionnaire designed to 
measure the physical and psychological impact of MS from the patient’s perspective.  
Dimension 
Items  
Item Scores 
Physical Scale 
1-20 
1 = Not at all 
2 = A little 
3 = Moderately 
4 = Extremely 
Psychological Scale 
21-29 
1 = Not at all 
2 = A little 


 
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3 = Moderately 
4 = Extremely 
Score for the physical scale is calculated as follows: 
 
Items 1-20 are added  
 
A transformed score = 100 x (observed score - 20) /(80-20) is derived 
Score for the psychological scale is calculated as follows: 
 
Items 21-29 are added  
 
A transformed score = 100 x (observed score - 9) /(36-9) is derived 
Higher scale values indicate higher impact of MS disability on the patient. Missing scores 
in the specific scale are not imputed. 
MSIS-29 results by dimension will be summarized for baseline and weeks 24, 48, 72, 
and 96 visits. The mean change in each MSIS-29 dimension score from baseline to 
weeks 24, 48, and 96 will be analyzed using a longitudinal mixed effects model repeated 
measure (MMRM).  The fixed effects will include visit along with the following baseline 
covariates: baseline MSIS-29 score, number of previous DMTs (1 vs >1), baseline 
MSIS-29 score by visit interaction, and baseline EDSS score (< 2.5 vs. ≥ 2.5). Visit will 
be treated as a repeated variable within a patient. Patient and visit will be treated as 
factor variables. An unstructured variance−covariance structure will be applied to model 
the within-patient errors. The model will be fitted using the Restricted Maximum 
Likelihood method (REML). Denominator degrees of freedom will be estimated using 
Satterthwaite’s approximation. 
A plot of the least squares mean changes from baseline in MSIS-29 scores over time 
and the corresponding 95% confidence intervals will be presented for each dimension of 
the scale.  
4.6.2 
SATMED-q 
The Treatment Satisfaction with Medicines Questionnaire includes 17 questions scored 
on a 5-point Likert-type scale investigating the following dimensions. The bolded 
dimensions will be summarized: 
 
Dimension 
Items  
Item Scores 
Any Undesirable side 
effects 
1 
0=No 
1=Yes 
Undesirable Side 
effects 
1-3 
4 = Not at all 
3 = A little bit 
2 = Somewhat 


 
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1 = Quite a bit 
0 = Very much 
Treatment effectiveness 4-6 
0 = Not at all 
1 = A little bit 
2 = Somewhat 
3 = Quite a bit 
4 = Very much 
Convenience for use 
7-9 
0 = Not at all 
1 = A little bit 
2 = Somewhat 
3 = Quite a bit 
4 = Very much 
Impact on daily 
activities 
10-12 
0 = Not at all 
1 = A little bit 
2 = Somewhat 
3 = Quite a bit 
4 = Very much 
Medical care 
13-14 
0 = Not at all 
1 = A little bit 
2 = Somewhat 
3 = Quite a bit 
4 = Very much 
Global satisfaction 
15-17 
0 = Not at all 
1 = A little bit 
2 = Somewhat 
3 = Quite a bit 
4 = Very much 
 
Items are summed to yield the dimension scores. Higher scores indicate higher 
satisfaction with treatment. Missing score should be substituted by the worst possible 
score where applicable (items 1 to 3: if question “Have you experienced any undesired 
effects caused by the medicine” = “Y”, then missing=”Quite a bit”, otherwise missing will 
not be imputed; items 4 to 17: missing=”Not at all”). If two or more answers are missing 
in a given dimension, the dimension should be discarded. If two contiguous response 
categories are selected for one item, the worst score should be selected as valid. When 
two non-contiguous response categories are selected, the response should be 
considered as missing.  
Analysis of the SATMED-q scores will be based on a longitudinal MMRM similar to the 
planned analyses of the MSIS-29 scores as described above. 
A plot of the least squares mean changes from baseline in SATMED-q scores over time 
and the corresponding 95% confidence intervals will be presented for each bolded 
dimension of the scale. 
4.6.3 TSQM II  
The Treatment Satisfaction Questionnaire for Medication Version II consists of 11 
questions and 4 dimensions 
Dimension 
Cluster of 
Score 
Scoring 


 
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Items that 
are added  
Effectiveness 
1-2 
1 = Extremely Dissatisfied 
2 = Very Dissatisfied 
3 =Dissatisfied 
4 = Somewhat Satisfied 
5 = Satisfied 
6 = Very Satisfied 
7 = Extremely Satisfied 
([(item 1 + item 2) – 
2]/12) * 100 
 
If one item is missing: 
([(Use the completed 
item)) – 1] / 6) * 100 
 
Side Effects 
4-6 
1 = Extremely Dissatisfied 
2 = Very Dissatisfied 
3 = Somewhat Dissatisfied 
4 = Slightly Dissatisfied 
5 = Not at all Dissatisfied 
(6) = Not Applicable 
 
 
([Sum(item 4 - item 6) 
– 3] /12) * 100 
 
If one item is missing: 
([(Sum(the two 
completed items)) – 
2]/8) * 100 
 
 
Convenience 
7-9 
1 = Extremely Dissatisfied 
2 = Very Dissatisfied 
3 =Dissatisfied 
4 = Somewhat Satisfied 
5 = Satisfied 
6 = Very Satisfied 
7 = Extremely Satisfied 
([Sum(Item 7 - item 9) 
– 3]/18) * 100 
 
If one item is missing: 
([(Sum(the two 
completed items)) – 
2]/12) * 100 
Global Satisfaction 
10-11 
1 = Extremely Dissatisfied 
2 = Very Dissatisfied 
3 =Dissatisfied 
4 = Somewhat Satisfied 
5 = Satisfied 
6 = Very Satisfied 
7 = Extremely Satisfied 
 ([Sum(Item 10 to Item 
11) – 2] /12) * 100 
 
If one item is missing: 
([(Use the completed 
item)) – 1] divide by 6) * 
100 
 
All missing or ‘not applicable’ responses for Side Effects (relevant to item 4 – item 6) will 
be imputed as “Extremely Dissatisfied” if the question “As a result of taking this 
medication, do you experience any side effects at all?” is answered as “Yes”; otherwise 
will not be imputed. If two or more item is missing in a subscale, the subscale will be 
discarded.  
Analysis of the TSQM II scores will follow the MMRM approach similar to the analysis of 
the MSIS-29 scores as described above. 
A plot of the least squares mean changes from baseline in TSQM-II scores over time 
and the corresponding 95% confidence intervals will be presented for each of the four 
dimension scales.  
4.7 
SAFETY ANALYSES 
All safety analyses will be based on the safety population. For all change from baseline 
analyses, unless noted otherwise, baseline will be defined as the last non-missing value 
on or before the first infusion.  


 
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Treatment emergent AEs (TEAEs) are defined as AEs that occur on or after treatment 
on Day 1 or existing events that worsened after first study dose. Treatment emergent 
serious AEs (SAEs) are defined as SAEs that occur on or after treatment on day 1 or 
existing events that increased in severity after first study dose. AEs will be coded using 
the current MedDRA Dictionary and summarized by NCI CTCAE v4.0 grade.  
Relapse is part of the efficacy outcome as a component of protocol defined events and 
will be reported in the efficacy results section.  
Visit windows will be used in analyses that summarize laboratory measurements, vital 
signs. Visit window specifications will be provided in the separate Module 2.  
4.7.1 
Exposure of Study Medication 
Patients will be considered to have received a dose of treatment if they were 
administered at least part of one infusion of a dose (including day 1 or day 15 for the first 
dose).  
The treatment duration (weeks) and the number of doses received (day 1 and day 15 
infusions are considered as one dose) will be summarized.  
The number and percent of patients with study treatment intervention and the type of 
intervention (slowed down, interrupted, or discontinued infusion) will be summarized. 
The summaries will be presented by dose (dose 1 day 1, dose 1 day 15, dose 2, dose 3, 
dose 4) and overall. 
Kaplan-Meier plots of time to discontinuation of study treatment will be presented. 
4.7.2 
Adverse Events 
All TEAE will be coded, summarized by NCI CTCAE v4.0 grade, and tabulated by body 
system and Preferred Term for individual adverse events within each body system.  
Grade 3 to 5 adverse events, serious adverse events, adverse events leading to 
treatment discontinuation, time to withdrawal from treatment due to an adverse event, 
adverse events leading to infusion adjustment, and treatment-related adverse events will 
be summarized.  In addition, all adverse events leading to withdrawal from treatment and 
deaths will be listed if applicable. 
Number of events per 100 Patient-Years along with 95% exact confidence intervals will 
be summarized for all AE, serious AE and serious infections. 
The number and percentage of patients with at least one infusion related reaction (IRR), 
and the intensity (highest grade for each patient) will be summarized in total, by dose 
(dose 1 day 1, dose 1 day 15, dose 2, dose 3, dose 4) and by pre-medication. In 


 
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addition, the total number of IRRs will be summarized (multiple events will be counted) in 
total and by dose. 
4.7.3 
Laboratory Data 
Associated laboratory parameters, such as hepatic function, renal function, and 
hematology values, will be grouped and presented together. A summary of the number 
and percentage of patients with abnormal laboratory outcomes will be produced for each 
parameter.  
4.7.4 
Vital Signs 
Changes in physical findings and vital signs with onset on or after the first OCR infusion 
will be summarized at each scheduled visit. 
4.7.5 
Safety Endpoints of Special Interest 
All reported AESI will be summarized overall and by NCI CTCAE v4.0 grade, and 
tabulated by specific MedDRA bucket terms and preferred terms. The following types of 
events are of special interest: 
 
Drug-induced liver injury 
 
Suspected transmission of an infectious agent via product 
4.8 
MISSING DATA 
AEs with missing relationship to study drug will be considered as 'Related'.  AEs with 
missing CTCAE grade will be imputed as grade 3. AE with missing seriousness will be 
graded as serious. 
Missing and partial dates for AEs and concomitant medications will be handled 
according to Roche STREAM algorithm. 
4.9 
INTERIM ANALYSES 
Two interim analyses were performed during the course of the study, according to 
patient enrollment and availability of data of interest.  Interim analyses were used for 
hypothesis generation, abstraction/publication for major scientific conferences, or other 
purposes, as applicable. The statistical analysis plan of the interim analyses were 
detailed and documented in a separate DAP Module 1 CHORDS Study_Interim_v1.0. 
Since no adjustment of the study design or course are planned as a result of the interim 
looks, no adjustments to the type I error will be applied. 
 
 


 
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5. 
REFERENCES 
Ulm K. A simple method to calculate the confidence interval of a standardized mortality 
ratio (SMR), Am J Epidemiol. 1990 Feb;131(2):373-5 


 
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Appendix 1  
Protocol Synopsis 
TITLE: 
AN OPEN-LABEL STUDY TO EVALUATE THE EFFECTIVENESS 
AND SAFETY OF OCRELIZUMAB IN PATIENTS WITH 
RELAPSING REMITTING MULTIPLE SCLEROSIS WHO HAVE 
HAD A SUBOPTIMAL RESPONSE TO AN ADEQUATE COURSE 
OF DISEASE-MODIFYING TREATMENT 
PROTOCOL NUMBER: 
MN30035 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
100,593 
TEST PRODUCT: 
Ocrelizumab (RO4964913) 
PHASE: 
IIIb  
INDICATION: 
Relapsing remitting multiple sclerosis 
SPONSOR: 
Genentech, Inc. 
 
Objectives and Endpoints 
Primary Objective 
The primary objective of this study is to assess the effectiveness of ocrelizumab 600 mg 
intravenously (IV) every 24 weeks over 96 weeks in patients with relapsing remitting multiple 
sclerosis (RRMS) who have had a suboptimal response to an adequate course of a 
disease-modifying treatment (DMT).   
A suboptimal response is defined by having one or more clinically reported relapse(s), OR one 
or more T1 gadolinium (Gd)-enhanced lesion(s), OR two or more new or enlarging T2 lesions 
on magnetic resonance image (MRI) despite being on a stable dose of the same DMT for at 
least 6 months.  In addition, in patients receiving stable doses of the same approved DMT for 
more than a year, the event must have occurred within the last 12 months of treatment with this 
DMT.   
Secondary Objective 
The secondary objective of this study is to evaluate the safety and tolerability of ocrelizumab 
600 mg IV given every 24 weeks in patients with RRMS who have had a suboptimal response 
to an adequate course of a DMT as measured by the nature and incidence of adverse events. 
Exploratory Objective 
The exploratory objective of this study is to further assess the effectiveness of ocrelizumab by 
monitoring patient-reported outcomes (PROs) related to quality of life and treatment satisfaction. 
Study Design 
Description of the Study 
This study is a prospective, multicenter, open-label, effectiveness, and safety study in patients 
with RRMS who have had a suboptimal response to an adequate course of a DMT.  This study 
will be conducted in North America.  An adequate course of prior DMT is defined as the same 
DMT administered for at least 6 months.  Ocrelizumab will be administered as an initial dose of 
two 300-mg infusions (600 mg total) separated by 14 days (i.e., Days 1 and 15) followed by one 
600-mg infusion every 24 weeks for the study duration.   


 
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Patients will be assessed for effectiveness and safety every 24 weeks.  The study will consist of 
the following periods, described in detail below: 
 
Screening Period:  Up to 4 weeks 
 
Treatment Period:  Open-label treatment period of 72 weeks (4 doses) 
 
Safety Follow-up Period:  Observation 24 weeks after the last infusion of study drug for 
patients who discontinue or who chose not to continue with commercially available 
ocrelizumab at the end of study 
 
Eligible patients may choose to participate in an optional shorter infusion substudy at the 
Week 96 visit, during which they will receive ocrelizumab infused over a shorter time period 
than the approved administration rate (Appendix 2).   
Number of Patients 
This study will enroll approximately 600 patients with RRMS who have had a suboptimal 
response to an adequate course of a DMT.   
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
Signed Informed Consent Form 
 
Able to comply with the study protocol, in the investigator’s judgment 
 
Age 1855 years, inclusive 
 
Have a definite diagnosis of multiple sclerosis (MS), confirmed per the revised 2010 
McDonald criteria (Polman et al. 2011; Appendix 4), and have the relapsing remitting form 
of MS 
 
Have a length of disease duration, from first symptom, of  12 years 
 
Have been treated with an adequate course of treatment with no more than three prior 
DMTs   
 Adequate treatment is defined as  6 months on a DMT. 
 Discontinuation of the most recent adequately used DMT must have been due to 
suboptimal response as defined below. 
 
Suboptimal response while on his/her last adequately used DMT (for  6 months); a 
suboptimal response is defined by having one of the following qualifying events despite 
being on a stable dose of the same DMT for at least 6 months: 
 
One or more clinically reported relapse(s) 
 
OR one or more T1 Gd-enhanced lesion(s) 
 
OR two or more new or enlarging T2 lesions on MRI 
These qualifying events must have occurred while on the last adequately used DMT.  In 
addition, in patients receiving stable doses of the same approved DMT for more than a 
year, the event must have occurred within the last 12 months of treatment with this DMT 
from the date of screening. 
 
Expanded Disability Status Scale (EDSS) of 0 to 5.5, inclusive, at screening 
 
For women of childbearing potential:  agreement to use an acceptable birth control method:  
 
Progesterone-only oral hormonal contraception, where inhibition of ovulation is not 
the primary mode of action 
 
Male or female condom with or without spermicide 
 
Cap, diaphragm, or sponge with spermicide 
 
A combination of male condom with either cap, diaphragm, or sponge with spermicide 
(double-barrier methods are also considered acceptable, but not highly effective, birth 
control methods) 
 


 
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Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
History of primary progressive multiple sclerosis (PPMS), progressive relapsing multiple 
sclerosis (PRMS), or secondary progressive multiple sclerosis (SPMS) 
 
Inability to complete an MRI (contraindications for MRI include but are not restricted to 
claustrophobia, weight, pacemaker, cochlear implants, presence of foreign substances in 
the eye, intracranial vascular clips, surgery within 6 weeks of entry into the study, coronary 
stent implanted within 8 weeks prior to the time of the intended MRI, inability to tolerate 
Gd-enhancing ligands, etc.). 
 
Known presence of other neurological 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 central nervous system (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; MELAS [mitochondrial myopathy, encephalopathy, lactic acidosis, stroke] 
syndrome) 
 Neuromyelitis optica 
 History or known presence of systemic autoimmune disorders potentially causing 
progressive neurologic disease (e.g., lupus, anti-phospholipid antibody syndrome, 
Sjogren’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 (PML) 
 
Pregnancy or lactation, or intention to become pregnant during the study 
 Women of childbearing potential must have a negative serum or urine pregnancy test 
result within 14 days prior to initiation of study drug. 
 
Any concomitant disease that may require chronic treatment with systemic corticosteroids 
or immunosuppressants during the course of the study 
 
Lack of peripheral venous access 
 
Significant, uncontrolled disease, such as cardiovascular (including cardiac arrhythmia), 
pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine, and 
gastrointestinal or any other significant disease that may preclude patient from participating 
in the study 
 
Congestive heart failure (New York Heart Association [NYHA] Class III/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 severe 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 of or currently active primary or secondary immunodeficiency 
 
History or known presence of recurrent or chronic infection (e.g., HIV, syphilis, TB) 
 
History of recurrent aspiration pneumonia requiring antibiotic therapy 


 
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 
History of malignancy, including solid tumors and hematological malignancies, except basal 
cell, in situ squamous cell carcinoma of the skin, and in situ carcinoma of the cervix of the 
uterus that have been excised with clear margins 
 
History of severe allergic or anaphylactic reactions to humanized or murine monoclonal 
antibodies 
 
History of coagulation disorders 
 
History of alcohol or drug abuse within 24 weeks prior to screening 
 
Previous treatment with natalizumab within 12 months prior to screening unless failure was 
due to confirmed, persistent anti-drug antibodies  
 Patients previously treated with natalizumab will be eligible for this study only if duration 
of treatment with natalizumab was  1 year and natalizumab was not used in the 12 
months prior to screening.  Anti-JCV antibody status (positive or negative) and titer (both 
assessed within the year of screening) must be documented prior to enrollment.  When 
assessed, anti-JCV antibody status should be determined using an analytically and 
clinically validated immunoassay (e.g., ELISA). 
 
Previous treatment with systemic cyclophosphamide, azathioprine, mycophenolate mofetil, 
cyclosporine, or methotrexate  
 
Treatment with IV immunoglobulin within 12 weeks prior to baseline 
 
Treatment with dalfampridine (Ampyra) unless on stable dose for  30 days prior to 
screening 
 Wherever possible, patients should remain on stable doses throughout the treatment 
period. 
 
Receipt of a live vaccine within 6 weeks prior to baseline; in rare cases when patient 
requires vaccination with a live vaccine, the screening period may need to be extended but 
cannot exceed 8 weeks 
 
Systemic corticosteroid therapy within 4 weeks prior to screening 
 The screening period may be extended (but cannot exceed 8 weeks) for patients who 
have used systemic corticosteroids for their MS before screening.   
 There should be 4 weeks from last dose of systemic corticosteroid therapy prior to first 
infusion. 
 
Previous treatment with fingolimod (Gilenya®) or dimethyl fumarate (Tecfidera) in patients 
whose lymphocyte count is below the lower limit of normal (LLN) 
 
Contraindications to or intolerance of oral or IV corticosteroids, including IV 
methylprednisolone (or equivalent steroid) administered according to the country label, 
including: 
 
Psychosis not yet controlled by a treatment 
 
Hypersensitivity to any of the constituents preceding 
 
Treatment with alemtuzumab (Lemtrada) 
 
Treatment with a B-cell targeted therapies (e.g., rituximab, ocrelizumab, atacicept, 
belimumab, or ofatumumab) 
 
Treatment with a drug that is experimental (Exception:  treatment with an experimental drug 
that was subsequently approved in the patient’s country is allowed.) 
 
Laboratory test results as follows: 
 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) 
 
Lymphocyte count below LLN 
 
CD4 count  300/L 
 
AST or ALT  3.0  the upper limit of normal (ULN) 


 
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 
Platelet count  100,000/L (  100  109/L) 
 
Total neutrophil count below LLN  
Re-testing before baseline:  in rare cases in which the screening laboratory 
samples are rejected by the laboratory (e.g., hemolyzed sample) or the results are 
not assessable (e.g., indeterminate) or abnormal, the tests need to be repeated.  
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 enrollment must meet study criteria.  In such circumstances, 
the screening period may need to be prolonged but should not exceed 8 weeks. 
 
End of Study 
The end of the treatment period is defined as the date when the last patient, last visit (LPLV) at 
96 weeks occurs (or at Week 100 in the substudy).  
Length of Study 
The total length of the study is expected to be approximately 4 years from the first patient 
enrolled to LPLV. 
The end of study is defined as the LPLV of the safety follow-up. 
Investigational Medicinal Products 
Test Product (Investigational Drug) 
Dose 1 of ocrelizumab will be administered as two 300-mg IV infusions (600 mg total) separated 
by 14 days (i.e., Days 1 and 15).  Subsequent doses will be administered as one 600-mg IV 
infusion every 24 weeks, for a maximum of 4 doses. 
Non-Investigational Medicinal Products 
Premedicate with 100-mg methylprednisolone (or equivalent) completed approximately 
30 minutes prior to each ocrelizumab infusion and with an antihistaminic drug (e.g., 
diphenhydramine) approximately 30  60 minutes before each infusion of ocrelizumab to reduce 
the frequency and severity of infusion-related reactions (IRRs). 
The addition of an antipyretic (e.g., acetaminophen/paracetamol) may also be considered to 
further reduce the frequency and severity of IRRs. 
Statistical Methods 
Primary Efficacy Outcome Measures 
The primary efficacy assessment will be the proportion of patients who are free of any 
protocol-defined events during a 96-week period.  The definition of a protocol-defined event is 
the occurrence of at least one of the following while on treatment with ocrelizumab: 
 
A protocol-defined relapse  
 
A T1 Gd-enhanced lesion on brain MRI 
 
A new and/or enlarging T2 lesion on brain MRI 
 
Confirmed disability progression (24 weeks) 
 
Determination of Sample Size   
Assuming a) the expected proportion of patients who will be event free during 96 weeks is 45%; 
b) the type one error rate is 5% and the half-width of 95% confidence interval (CI) for the 
proportion is 4%; c) the probability that half-width of 95% CI is at most 4% is 80%, then the 
required sample size will be n  600. 
Interim Analyses  
It is estimated that two to three interim analyses will be performed during the course of the study, 
according to patient enrollment and availability of data of interest.  Interim analyses may be 
used for internal decision making, hypothesis generation, abstraction/publication for major MS 
conferences, or other purposes, as applicable.  Details on the timing and scope of interim 
analyses will be described in the Statistical Analysis Plan 


 
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Appendix 2  
Schedule of Assessments 
 
 Screening 
Treatment Period 
End of 
Treatment/ 
Early With-
drawal 
Visit b 
Unscheduled 
Visit  
(due to 
relapse) c 
Safety  
Follow-up 
Visit d 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
Week 
4 a 
   
2  
24  
48  
72  
96  
Study Day 
(window in days) 
28  
1 
Baseline 
15 
( 2) 
169 
( 14) 
337 
( 14) 
505 
( 14) 
673 
( 14) 
 
 
Informed consent e 
x 
  
  
  
  
  
  
 
  
Medical history and demographic data f 
x 
  
  
  
  
  
  
 
  
Review inclusion and exclusion criteria 
x 
x 
  
  
  
  
  
 
  
Physical examination g 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Height 
x 
 
 
 
 
 
 
 
 
Weight 
x 
 
  
  
  
  
  
 
  
Vital signs h 
x 
x 
x 
x 
x 
x 
x 
x 
  
Laboratory Assessments i 
Hematology, chemistry, urinalysis j 
x 
x k 
  
x 
x 
x 
x 
 
  
Pregnancy test l 
x 
x 
x 
x 
x 
x 
x 
 
 x 
Hepatitis screening m 
x 
 
  
  
  
  
  
 
  
Hepatitis B virus DNA test m 
x 
  
  
x 
x 
x 
x 
 
  
Immunoglobulin levels n 
x 
  
  
x 
x 
x 
x 
 
 x 
Lymphocyte subtypes o 
 x 
 
 
x 
x 
x 
x 
 
 x 


 
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 Screening 
Treatment Period 
End of 
Treatment/ 
Early With-
drawal 
Visit b 
Unscheduled 
Visit  
(due to 
relapse) c 
Safety  
Follow-up 
Visit d 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
Week 
4 a 
   
2  
24  
48  
72  
96  
Study Day 
(window in days) 
28  
1 
Baseline 
15 
( 2) 
169 
( 14) 
337 
( 14) 
505 
( 14) 
673 
( 14) 
 
 
EDSS score  
x 
x k 
 
x 
x 
x 
x 
x 
 
Neurological examination p 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Patient-Reported Outcome Assessments q 
 
x 
 
x 
x 
x 
x 
 
 
Brain MRI r 
 
x s 
  
x 
x 
 
x b 
 
  
Recording of potential relapses 
  
x 
x 
x 
x 
x 
x 
x 
x 
Adverse event assessment t 
  
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant treatment review 
  
x 
x 
x 
x 
x 
x 
x 
 x u 
Methylprednisolone premedication v 
  
x 
x 
x 
x 
x 
 
 
  
Ocrelizumab administration w 
  
x 
x 
x 
x 
x 
 
 
  
-hCG  beta human chorionic gonadotropin; eCRF  electronic Case Report Form; EDSS  Expanded Disability Status Scale; HBcAb  hepatitis B 
core antibody; HBsAg  hepatitis B surface antigen; HBV  hepatitis B virus; HepCAb  hepatitis C antibody; IRR  infusion-related reaction; 
IV  intravenous; MRI  magnetic resonance imaging; MS  multiple sclerosis; PCR  polymerase chain reaction; PML  progressive multifocal 
leukoencephalopathy; PRO  patient-reported outcome; QC  quality control. 
a The screening period will last up to 4 weeks, but it may be prolonged for up to 8 weeks for relevant clinical, administrative, or operational reasons. 
b When a patient discontinues treatment, all assessments must be completed/obtained, except for MRI if done within the past 8 weeks unless 
clinically indicated. 
c Additional assessments may be conducted, as determined by the investigator, in order to investigate adverse events. 


 
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d The Safety Follow-up Period will begin when the patient completes the study and does not continue with commercially available ocrelizumab, or 
discontinues from treatment early.  Patients will be assessed in Safety Follow-up every 24 weeks for 48 weeks counting from the date of the last 
infusion of ocrelizumab.  After 48 weeks, if the peripheral blood B-cell count remains depleted, monitoring of the patient should continue at 
24-week intervals until the B-cell count has returned to the baseline value or to the lower limit of the normal range, whic hever is lower.  
During the Safety Follow-up Period, patients who receive other B-cell targeted therapies will only be followed for an additional period of 
approximately 48 weeks from the start of the alternative MS treatment; they will not be entered into  the prolonged B-cell monitoring period 
thereafter.  
e Written informed consent will be obtained from all patients during screening in order to be eligible for the study. 
f Medical history includes clinically significant diseases, surgeries, reproductive status, smoking history, and all medications (e.g., prescription 
drugs, over-the-counter drugs, herbal or homeopathic remedies, and nutritional supplements) used by the patient within 4 weeks prior to the 
screening visit.  Demographic data will include age, sex, and self‑reported race/ethnicity. 
g A full physical examination will be conducted at the screening and early termination visits.  At all other visits, a limited physical 
examination will be conducted.  Any abnormality identified at baseline should be recorded on the eCRF.  Changes from baseline abnormalities 
should be recorded at each subsequent physical examination.  New or worsened clinically significant abnormalities should be r ecorded as 
adverse events, if appropriate. 
h Vital signs will include the measurements of heart rate, systolic and diastolic blood pressures, and temperature.  Vital signs should be taken 
within 45 minutes prior to the premedication methylprednisolone infusion.  In addition, vital signs should be obtained prior to the ocrelizumab 
infusion then every 15 minutes for the first hour, followed by every 30 minutes until 1 hour after the end of the infusion.   
i Needs to be available prior to dosing (to be taken up to 14 days prior to dosing).  In rare cases in which the result is not assessable (e.g., 
indeterminate) or is abnormal, the tests need to be repeated.  Any abnormal screening laboratory value that is clinically rel evant should be 
retested in order to rule out any progressive or uncontrolled underlying condition.     
j Hematology will include hemoglobin, hematocrit, RBCs, WBC absolute and differential, ANC, and quantitative platelet count .  Chemistry will 
include AST, ALT, GGT, total bilirubin, urea, uric acid, creatinine, potassium, sodium, calcium, and phosphorus.  Urinalysis or urine dipstick 
will be used to assess kidney function. 
k If the screening assessments have been conducted/obtained within 14 days prior to dosing, respective baseline assessments do not need to be 
repeated prior to dosing. 
l Serum -hCG must be performed at screening in women of childbearing potential.  Subsequently, urine -hCG (sensitivity  25 mIU/mL) must be 
collected.  On infusion visits, the urine pregnancy test should be performed prior to methylprednisolone infusion in all women of childbearing 
potential.  If positive, ocrelizumab should be withheld and pregnancy status confirmed.   
m All patients must have negative HBsAg result and negative HepCAb screening tests prior to enrollment in the study.  If the total HBcAb is positive 
at screening, HBV DNA measured by PCR must be negative in order for a patient to be eligible for the study.  For enrolled patients with negative 
HBsAg and positive total HBcAb, HBV DNA (by PCR) must be repeated every 24 weeks. 
n Immunoglobulin levels collected only and stored for further analysis upon request.   


 
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o Whole-blood samples will be collected to determine the duration of B-cell depletion and recovery (CD19) and T-cell counts (CD4, CD8).   
p Neurological examinations will be used to distinguish relapse in MS from another neurological (non-MS) disorder.  Potential relapses should be 
recorded throughout the treatment period.  Investigators will also screen patients for signs and symptoms of worsening neurological function 
localized to the cerebral cortex, such as cortical symptoms/signs, behavioral and neuropsychological alteration, retrochiasmal visual defects, 
hemiparesis, cerebellar symptoms/sings (e.g., gait abnormalities, limb incoordination).  Patients with suspected PML should be withheld from 
ocrelizumab treatment until PML is ruled out by complete clinical evaluation and appropriate diagnostic testing (see Appendix 6).  A patient with 
confirmed PML should be withdrawn from the study.   
q PRO assessments will consist of the following:  Multiple Sclerosis Impact Scale 29 (MSIS-29), the Treatment Satisfaction Questionnaire for 
Medication (TSQM II), and the Treatment Satisfaction with Medicines Questionnaire (SATMED-Q).  Please note that all PROs are required to be 
administered prior to administration of study drug and prior to any other study assessment(s) to ensure the validity of the instru ments is not 
compromised.   
r Should only be done at scheduled visits unless PML is suspected.   
s MRI has to be conducted before the baseline visit, and results must be available prior to treatment.  Prior to initiation of treatment on 
Day 1/Baseline, a QC report for the baseline MRI scan must have been received from the centralized reading center confirming scan passed 
QC.   
t After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention (e.g., invasive procedures such as biopsies, discontinuation of medications) should be reported.  After initiation of study drug, related 
serious adverse events must be collected and reported regardless of the time elapsed from the last study drug administration, even if the study 
has been closed.  Unrelated serious adverse events must be collected and reported during the study through the end of the Safety Follow-up 
period, which is at least 48 weeks after the last infusion but may be extended in patients whose B  cells take longer to replete.  Non-serious 
adverse events have to be reported until the end of the Safety Follow-up Period.   
u Medications used after treatment discontinuation should be recorded during the Safety Follow -up Period. 
v All patients must receive prophylactic treatment with 100 mg methylprednisolone (or equivalent), administered by slow IV infusion, to be 
completed approximately 30 minutes before the start of each ocrelizumab infusion.  Prophylactic treatment with an analgesic/antipyretic (e.g., 1 g 
acetaminophen) and/or an IV or oral antihistamine (e.g., IV diphenhydramine 50 mg or equivalent dose of alternative) is strongly recommended 
3060 minutes prior to the start of ocrelizumab infusion to reduce the risk of IRRs. 
w Dose 1 of ocrelizumab will be administered as two 300-mg IV infusions (600 mg total) separated by 14 days (i.e., Days 1 and 15).  Subsequent 
doses will be administered as one 600-mg IV infusion every 24 weeks for a maximum of 4 doses.  


 
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Appendix 3  
Data Handling Rules 
Assessment of clinical relapse:  
1. Check whether the following eCRF question is answered ‘yes’: “Did suspected MS 
relapse symptoms persist for > 24 hours and were not being attributable to 
confounding clinical factors? (e.g. fever, infection, injury, adverse reactions to 
concomitant medication”  
2. Check whether the first EDSS assessment at a visit (unscheduled or scheduled) on 
or after the onset date of the relapse is increased by ≥ 0.5 steps from the previous 
EDSS; OR SELECTED FSS domains relevant to the relapse event (pyramidal, 
ambulation, cerebellar, brainstem, sensory, or converted visual) are increased by ≥ 2 
points on one domain or ≥ 1 point on two or more domains. When deriving this step 
do the following:  
 
Select the last EDSS/FSS score before each clinical relapse onset date  
 
Select the first EDSS/FSS score on or after each clinical relapse onset date  
 
Calculate the difference between the two scores above  
3. Select clinical relapses where there is an increase of ≥ 0.5 in EDSS OR ≥2 on one 
appropriate FSS domain OR ≥ 1 on two or more appropriate FSS domains  
For each relapse that satisfies the 3 criteria above, check if the following relapses are 
within 30 days (i.e., the onset dates are ≤ 30 days apart). If they are within 30 days, then 
the later relapses are not protocol-defined relapses  
Additional data handling rules are specified throughout the document and in DAP 
Module 2. 


 
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Appendix 4  
Programming Codes for Statistical Analyses 
Kaplan-Meier method 
proc lifetest data=dataset method=km conftype=loglog outsurv=surv   
plots=none notable STDERR; 
time aval*eventyn(1); 
run; 
 


 
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Appendix 5  
Reasons for Exclusion from the Per-Protocol Population 
1. Select study inclusion criteria 
 
Had more than 3 adequate prior DMTs (IC06) 
 
No suboptimal response on the most recent adequately used DMT (IC07) 
 
Suboptimal response while on last DMT that is less than 6 months (IC06) 
 
Disease duration from first symptom of more than 12 years (Due to previous 
protocol versions has ≤10 years as inclusion criteria, deviation code includes 
a mixture of deviations of >10 years and >12 years of duration. Thus for this 
criteria, program on clinical data will be used to identify patients with 
deviation.) 
 
2. Select study exclusion criteria 
 
History of PPMS, PRMS, or SPMS (EC01) 
 
Previous treatment with natalizumab within 12 months prior to screening 
unless failure was due to confirmed, persistent ADAs (EC22) 
 
Systemic corticosteroid therapy within 4 weeks prior to screening (EC24) 
 
 


 
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Appendix 6  
Statistical Analysis Plan for Shorter Infusion Substudy 
Background 
Ocrevus (ocrelizumab) is approved by the U.S. Food and Drug Administration (FDA) for 
the treatment of adults with primary progressive multiple sclerosis (PPMS) and relapsing 
multiple sclerosis (RMS).  According to the currently approved U.S. label, ocrelizumab 
must be administered at a 600-mg dose through slow intravenous (IV) infusion.  The first 
dose is given as two doses, separated by 14 days, and administered as two 300-mg 
infusions over the course of 2.5 hours, while subsequent doses are given as a single 
600-mg infusion over 3.5 hours.  This substudy will explore the effect of a shorter 
infusion of ocrelizumab on the rate and severity of infusion-related reactions (IRRs).   
The most common safety events reported with ocrelizumab are IRRs.  IRRs occur more 
frequently during the first infusion of the first dose.  The majority of IRRs (>90% of 
patients reporting IRRs) were of mild to moderate intensity, and the intensity of IRRs 
decreased with subsequent dosing.  The most frequently reported IRR symptoms during 
infusion in the ocrelizumab group were pruritus, rash, throat irritation, and flushing 
(33.0%, 29.2%, 29.8%, and 16.8% of patients with IRR, respectively) (see the 
Ocrelizumab Investigator’s Brochure).    
A Phase II, parallel-group, dose-finding trial (WA21493) evaluated ocrelizumab 
compared with placebo and Avonex (interferon-β1a) in patients with RRMS for up to 96 
weeks.  In this study, both the 600-mg and 1000-mg dose were administered over 4 
cycles.  After the first cycle, during which only the 600-mg dose was divided in half and 
given over a 15-day interval, subsequent cycles involved administration as a single, 
undivided dose.  Doses were administered over approximately 240 minutes.  The 
infusion schedule in this study shows that, both for the 600- and 1000-mg dose, 
approximately 400 mg of ocrelizumab were infused within 2 to 2.5 hours.  However, in 
the remaining 1.5 to 2 hours of the infusion, only 200 mg remained to be infused for the 
lower dose, while in the 1000-mg dose, 600 mg were given within the same 
timeframe.  Based on this infusion schedule, a dose/infusion rate/IRR relationship was 
not clearly observed.  
The lack of dose/infusion rate/IRR relationship based on the current clinical data is 
supportive of the hypothesis that administration of ocrelizumab over a shorter infusion 
time should not pose a potential additional risk to patients in terms of increased risk of 
IRRs, but would help convenience of use and compliance for both patients and 


 
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healthcare practices.  In addition, procedures are in place to further mitigate risk of IRR, 
such as a pre-treatment schedule and guidance around infusion adjustment, if required.    
After the infusion, patients will be followed for safety, per the substudy schedule of 
activities, to monitor for any effects of the shorter administration.    
 
Substudy Design 
This is an open-label, non-randomized substudy to MN30035 designed to evaluate the 
safety and tolerability of ocrelizumab infused over a shorter time period than the 
approved administration rate.  Patients who complete their Week 72 ocrelizumab 
infusion and do not experience any serious IRR (see Section protocol 5.2.2 for 
seriousness criteria) throughout the main study will be eligible to enroll in this optional 
substudy and receive one additional shorter infusion of ocrelizumab at the Week 96 visit.   
Premedication in the substudy will be administered per the main study methods (protocol 
Section 4.3.3).  Ocrelizumab will then be administered as a single 600-mg dose at a 
shorter infusion rate (i.e., over the course of approximately 2 hours instead of 3.5 hours) 
than in the main study.   
Ocrelizumab infusion rate will be slowed and/or stopped if a patient experiences a 
Grade 3 or higher IRR or other serious adverse event.   
Patients who received ocrelizumab at a shorter infusion rate at the Week 96 visit will 
return for a substudy follow-up visit approximately 30 days after treatment.   
The end of the treatment period in the substudy is defined as the date when the last 
patient in the substudy completes the substudy follow-up visit (Week 100). 
Protocol Synopsis 
Refer to the main study protocol synopsis.  For additional details, see the Schedule of 
Assessments in Appendix A and Rate of Shorter Infusion in Appendix B. 
Outcome Measures 
The primary objective of the substudy is to evaluate the rate and severity of IRRs of the 
ocrelizumab 600-mg infusion administered over the course of approximately 2 hours, 
instead of the currently approved duration of 3.5 hours, in patients with MS who have 
had prior treatment with ocrelizumab in study MN30035 (CHORDS), as measured by the 
rate and frequency of National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 4.0 (NCI CTCAE v4.0) Grade 3 and 4 IRRs. Specifically, the 
safety outcome measures are listed below. 


 
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 
Rate and frequency of Grade 3 or 4 IRRs with onset on or after the shorter 
ocrelizumab infusion at Week 96 and at the substudy follow-up 
 
Changes in physical findings and vital signs with onset on or after the shorter 
ocrelizumab infusion at Week 96 and at the substudy follow-up 
 
Determination of Sample Size 
This substudy will enroll approximately 100 patients from MN30035 who did not 
experience any serious IRR throughout the main study. Based on the sample size of 100 
patients used for analysis, the 95% CIs for some assumed Grade 3 or 4 IRRs are 
provided in Table 1. 
Table 1:  Determination of Substudy Sample Size 
Number of Patients with 
Grade 3 or 4 IRRs 
Grade 3 or 4 IRRs (%) 
(N100) 
95% CIs for Grade 3 or 4  
IRRs (%) 
1 
1.00 
 (0.03, 5.45) 
2 
2.00 
(0.24, 7.04) 
3 
3.00 
(0.62, 8.52) 
4 
4.00 
(1.10, 9.93) 
5 
5.00 
(1.64, 11.28) 
6 
6.00 
(2.23, 12.60) 
7 
7.00 
(2.86, 13.89) 
The 95% CIs for the IRR (%) are calculated based on the Clopper and Pearson method. 
 
Analysis Timing 
The final analysis will be conducted when all patients enrolled in the substudy have 
received the shorter infusion and completed the 30-day safety follow-up assessments. 
Interim look for safety monitoring purpose can be conducted when deemed necessary. 
 
Study Conduct 
 
Randomization Issues 
Not applicable. 
 
Statistical Methods 
Safety analyses will include all patients who received any dose of study treatment 
through shorter infusion in the substudy.  


 
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Safety will be summarized using descriptive statistics.  Continuous variables will be 
summarized using n (sample size), mean, standard deviation, median, minimum, and 
maximum.  Frequency distributions (patient counts and associated percentages) will be 
used to summarize categorical variables.  When applicable, 95% confidence intervals 
(CIs) will be provided for the mean and proportion.  The Clopper and Pearson method 
will be used to calculate exact CIs for proportion when applicable.   
 
 Analysis of Study Conduct 
Patient disposition including the number of patients enrolled, discontinued, and 
completed the shorter infusion substudy will be summarized. Reasons for treatment and 
substudy discontinuations will also be summarized. Major protocol deviations that 
happened during the substudy period will also be summarized when applicable. 
 
 Demographics and Baseline Characteristics 
Patients’ demographics, neurological examination, MS disease history (e.g., duration 
since MS first symptom, duration since MS diagnosis) at enrollment of the main study 
and previous DMTs before receiving any ocrelizumab in the main study will be 
summarized. 
 
 Safety Analyses 
Safety analyses of the substudy will include all patients who enrolled into the substudy 
and received >0 dose of the Week 96 shorter infusion.  
 
 Summary of IRRs 
The number and proportion of patients in the substudy who experienced Grade 3 or 4 
IRRs with onset on or after the shorter infusion (including the safety follow-up period) will 
be summarized with the associated 95% exact confidence interval. The 2-sided 95% 
exact confidence interval will be calculated using the Clopper and Pearson method.  
The incidence rate and the 2-sided 95% exact confidence interval will also be calculated 
for all Grade 1-4 IRRs.  
The number and proportion of patients in the substudy who experienced local IRR and 
systemic IRR will also be summarized with 95% exact confidence interval. 


 
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Listings of Grade 3 or 4 IRRs, and IRRs that led to interruption of the shorter infusion or 
treatment withdrawal will be provided, if applicable, on the symptom of the IRR, CTCAE 
grade, infusion rate at the onset of IRR, action taken on ocrelizumab administration 
following the IRR, and the history of IRR events during the long infusion study period 
(e.g., highest CTCAE grade, frequency) 
 
 Adverse Events 
All adverse events occurring on or after the shorter infusion (including the safety follow-
up period) will be coded, summarized by NCI CTCAE v4.0 grade, and tabulated by body 
system and Preferred Term for individual adverse events within each body system.  All 
adverse events, Grade 3 to 5 adverse events, serious adverse events, adverse events 
leading to treatment discontinuation, time to withdrawal from the study due to an adverse 
event, adverse events leading to infusion adjustment, and treatment-related adverse 
events will be summarized.  In addition, all serious adverse events and deaths will be 
listed if applicable. 
 
 Exposure of Study Medication 
Ocrelizumab exposure will be summarized including duration of the shorter-infusion drug 
administration, actual volume and dosage of ocrelizumab administered.  
Number and percentage of patients who experienced shorter infusion interventions 
(slowing, interruption or stopping) will be summarized. 
Duration of the shorter infusion will also be summarized for patients who experienced 
each type of interventions and for patients who did not experience any intervention 
separately. 
 
 Laboratory Data 
 A summary of the number and percentage of patients with abnormal laboratory 
outcomes will be produced for each laboratory parameter. 
 
 Vital Signs  
Changes in physical findings and vital signs with onset on or after the shorter infusion at 
Week 96 and at the substudy follow-up visit will be summarized. 


 
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 Missing Data 
Missing and partial dates for AEs will be handled according to Roche STREAM 
algorithm. 
For partial or missing shorter infusion administration start/end time, data will not be 
imputed considering the potential impact of imputed time points on the duration of the 
shorter infusion (about 2 hours). 
Missing assessments for continuous variables, such as physical examinations and vital 
signs, will not be imputed. 
 
Interim Analyses 
No formal interim analysis is planned for the substudy. Interim looks may be performed 
for safety monitoring or publication purpose.  
 
Scope of Planned Analyses 
The final substudy analysis will include all patients and all data collected during the 
shorter infusion study period (including Week 96 and the safety follow up period). 
Specific list of planned outputs will be available in DAP Module 2. 
 


 
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Appendix A 
 
Schedule of Assessments 
 
Week 96  
Treatment Visit 
(14 days)  
Substudy  
Follow-up Visit  
(3014 days later) a 
Informed consent b 
x 
 
Review inclusion and exclusion criteria 
x 
 
Physical examination c 
x 
x 
Weight 
x 
 
Vital signs d 
x 
x 
Brain MRI e 
x 
 
Pregnancy test f 
x 
 
Adverse event assessment g 
x 
x 
Concomitant treatment review 
x 
x h 
Methylprednisolone and antihistamine 
premedication i 
x 
 
Ocrelizumab administration  
x 
 
eCRFelectronic case report form; IRRinfusion-related reaction; IVintravenous; MRImagnetic 
resonance imaging; PMLprogressive multifocal leukoencephalopathy. 
a Conducted 30 days after the shorter infusion with ocrelizumab.   
b Written informed consent will be obtained from all patients in order to be eligible for the study 
and prior to any study procedures. 
c A limited physical examination may be conducted.  Any abnormality identified should be 
recorded on the eCRF.  New or worsened clinically significant abnormalities should be 
recorded as adverse events, if appropriate 
d Vital signs will include the measurements of heart rate, systolic and diastolic blood pressures, 
and temperature.  Vital signs should be taken approximately 45 minutes prior to the 
premedication methylprednisolone infusion.  In addition, vital signs should be obtained prior to 
the ocrelizumab infusion then approximately every 15 minutes for the first hour, followed by 
approximately every 30 minutes until 1 hour after the end of the infusion. 
e Should only be done if PML is suspected, and should not be done in addition to an MRI at 
Week 96 conducted in the main study.  If needed, should be done pre-dose. 
f Pregnancy test should not be done in addition to the pregnancy test at Week 96 conducted in 
the main study.   If needed, should be done pre-dose.  
g After informed consent has been obtained but prior to initiation of study drug, only serious 
adverse events caused by a protocol-mandated intervention (e.g., invasive procedures such as 
biopsies, discontinuation of medications) should be reported.  After initiation of study drug, 
related serious adverse events must be collected and reported regardless of the time elapsed 
from the study drug administration, even if the substudy has been closed.  Unrelated serious 
adverse events must be collected and reported during the substudy and substudy follow-up.  
Non-serious adverse events have to be reported until the end of substudy follow-up.   
h Medications used after treatment discontinuation should be recorded during substudy follow-up. 
i All patients must receive prophylactic treatment with 100 mg methylprednisolone (or 
equivalent), to be completed approximately 30 minutes before the start of each ocrelizumab 
infusion, and with an antihistaminic drug (e.g., diphenhydramine) approximately 3060 minutes 
before each infusion of ocrelizumab.  Prophylactic treatment with an analgesic/antipyretic 


 
Ocrelizumab—Genentech, Inc. 
50/Statistical Analysis Plan MN30035 
 
(e.g., 1 g acetaminophen) is strongly recommended 3060 minutes prior to the start of 
ocrelizumab infusion to reduce the risk of IRRs. 
 
Appendix B 
 
Infusion rates for 600-mg ocrelizumab Shorter Dose 
 
Time (min) 
Infusion rate 
(mL/hr) 
Infusion rate 
(mg/hr) 
Max Dose per 
Interval  (mg) 
Cumulative 
Dose 
(mg) 
015 
100 
120 
30 
30 
1530 
200 
240 
60 
90 
3060 
250 
300 
150 
240 
6090 
300 
360 
180 
420 
90120 
300 
360 
180 
600 
Infusion time:  120 min.   
Preparation per U.S. label:  600 mg ocrelizumab/500 mL normal saline toward a drug 
concentration of approximately 1.2 mg/mL. 
 


 
 
 
Statistical Analysis Plan (SAP) Initial /Final Sign-Off Sheet 
Study title: 
AN OPEN-LABEL STUDY TO EVALUATE THE EFFECTIVENESS 
AND SAFETY OF OCRELIZUMAB IN PATIENTS WITH RELAPSING 
REMITTING MULTIPLE SCLEROSIS WHO HAVE HAD A 
SUBOPTIMAL RESPONSE TO AN ADEQUATE COURSE OF 
DISEASE-MODIFYING TREATMENT 
Protocol #: 
MN30035 
SAP Version: 
2.0 
Authors: 
 
 
Study Statistician: 
                                            Signature                    Date 
 
 
Reviewers: 
Study Medical Director: 
              Signature                     Date 
 
 
Study Statistical Programmer: 
                          Signature                    Date 
 
 
:
                                     Signature                    Date 
 
 
Approvers: 
: 
                                     Signature                     Date 
* The Biostatistics approver has ensured that key team members have been involved, contributed and 
reviewed the content of the List of Planned Outputs as described in the SAP Module guideline.